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We aimed to assess the impact of aerobic exercise (AE) on parameters related to cardiotoxicity in breast cancer (BC) patients receiving anthracycline or trastuzumab.We performed a systematic review and meta-analysis of comparative studies on AE via the screening of standard databases from their inception to January 18, 2022. The risk of bias was assessed qualitatively using the domains outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data were analyzed quantitatively using fixed effects meta-analysis and subgroup analysis in RevMan software. Notable outcomes included imaging outcomes of cardiotoxicity, cardiorespiratory fitness, and cardiac biomarkers.A meta-analysis of the pooled evidence obtained from seven studies revealed that AE significantly increased peak oxygen consumption (VOIn BC patients receiving anthracyclines or trastuzumab, the effects of AE on the levels of cardiotoxicity were mixed; the diastolic functions and VO

Multifocal esophageal squamous cell carcinomas (ESCCs) can be diagnosed as of multicentric origin (MO) or intramural metastasis (IMM). We aimed here to accurately discriminate MO from IMM and explore the tumor immune microenvironment of multifocal ESCCs. Multifocal ESCCs were identified in 333 ESCC patients, and in 145 patients discrimination between MO and IMM was not possible by histopathological examination. Of the 145 patients, tissues of 14 were analyzed by whole-exome sequencing (WES) of 71 different tumor regions, and MO, IMM, and MO/IMM mixed groups were identified in three, ten, and one cases, respectively, based on the similarity of genomic architecture between or among different tumors from one patient. Further phylogenetic analyses revealed complex clonal evolution patterns in IMM cases, and tumor cells disseminated from the primary tumors to IMM tumors were independent of lymph node metastasis. The NanoString-based assay showed that immune cell infiltrates were significantly enriched, and that the immune and proliferation pathways were more activated, in large tumors than in small ones in MO but not IMM cases. Similarly, PD-L1 expression and the density of paratumoral CD8

The treatment strategies for T1 oesophageal squamous cell carcinoma (ESCC) patients with or without lymph node metastasis (LNM) are different. Given the advantages of the minimally invasive, sensitive and real-time detection, liquid biopsy has become an important cancer diagnostic and prognostic tool.MiRNA array and small-RNA sequencing were performed. Then, 222 formalin-fixed and paraffin-embedded tumour samples and 229 pretreatment serum samples from T1 ESCC patients were used to verify and evaluate the results.We demonstrated that serum miR-20b-5p could predict LNM in T1 ESCC patients. The AUC for serum miR-20b-5p was higher (0.827) than those for lymphovascular invasion (LVI) (0.751, P = 0.2128), invasion depth (0.662, P = 0.0027) and tumour differentiation grade (0.634, P = 0.0019). A nomogram for predicting LNM with three independent significant predictors (miR-20b-5p, LVI and invasion depth) was constructed with a concordance index of 0.931. Serum miR-20b-5p was also significantly correlated with disease-free survival (P 0.001). An algorithm of improved T1 ESCC treatment strategy after biopsy and/or after endoscopic resection based on serum miR-20b-5p level was constructed.This study suggests that serum miR-20b-5p is a potential biomarker for predicting LNM and can be helpful for precise clinical decision-making strategies and improve treatment outcomes for T1 ESCC patients.

To investigate the appropriate timing of radiotherapy (RT) after mastectomy and adjuvant chemotherapy for women with high-risk breast cancer.Post hoc analyses of 584 patients with stage II and III breast cancer from a randomised controlled clinical trial were performed. All patients underwent mastectomy followed by sequential chemotherapy and RT. The optimal cut-off values for the surgery-RT interval (SRI) and the chemotherapy-RT interval (CRI) for overall survival (OS) were determined using the hazard ratio for continuous predictors. The locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and OS rates were estimated using the Kaplan-Meier method. Multivariate analyses were performed using Cox proportional hazards regression.Median follow-up time was 83.5 months. Median SRI and CRI were 168 and 27 days, respectively. An SRI ofgt;210 days was independently associated with higher DM (HR 2.65, 95% CI: 1.49-4.71; HR 2.78, 95% CI 1.51-5.26), lower OS (HR 2.44, 95% CI: 1.28-4.54; HR 2.50, 95% CI: 1.41-4.35), and lower DFS (HR 2.57, 95% CI: 1.45-4.57; HR 2.70, 95% CI: 1.45-5.00) than SRI oflt;180 or 180-210 days. Furthermore, a CRI of more than 42 days was independently associated with higher DM (HR 1.89, 95% CI: 1.17-3.06; HR 1.96, 95% CI: 1.19-3.22), lower OS (HR 2.44, 95% CI: 1.41-4.35; HR 1.92, 95% CI: 1.10-3.33), and lower DFS (HR 1.84, 95% CI: 1.14-2.96; HR 1.82, 95% CI: 1.12-2.94) than a CRI oflt;28 or 28-42 days. However, SRI and CRI had no significant effect on LRR.Based on the present findings, the timing of the initiation of RT both after mastectomy and after the completion of adjuvant chemotherapy is crucial for patients with high-risk breast cancer.

PURPOSE To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

The current study aimed to screen the sensitive methylation sites of non-small cell lung cancer by whole-genome sequencing and construct an early warning system for lung cancer. For this purpose, from June 2017 to December 2020, fresh NSCLC tissues and paired adjacent NSCLC tissues from 45 patients were collected. DNA and total RNA were extracted from non-small cell lung cancer (NSCLC) and paired non-cancerous lung tissues. The DNA library combined with a biotinylated probe was collected by Dynabeads m270 streptavidin beads. The concentration of the final library was determined by qubit dsDNA HS assay. Quantitative analysis of DMR methylation in 45 paired tumor and normal lung tissues was performed. RT qPCR and Western blot were used to verify the mRNA expression of candidate genes. Results showed that the methylation rate of CpG 7 in stxbp6 in stage III NSCLC was higher than that in stage I and early-stage II NSCLC; The methylation rates of cpg1 and 38-39 units in fzd10 were higher in stage I NSCLC than in stage II and III NSCLC; The methylation rates of CpG 6 in stxbp6 and CpG 4 and 20-21 in bcl6b in patients with tumor diameter > 3cm were higher than those in patients with tumor diameter < 3cm; Methylation of CpG unit 3 in stxbp6 is associated with age. Stxbp6, bcl6b, fzd10 and hspb6 mRNA expression were down-regulated in patients under 45 years old. The methylation rates of CpG 7 in stxbp6, CPG 6 in stxbp6 and CpG 4 and 20-21 in bcl6b were negatively correlated with the survival time of patients; The methylation rates of CpG 1 and 38-39 units in fzd10 were positively correlated with survival time (P

The aim of the study was to investigate the clinical significance of Ly-1 antibody reactive clone (LYAR) in non-small-cell lung cancer (NSCLC).The expressions of LYAR at the protein level in representative paired NSCLC tumor tissues and adjacent non-tumor tissues were measured by Western blot and immunohistochemistry. Kaplan-Meier method was used to calculate the survival curve of patients with NSCLC. Cell Counting Kit-8 assay and flow cytometry were used to estimate the cell proliferation and cell cycle, respectively. Terminal-deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was performed to detect cell apoptosis.LYAR was dramatically overexpressed in NSCLC tissues which were closely related to the survival of patients with NSCLC. In clinical studies, the expression of LYAR was related to the clinical stage, histological differentiation, and Ki-67 expression. A positive correlation was found between LYAR and Ki-67 expression by Spearman's correlation test. After serum starvation for 72 h, serum re-addition significantly increased the expression of LYAR, PCNA, and Cyclin A and promoted the cell cycle progression. LYAR knockdown inhibited the proliferation and induced the G0/G1 cell cycle arrest and apoptosis of A549 cells.The present study revealed the clinical significance of LYAR in NSCLC. LYAR might serve as a tumor promoter in NSCLC progression by promoting the proliferation and inhibiting the apoptosis of NSCLC cells. Inhibiting the expression of LYAR was considered as a potential novel therapeutic strategy for NSCLC.

Background Snail control is critical to schistosomiasis control efforts in China. However, re-emergence of Oncomelania hupensis is challenging the achievements of schistosomiasis control. The present study aimed to test whether the amphibious snails can spread across watersheds using a combination of population genetics and geographic statistics. Methods The digital maps and attributes of snail habitats were obtained from the national survey on O. hupensis. Snail sampling was performed in 45 counties of Sichuan Province. The cox1 gene of specimens was characterized by sequencing. Unique haplotypes were found for phylogenetic inference and mapped in a geographical information system (GIS). Barriers of gene flow were identified by Monmonier’s maximum difference algorithm. The watercourses and watersheds in the study area were determined based on a digital elevation model (DEM). Plain areas were defined by a threshold of slope. The slope of snail habitats was characterized and the nearest distance to watercourses was calculated using a GIS platform. Spatial dynamics of high-density distributions were observed by density analysis of snail habitats. Results A total of 422 cox1 sequences of O. hupensis specimens from 45 sampling sites were obtained and collapsed into 128 unique haplotypes or 10 clades. Higher haplotype diversity in the north of the study area was observed. Four barriers to gene flow, leading to five sub-regions, were found across the study area. Four sub-regions ran across major watersheds, while high-density distributions were confined within watersheds. The result indicated that snails were able to disperse across low-density areas. A total of 63.48% habitats or 43.29% accumulated infested areas were distributed in the plain areas where the overall slope was < 0.94°. Approximately 90% of snail habitats were closer to smaller watercourses. Historically, high-density areas were mainly located in the plains, but now more were distributed in hilly region. Conclusions Our study showed the cross-watershed distribution of Oncomelania snails at a large scale. Natural cross-watershed spread in plains and long-distance dispersal by humans and animals might be the main driver of the observed patterns. We recommend cross-watershed joint control strategies for snail and schistosomiasis control. Graphical Abstract

Purpose The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis. Methods and materials Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments. Results From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group. Conclusion Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.

The effect evaluation of the antibiotic susceptibility test based on bacterial solution is of great significance for clinical diagnosis and prevention of antibiotic abuse. Applying a microfluidic chip as the detection platform, the detection method of using microscopic images to observe bacteria under antibiotic can greatly speed up the detection time, which is more suitable for high-throughput detection. However, due to the influence of the depth of the microchannel, there are multiple layers of bacteria under the focal depth of the microscope, which greatly affects the counting and recognition accuracy and increases the difficulty of relocation of the target bacteria, as well as extracting the characteristics of bacterial liquid changes under the action of antibiotics. After the focal depth of the target bacteria is determined, although the z-axis can be controlled with the help of a three-dimensional micro-operator, the equipment is difficult to operate and the long-term changes of the target bacteria cannot be tracked quickly and accurately. In this paper, the YOLOv5 algorithm is adopted to accurately identify bacteria with different focusing states of multi-layer bacteria at the z-axis with any focal depth. In the meantime, a certain amount of microspheres were mixed into bacteria to assist in locating bacteria, which was convenient for tracking the growth state of bacteria over a long period, and the recognition rates of both bacteria and microspheres were high. The recognition accuracy and counting accuracy of bacteria are 0.734 and 0.714, and the two recognition rates of microspheres are 0.910 and 0.927, respectively, which are much higher than the counting accuracy of 0.142 for bacteria and 0.781 for microspheres with the method of enhanced depth of field (EDF method). Moreover, during long-term bacterial tracking and detection, target bacteria at multiple z-axis focal depth positions can be recorded by the aid of microspheres as a positioning aid for 3D reconstruction, and the focal depth positions can be repositioned within 3–10 h. The structural similarity (SSIM) of microscopic image structure differences at the same focal depth fluctuates between 0.960 and 0.975 at different times, and the root-mean-square error (RMSE) fluctuates between 8 and 12, which indicates that the method also has good relocation accuracy. Thus, this method provides the basis for rapid, high-throughput, and long-term analysis of microscopic changes (e.g., morphology, size) of bacteria detection under the addition of antibiotics with different concentrations based on microfluidic channels in the future.

Liver fibrosis is one of the most severe pathologic consequences of chronic liver diseases, and effective therapeutic strategies are urgently needed. Proton pump inhibitors (PPIs) are H + /K + -ATPase inhibitors and currently used to treat acid-related diseases such as gastric ulcers, which have shown other therapeutic effects in addition to inhibiting acid secretion. However, few studies have focused on PPIs from the perspective of inhibiting hepatic fibrosis. In the present study, we investigated the effects of pantoprazole (PPZ), a PPI, against liver fibrosis in a bile duct ligation (BDL) rat model, human hepatic stellate cell (HSC) line LX-2 and mouse primary HSCs (pHSCs), and explored the potential mechanisms underlying the effects of PPZ in vitro and in vivo. In BDL rats, administration of PPZ (150 mg· kg −1 · d −1 , i.p. for 14 d) significantly attenuated liver histopathological injury, collagen accumulation, and inflammatory responses, and suppressed fibrogenesis-associated gene expression including Col1a1, Acta2, Tgfβ1 , and Mmp-2 . In LX-2 cells and mouse pHSCs, PPZ (100–300 μM) dose-dependently suppressed the levels of fibrogenic markers. We conducted transcriptome analysis and subsequent validation in PPZ-treated LX-2 cells, and revealed that PPZ inhibited the expression of Yes-associated protein (YAP) and its downstream targets such as CTGF, ID1, survivin, CYR61, and GLI2. Using YAP overexpression and silencing, we demonstrated that PPZ downregulated hepatic fibrogenic gene expression via YAP. Furthermore, we showed that PPZ promoted the proteasome-dependent degradation and ubiquitination of YAP, thus inhibiting HSC activation. Additionally, we showed that PPZ destabilized YAP by disrupting the interaction between a deubiquitinating enzyme OTUB2 and YAP, and subsequently blocked the progression of hepatic fibrosis.

Background General role of cancer-associated fibroblast (CAF) and its infiltration characteristics in gastric cancer remains to be unknown. Methods We estimate CAF infiltration in bulk tumor tissue with RNA-seq data and analyzed its relationship with gastric cancer subtype, survival and immune microenvironment. Results We revealed CAF intend to have higher infiltration in diffuse, genomically stable, and advanced gastric cancer. CAF is associated with immunosuppressive microenvironment. Wide transcriptomics alterations occur in high CAF infiltrated gastric cancer, PI3K/AKT, TGFB and Hedgehog pathway are remarkable in this procedure. We utilized receptor tyrosine kinases and TGFB pathway ligands to construct risk score system that can predict survival. Conclusion Thus, CAF is associated with aggressive phenotype of gastric cancer and risk score based on RTK and TGFB pathway ligands expression is a promising tool for assessment of gastric cancer survival.

Purpose In addition to impacting incidence, risk factors for breast cancer may also influence recurrence and survival from the disease. However, it is unclear how these factors affect combinatorial biomarkers for aiding treatment decision-making in breast cancer. Methods Patients were 8179 women with histologically confirmed invasive breast cancer, diagnosed and treated in a large cancer hospital in Beijing, China. Individual clinicopathological (tumor size, grade, lymph nodes) and immunohistochemical (IHC: ER, PR, HER2, KI67) markers were used to define clinically relevant combinatorial prognostic biomarkers, including the Nottingham Prognostic Index (NPI: combining size, grade, nodes) and IHC4 score (combining ER, PR, HER2, KI67). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between breast cancer risk factors and quartiles (Q1–Q4) of NPI and IHC4 were assessed in multivariable polytomous logistic regression models. Results Overall, increasing parity (ORtrend(95% CI) = 1.20(1.05–1.37);Ptrend = 0.007), overweight (OR(95% CI)vs normal = 1.60(1.29–1.98)), and obesity (OR(95% CI) vs normal = 2.12(1.43–3.14)) were associated with higher likelihood of developing tumors with high (Q4) versus low (Q1) NPI score. Conversely, increasing age (ORtrend(95% CI) = 0.75(0.66–0.84);Ptrend vs normal = 0.82(0.66–1.02)) and obese (OR(95% CI) vs normal = 0.52(0.36–0.76)) women less likely to develop high IHC4 tumors. Notably, elevated BMI was associated with higher NPI irrespective of hormone receptor-expression status. Conclusions Our findings indicate that factors affecting breast cancer incidence, particularly age, parity, FHBC, and BMI, may impact clinically relevant prognostic biomarkers with implications for surveillance, prognostication, and counseling.

The organic solute transporter α-β (OSTα-OSTβ) is a heteromeric transporter localized to the basolateral membranes of liver, intestinal, and kidney epithelial cells and functions to extrude bile acids and steroids from these tissues. OSTα-OSTβ expression is variable among species and tissues. This transporter plays important roles in maintaining BA homeostasis and may correlate with the progression of diseases relevant to cholestasis or BA malabsorption. Crosstalk between multiple nuclear receptors and cytokines reveals a more intricate means of regulating OSTα-OSTβ. Human OSTα/β and mouse Ostα/β promoters are endowed with binding sites for several transcription factors. This review aims to uncover the current regulatory mechanism of OSTα-OSTβ, explain the rationale underlying this approach and provide practical evidence. Therapeutic strategies targeting OSTα-OSTβ or its upstream regulators may be essential to correct abnormal BA levels and intervene in the progression of diseases relevant to the disturbance of BA homeostasis.

Grid management is a grassroots governance strategy widely implemented in China since 2004 to improve the government’s efficiency to actively find and solve problems among populated regions. A grid-based strategy surveillancing high-risk groups, including mobile and migrant populations (MMPs), in the China–Myanmar border region has played an indispensable role in promoting and consolidating the malaria elimination efforts by tracking and timely identification of potential importation or re-establishment of malaria among MMPs. A sequential mixed methods was implementated to explore the operational mechanism and best practices of the grid-based strategy including through the focus group discussions (FGDs), comparison of before and after the implementation of a grid-based strategy in the field sites, and data collection from the local health system.This paper distills the implementation mechanism and highlights the role of the grid-based strategy in the elimination and prevention of re-establishment of malaria transmission.

To assess the influence of age as a continuous variable on the prognosis of pT1-2N1 breast cancer and examine its decision-making value for postmastectomy radiotherapy (PMRT).We retrospectively evaluated 5438 patients with pT1-2N1 breast cancer after mastectomy in 11 hospitals. A multivariable Cox proportional hazards regression model with penalized splines was used to examine the relationship between age and oncologic outcomes.The median follow-up was 67.0 months. After adjustments for confounding characteristics, nonsignificant downward trend in locoregional recurrence (LRR) risk was observed with increasing age (P-non-linear association = 0.640; P-linear association = 0.078). A significant non-linear association was found between age and disease-free survival (DFS) and overall survival (OS) (P-non-linear association0.05; P-linear association0.05, respectively). The DFS and OS exhibited U-shaped relationships, with the hazard ratios (HRs), reaching a nadir at 50 years old. A decreased risk of LRR with PMRT vs. no PMRT (HR = 0.304, 95% CI: 0.204-0.454) was maintained in all ages. The HR of PMRT vs. no PMRT for DFS and OS gradually increased with age. In patients ≤50 years old, PMRT was independently associated with favorable LRR, DFS, and OS, all P 0.05). In patients50 years old, PMRT was independently associated with reduced LRR (P = 0.004), but had no effect on DFS or OS.Age was an independent prognostic factor for pT1-2N1 breast cancer; PMRT provided survival benefits for patients ≤50 years old, but not for patients50 years old.

The expansion of a hexanucleotide repeat GGGGCC (G4C2) in the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 expansion leads to repeat-associated non-AUG (RAN) translation and the production of toxic dipeptide repeat (DPR) proteins, but the mechanisms of RAN translation remain enigmatic. Here, we report that the RNA helicase DHX36 is a robust positive regulator of C9orf72 RAN translation. DHX36 has a high affinity for the G4C2 repeat RNA, preferentially binds to the repeat RNA’s G-quadruplex conformation, and efficiently unwinds the G4C2 G-quadruplex structures. Native DHX36 interacts with the G4C2 repeat RNA and is essential for effective RAN translation in the cell. In induced pluripotent stem cells and differentiated motor neurons derived from C9orf72-linked ALS patients, reducing DHX36 significantly decreased the levels of endogenous DPR proteins. DHX36 is also aberrantly upregulated in tissues of C9orf72-linked ALS patients. These results indicate that DHX36 facilitates C9orf72 RAN translation by resolving repeat RNA G-quadruplex structures and may be a potential target for therapeutic intervention.

This study summarizes the anatomical features of the superior laryngeal nerve in Chinese to enable the rapid location of the superior laryngeal nerve during an operation.Retrospective analysis of anatomical data.Hangzhou First People's Hospital Affiliated to Nanjing Medical University.A total of 71 embalmed human cadavers (132 heminecks) were examined over 3 months. The length and diameter of the internal and external branches of the superior laryngeal nerve and their relationships with different landmarks were recorded.The total length of the internal branch of the superior laryngeal nerve was 23.4 ± 6.9 mm. The length of the external branch of the superior laryngeal nerve was 47.7 ± 11.0 mm. Considering the midpoint of the lower edge of the thyroid cartilage as the starting point and using that edge as a horizontal line, when the entry point is above that line, the external branch of the superior laryngeal nerve can be found within 41.1 mm and at an angle of 57.2°. When the entry point is below the lower edge of the thyroid cartilage, the external branch of the superior laryngeal nerve can be found within 34.0 mm and at an angle of 36.5°.The superior laryngeal nerve in Chinese people has distinct anatomical characteristics. This article provides a new method of quickly locating the external branch of the superior laryngeal nerve during the operation, which can reduce the probability of damaging the external branch of the superior laryngeal nerve.

Insulin-induced gene 2 (INSIG2) functions as a blocker of cholesterol biosynthesis and has been shown to be involved in colon and pancreatic cancer pathogenesis. Cholesterol is a risk factor for breast cancer pathophysiology; however, the underlying mechanisms are not well-defined. Hence, our goal was to determine the role of INISG2 in breast cancer. INSIG2 mRNA and protein expression was correlated to metastatic potential of breast cancer cell lines. Knockdown of INSIG2 inhibited epithelial-to-mesenchymal transition. Conversely, overexpression of INSIG2 induced epithelial-to-mesenchymal transition. Knockdown of INSIG2 did not affect cell proliferation but resulted in altered metabolism in vitro and attenuated experimental metastasis in vivo. Analysis of breast cancer tissue microarrays revealed significantly higher INSIG2 protein expression in breast cancer tissues. INSIG2 protein expression was correlated to hormone receptor status, with significantly higher expression in patients with triple-negative and human epidermal growth factor receptor 2 molecular subtypes of invasive breast cancer. Analysis of The Cancer Genome Atlas, however, revealed significantly lower INSIG2 mRNA expression in triple-negative breast cancer patients. Higher INSIG2 mRNA expression was correlated to poor survival probability. Asian patients with high INSIG2 mRNA expression had significantly lower survival probability compared with Asian patients with low/medium INSIG2 mRNA expression. These results reveal a yet undefined role of INSIG2 in breast cancer, potentially more relevant for breast cancer patients in Asia.

BACKGROUND Given the lower incidence of lymphoma-related death but higher background mortality in patients with early-stage mucosa-associated lymphoid tissue (MALT) lymphoma, it is critically important to examine how age affects a treatment’s survival benefit. METHODS 9,467 patients with early-stage MALT lymphoma in the Surveillance, Epidemiology, and End Results (SEER) database treated between 2000-2015 were extracted and analyzed. Primary therapy was classified as radiotherapy (n = 3,407), chemotherapy (n = 1,294), and other/unknown treatments including observation (n = 4,766). Inverse probability of treatment weighting (IPTW) was conducted to balance baseline characteristics between groups. Relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression were conducted to compare survival differences between treatment modalities by controlling for the background mortality. Radiotherapy–age interaction was examined.RESULTS Across age-groups, early-stage MALT lymphoma patients were at lower risk of lymphoma-related death than death due to other causes. The 10-year overall survival (OS, 73.8%) and RS (96.6%) rates were significantly higher, and the SMR (1.14) significantly lower, with radiotherapy than with chemotherapy (OS, 61.7%; RS, 86.4%; SMR, 1.54; P < 0.001) or other/unknown treatments (OS, 61.1%; RS, 87.2%; SMR, 1.41; P < 0.001). By multivariable analysis and IPTW, radiotherapy remained an independent predictor of better RS (HR 0.81, 95%CI, 0.73-0.89; P < 0.001). A significant interaction between age and radiotherapy was identified for both RS (Pinteraction = 0.016) and OS (Pinteraction = 0.024), indicating greater benefit in young adults.CONCLUSION Radiotherapy can provide significant survival benefit in early-stage MALT lymphoma, especially in young adults.

Background The incidence of aberrant catheterization into a ureter is extremely low, and there is a 20% chance that the balloon cannot be deflated. Regrettably, the mechanism underlying this complication remains unknown. There has been no reported case of a Foley catheter successfully removed from the ureter via percutaneous puncture. Case presentation A 86-year-old man complained of increasing abdominal pain after an 18F Foley catheter was inserted into his urethra. His attending physician attempted but failed to deflate the balloon. A bedside ultrasound and CT scan revealed that the catheter tip was in the right lower ureter. Several measures, including cutting the catheter and inserting a rigid guidewire, were then attempted but failed to deflate the balloon. Finally, the inflated balloon was punctured with a PTC needle under ultrasound-guidance, and the misplaced Foley catheter was removed. Two days after the pelvic drainage tube was removed, the patient was discharged. Conclusion This is the first reported case of a Foley catheter being removed from the ureter via percutaneous puncture. The mechanism by which the balloon is unable to deflate may be related to the passive twist of the catheter. In such a case, an overall assessment of the patient's condition should be performed, and non-invasive to invasive interventions should be phased in.

Significance Protein homeostasis is fundamental to the functioning of all living cells. Perturbation of the homeostasis, or proteotoxicity, plays an important role in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative diseases. To guard against proteotoxicity, cells have evolved sophisticated quality-control mechanisms that make adaptations including enhanced turnover of misfolded proteins. However, how the quality-control systems are coordinated through higher-order regulatory pathways is not fully understood. We have discovered a unique suppressor of proteotoxicity, the ubiquitin-specific protease USP7, whose action is conserved from invertebrate to mammalian systems and mediated by a substrate cascade involving NEDD4L and SMAD2. These findings reveal a previously unknown regulatory pathway for protein quality control and provide new strategies for developing interventions for neurodegenerative diseases., An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in a Caenorhabditis elegans model of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved in Drosophila and mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

Malignant mesothelioma (MM) is a rare, highly aggressive tumor. The first symptom of MM is mostly serous effusion, and cytology can be used in diagnosis based on effusion, providing patients with an earlier diagnosis and treatment opportunity. A total of 67 specimens were embedded into cell blocks, and BAP1 immunocytochemistry (ICC) was performed. CDKN2A fluorescence in situ hybridization (FISH) was performed in 45 cases. The sensitivity, specificity and the association between the degree of cell atypia and the results of two auxiliary methods were analyzed. BAP1 ICC showed nonexpression in 13 of 24 cases of MM and 0 of 21 cases of benign mesothelial proliferation (BMP). The sensitivity was 54.2% (13/24), and the specificity was 100% (21/21). In addition, 22 metastatic adenocarcinoma (MA) cases all showed BAP1 expression. MM with BAP1 expression had more obvious cell atypia. CDKN2A deletion was found in 12 of 24 MM cases and 0 of 21 BMP cases. The sensitivity was 50% (12/24), and the specificity was 100% (21/21). BAP1 ICC and CDKN2A FISH are useful methods to differentiate MM from BMP. The cell atypia of MM with BAP1 expression was more obvious than MM with BAP1 nonexpression.

Background: The efficacy of oral chlorhexidine (oCHG) for decontamination in intensive care unit (ICU) patients is controversial. The purpose of this study was to evaluate the effect of oCHG decont...

Background Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) is a minimally invasive technique for cytological and histological diagnosis. The objective of this study was to explore the role of cytological diagnosis in EBUS‐TBNAs. Methods Eight hundred and thirteen consecutive cases performed EBUS‐TBNA with both cytological and histological diagnoses were retrospectively reviewed. All patients were followed up for clinical data. Results Before immunohistochemical examination, the cytological sensitivity, specificity, and diagnostic accuracy of EBUS‐TBNAs were 92.9% (421/453), 98.9% (348/352), 95.5% (769/805), respectively. After immunohistochemical examination, the sensitivity, specificity, and diagnostic accuracy were 93.0% (423/455), 99.4% (348/350), 95.8% (771/805), respectively. The majority of false‐negative were cases whose cytological diagnosis was “atypical” or the cytological diagnosis suggested “inadequate.” “Neoplastic” were also prone to false‐negative cytology. The diagnostic accordance rate of cytological subtyping was 90.3% for squamous‐cell carcinoma, 99.2% for adenocarcinoma, and 98.1% for small‐cell carcinoma before immunohistochemical examination, and became 85.9%, 98.5%, and 98.2% after immunohistochemical examination, respectively. Conclusion Cytological diagnosis in EBUS‐TBNAs had a good sensitivity and high specificity. The sensitivity and specificity of cytological diagnosis were proved to be higher after the immunohistochemical examination. At the same time, cytology had high accordance rate in subtype diagnosis. False‐negative results occurred more commonly in cases whose cytological diagnosis was “atypical” or the cytological diagnosis suggested “inadequate” or the corresponding histological diagnosis was “Neoplastic.”

Supplemental Digital Content is available in the text, Background The effects of oral contrast agents (OCAs) on dosimetry have not been studied in detail. Therefore, this study aimed to examine the influence of OCAs on dose calculation in volumetric-modulated arc therapy plans for rectal cancer. Methods From 2008 to 2016, computed tomography (CT) images were obtained from 33 rectal cancer patients administered OCA with or without intravenous contrast agent (ICA) and 14 patients who received no contrast agent. CT numbers of organs at risk were recorded and converted to electronic densities. Volumetric-modulated arc therapy plans were designed before and after the original densities were replaced with non-enhanced densities. Doses to the planned target volume (PTV) and organs at risk were compared between the plans. Results OCA significantly increased the mean and maximum densities of the bowels, while the effects of ICA on these parameters depended on the blood supply of the organs. With OCA, the actual doses for PTV were significantly higher than planned and doses to the bowel increased significantly although moderately. However, the increase in the volume receiving a high-range doses was substantial (the absolute change of intestine volume receiving ≥52 Gy: 1.46 [0.05−3.99, cubic centimeter range: −6.74 to 128.12], the absolute change of colon volume receiving ≥50 Gy: 0.34 [0.01−1.53 cc, range: −0.08 to 3.80 cc]. Dose changes due to ICA were insignificant. Pearson correlation showed that dose changes were significantly correlated with a high intestinal volume within or near the PTV (ρ > 0.5, P 0.3, P

Esophageal squamous cell carcinoma (ESCC) patients with a synchronous or metachronous lung tumor can be diagnosed with lung metastasis (LM) or a second primary tumor (SPT), but the accurate discrimination between LM and SPT remains a clinical dilemma. This study aimed to investigate the feasibility of using the whole-exome sequencing (WES) technique to distinguish SPT from LM. Methods: We performed WES on 40 tumors from 14 patients, including 12 patients with double squamous cell carcinomas (SCCs) of the esophagus and lung (lymph node metastases were sequenced as internal controls) diagnosed as LM according to pathological information and 2 patients with paired primary ESCC and non-lung metastases examined as external controls. Results: Shared genomic profiles between esophageal (T) and lung (D) tumors were observed in 7 patients, suggesting their clonal relatedness, thus indicating that the lung tumors of these patients should be LM. However, distinct genomic profiles between T and D tumors were observed in the other 5 patients, suggesting the possibility of SPTs that were likely formed through independent multifocal oncogenesis. Conclusions: Our data demonstrate the limitations and insufficiency of clinicopathological criteria and that WES could be useful in understanding the clonal relationships of multiple SCCs.

This study aimed to analyze the risk factors for complications after endoscopic treatment of early esophageal cancer and precancerous lesions and provides evidence for developing preventive measures against these complications. The clinical data of patients with early esophageal cancer and precancerous lesions treated in the Department of Endoscopy, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College from January 2009 to December 2015 were analyzed. The risk factors related to delayed bleeding, perforation, and stenosis were assessed. Of 459 patients, 15 (3.3%) had delayed bleeding, 16 (3.5%) had perforation, and 82 (17.9%) had stenosis. Conservative treatment was performed for patients with bleeding and perforation, and endoscopic dilation was performed to relieve stenosis. The independent risk factors for delayed bleeding were lesion size (OR = 1.51, P = 0.020), circumferential diameter [odds ratio (OR) = 1.24, P = 0.037]. The kind of operation method [endoscopic submucosal dissection (ESD)/cap-based endoscopic resection (EMR-Cap): OR = 15.38, P = 0.013) was the independent risk factor for perforation. The independent predictors of stenosis were circumferential diameter (OR = 1.58, P

Background Both tibial plateau fractures and extensor apparatus injuries are serious injuries to the knee joint that generally do not occur in the same patient. We report a rare case of open tibial plateau fracture combined with quadriceps tendon rupture and complete displacement of the patella into the tibial plateau fracture. Case presentation The case involved a male who was 19 years old who had been in a motorcycle accident. The patient was admitted to our department with an open tibial plateau fracture 3 h post-injury. X-ray showed a tibial plateau fracture and complete displacement of the patella into the tibial plateau. CT showed an avulsion fracture in the patella and tibial intercondylar eminence. Concomitant quadriceps tendon injury and both anterior and posterior cruciate ligament tibial insertion avulsion fractures were considered. The operative findings of emergency surgery confirmed our preoperative diagnosis. Single-stage quadriceps tendon repair and ORIF for the tibial plateau fracture were performed. Satisfactory restoration of function was acquired at the last follow up. Conclusion The most difficult aspect of this case was the determination of the cause of the intra-osseous dislocation of the patella into the tibial plateau. The most likely mechanism of the injury may be that the patient experienced transient posterior dislocation of the knee during the injury. Rupture of the quadriceps tendon should be considered with posterior dislocation of the knee, and the patella was pushed into the tibial plateau fracture by force after the rupture of the quadriceps tendon.

China lacks data demonstrating associations of cervical neoplastic lesions with CD4 T‐lymphocyte (CD4 cell) counts and antiretroviral therapy (ART) among HIV‐infected women, suggesting relevant investigations are needed. A total of 545 HIV‐infected women were enrolled in Yunnan, China, between 2011 and 2013. CD4 cell counts and ART were measured via medical records and cervical neoplastic lesions were measured by professional pathologists. Multivariable logistic models, which treated cervical intraepithelial neoplasia (CIN) 1+ and CIN2+ as outcomes, calculated adjusted odds ratio (aOR) of CD4 cell counts and ART. Subgroup analysis treating CIN1+ as the outcome was conducted by HIV infection duration (

The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.

Cognitive impairment has been revealed in primary Sjögren's syndrome (pSS). However, the underlying white matter structural connectivity (SC) changes have not been studied. This study aimed to investigate the altered white matter brain network in patients with pSS using diffusion tensor imaging (DTI).Forty-one pSS patients and sixty matched healthy controls (HCs) underwent neuropsychological tests and the subsequent MRI examinations. The clinical data were gathered from the medical record. The structural brain network was established using DTI, and a link-based comparison was performed between patients with pSS and HCs (false discovery rate correction, P 0.05). Furthermore, the mean fractional anisotropy (FA) of the altered SCs was correlated with the neuropsychological tests and clinical data in patients with pSS (Bonferroni correction, P 0.05).Compared with HCs, patients with pSS mainly exhibited decreased SC in the frontal and parietal lobes and some parts of the temporal and occipital lobes. In addition, increased SC was found between the right caudate nucleus and right median cingulate/paracingulate gyri. Specifically, the reduced SC between the left middle temporal gyrus and left middle occipital gyrus was negatively correlated with white matter high signal intensity (WMH).Patients with pSS showed diffusely decreased SC mainly in the frontoparietal network and exhibited a negative correlation between the reduced SC and WMH. SC represents a potential biomarker for preclinical brain impairment in patients with pSS.

To explore the efficacy and safety of G-SCF-mobilized donor lymphocyte infusion (DLI) for treatment of relapse of hematologic malignancies after allogeneic peripheral blood stem cell transplantation, we performed a retrospective analysis in a cohort of patients with morphologic (n = 36) or molecular (n = 22) relapse post transplantation. The 3-year post-DLI survival rates for therapeutic and preemptive DLI recipients were 16.7% and 33.3%, respectively. The occurrence of DLI-associated acute graft-versus-host disease predicted longer survival, whereas diagnosis of T cell acute lymphoblastic leukemia/lymphoma or myelodysplastic syndromes or early relapse after transplant ( 6 months) predicted shorter survival after therapeutic DLI. Cumulative incidence of progression to hematologic relapse and non-relapse mortality after preemptive DLI were 46.8% and 29.1%, respectively. Active disease prior to transplant and early molecular relapse after transplant ( 4 months) were the strongest predictors of non-relapse mortality after preemptive DLI. In conclusion, although therapeutic DLI had limited efficacy against T cell acute lymphoblastic leukemia/lymphoma or myelodysplastic syndromes or early post-transplant relapse, patients who developed DLI-associated acute graft-versus-host disease would benefit from this procedure in the setting of G-SCF-mobilized DLI. Furthermore, preemptive DLI could protect half of patients from hematologic relapse after transplantation with acceptable toxicity.

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PurposeDevelopment and validation of a nomogram for the prediction of lateral lymph node metastasis (LLNM) in medullary thyroid carcinoma (MTC).MethodsWe retrospectively reviewed the clinical features of patients with MTC in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017 and in our Department of Surgical Oncology, Hangzhou First People’s Hospital between 2009 and 2019. The log‐rank test was used to compare the difference in the Kaplan–Meier (K–M) curves in recurrence and survival. The nomogram was developed to predict the risk of LLNM in MTC patients. The prediction efficiency of the predictive model was assessed by area under the curve (AUC) and concordance index (C-index) and calibration curves. Decision curve analysis (DCA) was performed to determine the clinic value of the predictive model.ResultA total of 714 patients in the SEER database and 35 patients in our department were enrolled in our study. Patients with LLNM had worse recurrence rate and cancer-specific survival (CSS) compared with patients without LLNM. Five clinical characteristics including sex, tumor size, multifocality, extrathyroidal extension, and distant metastasis were identified to be associated with LLNM in MTC patients, which were used to develop a nomogram. Our prediction model had satisfied discrimination with a C-index of 0.825, supported by both training set and internal testing set with a C-index of 0.825, and 0.816, respectively. DCA was further made to evaluate the clinical utility of this nomogram for predicting LLNM.ConclusionsMale sex, tumor size >38mm, multifocality, extrathyroidal extension, and distant metastasis in MTC patients were significant risk factors for predicting LLNM.

PurposeTo investigate the prognostic significance of extranodal extension (ENE) in papillary thyroid cancer (PTC).MethodsSeven hundred forty-three PTC patients were enrolled in the study from January 2014 to December 2017. The patients were dichotomized according to the presence of ENE. Logistic analysis was used to compare differences between the two groups. Kaplan–Meier (K-M) curve and propensity score matching (PSM) analyses were used for recurrence-free survival (RFS) comparisons. Cox regression was performed to analyze the effects of ENE on RFS in PTC.ResultsThirty-four patients (4.58%) had ENE. Univariate analysis showed that age, tumor size, extrathyroidal extension, and nodal stage were associated with ENE. Further logistic regression analysis showed that age, extrathyroidal extension, and nodal stage remained statistically significant. Evaluation of K-M curves showed a statistically significant difference between the two groups before and after PSM. Cox regression showed that tumor size and ENE were independent risk factors for RFS.ConclusionsAge ≥55 years, extrathyroidal extension, and lateral cervical lymph node metastasis were identified as independent risk factors for ENE. ENE is an independent prognostic factor in PTC.

Background Both gastric adenocarcinoma with primitive enterocyte phenotype (GAPEP) (including hepatoid adenocarcinoma) and alpha-fetoprotein (AFP)-producing gastric adenocarcinoma have poor prognoses. However, the value of the serum AFP test and AFP/glypican-3 (GPC3)/spalt-like transcription factor 4 (SALL4) immunohistochemistry is still not clear, and these two methods have not yet been thoroughly compared. Methods We collected 421 consecutive non-neoadjuvant surgically or endoscopically resected gastric adenocarcinoma patients with serum AFP results before surgery (group A). We divided these cases into serum AFP-high (sAFP-H) and serum AFP-normal (sAFP-N) by serum AFP levels, and into GAPEP (expressing AFP, GPC3, or SALL4) and non-GAPEP (nGAPEP) by AFP/GPC3/SALL4 immunohistochemistry results. We also collected 12 non-resected gastric adenocarcinoma patients with serum AFP ≥ 7 ng/mL before treatment (group B). We analyzed these patients’ clinicopathological characteristics and prognoses. Results Seventeen (4.04%) patients in group A were sAFP-H. These patients were younger and mainly had tubular adenocarcinoma with later pT (P = 0.014) and pN (P = 0.047) categories and more lymphovascular invasion (P P = 0.008), and metastases or recurrence (P P = 0.001). Most group B patients with elevated serum AFP (especially > 1000 ng/mL) had simultaneous metastases, mainly liver metastases. Both the serological method and immunohistochemical method were useful for predicting prognosis (AUC sAFP = 0.625, AUC A/G/S-IHC = 0.723, z statistic = 1.726, P = 0.084). The serum AFP level (especially > 1000 ng/mL) is more specific (100%), and immunohistochemistry is more sensitive (50%). Conclusion Both the serum AFP level and immunohistochemical expression of AFP/GPC3/SALL4 can be used to indicate a poor prognosis for gastric adenocarcinoma.

To investigate the clinical characteristics, outcomes and prognosis of adult acute myeloid leukemia (AML) patients with NUP98 gene rearrangement.The clinical data of adult AML patients with NUP98 gene rearrangement from January 2015 to December 2019 were retrospectively analyzed, including clinical characteristics, laboratory examination, genetic anomaly, treatment strategy and survival.A total of 15 patients with NUP98 gene rearrangement were detected in 410 adult AML patients (3.7%). The ratio of male to female among 15 patients was 1.1∶1, and the median age was 43 (17-76) years old. The main FAB types were M2 and M4/M5, and including one unclassified. According to the genetic prognosis, 11 cases were intermediate risk, while 4 cases were high risk. The main type of NUP98 gene rearrangement was NUP98-HOXA9 (13/15, 86.7%). 10 patients underwent next generation sequencing, in which 5 patients showed epigenetic gene mutations, 3 patients showed FLT3-ITD or WT1 mutations, and 2 patients showed no mutation. After induction therapy, 13 of 15 patients achieved complete remission（CR）. 7 of 8 patients with standard induction therapy achieved CR. 7 elder or intolerance patients with demethylation drug and chemotherapy all achieved CR. The median follow-up time was 28 months. The median OS of 15 the patients was 31.5 months (95% CI 10.7%-52.2%), and the median OS of the patients in non-allogeneic hematopoietic stem cell transplantation (Allo-HSCT) group was 18.5 months (95% CI 17.8%-19.1%). The median OS was not reached for the patients in the Allo-HSCT group.Allo-HSCT can significantly improve the prognosis of AML patients with NUP98 rearrangement. NUP98 rearrangement can be accompanied by epigenetic gene mutations. For the elderly or patients who do not tolerate standard induction therapy, demethylation drugs combined with chemotherapy can achieve good outcomes.伴NUP98基因重排的成人急性髓系白血病的临床特点及预后分析.探讨伴NUP98基因重排的成人急性髓系白血病（AML）患者的临床特点、治疗效果及预后因素.回顾性分析2015年1月至2019年12月解放军总医院第一医学中心血液科收治的伴有NUP98基因重排的成人AML患者的临床表现、实验室检查、遗传学异常、治疗方案及生存情况等临床资料.410例成人AML患者中，共检测出15例伴有NUP98基因重排的患者，检出率为3.7%。15例患者的男女比例为1.1∶1，中位年龄43（17－76）岁，FAB分型主要为M2型和M4/M5型，遗传学预后分层11例为中危组，4例为高危组。NUP98基因重排类型主要为NUP98-HOXA9（13/15），10例患者行二代测序（NGS）检测，其中5例伴有多种表观遗传学基因突变，3例伴有FLT3-ITD或WT1突变，2例突变阴性；15例患者诱导治疗后13例获得完全缓解（CR），其中8例行标准诱导治疗后7例获得CR；7例老年或不能耐受标准化疗患者行DCAG方案诱导治疗全部获得CR。中位随访时间28个月，15例患者中位OS为31.5个月（95%CI 10.7%－52.2%），非异基因造血干细胞移植组（6例）中位OS为18.5个月（95%CI 17.8%－19.1%），异基因造血干细胞移植组（9例）中位OS未达到.异基因造血干细胞移植可明显改善伴有NUP98重排AML患者的预后，NUP98基因重排可同时伴有多种表观遗传学基因突变，对于老年或不耐受标准诱导治疗的患者应用含去甲基化药物的治疗可获得较好疗效.

In Asia, including Taiwan, malignant tumors such as Hepatocellular carcinoma (HCC) one of the liver cancer is the most diagnosed subtype. Magnetic resonance imaging (MRI) has been a typical diagnostic method for accurately diagnosing HCC. When it is difficult to demonstrate non-enhanced MRI of tumors, radiologists can use contrast agents (such as Gd3+, Fe3O4, or FePt) for T1-weighted and T2-weighted imaging remain in the liver for a long time to facilitate diagnosis via MRI. However, it is sometimes difficult for T2-weighted imaging to detect small tumor lesions because the liver tissue may absorb iron ions. This makes early cancer detection a challenging goal. This challenge has prompted current research to create novel nanocomposites for enhancing the noise-to-signal ratio of MRI. To develop a method that can more efficiently diagnose and simultaneously treat HCC during MRI examination, we designed a functionalized montmorillonite (MMT) material with a porous structure to benefit related drugs, such as mitoxantrone (MIT) delivery or as a carrier for the FePt nanoparticles (FePt NPs) to introduce cancer therapy. Multifunctional FePt@MMT can simultaneously visualize HCC by enhancing MRI signals, treating various diseases, and being used as an inducer of magnetic fluid hyperthermia (MFH). After loading the drug MIT, FePt@MMT-MIT provides both MFH treatment and chemotherapy in one nanosystem. These results ultimately prove that functionalized FePt@MMT-MIT could be integrated as a versatile drugs delivery system by combining with MRI, chemotheraeutic drugs, and magnetic guide targeting. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01052-7.

Liver fibrosis is an important process in chronic liver disease and is strongly related to poor prognosis. Dehydromevalonolactone (C8) is a natural product isolated from a fungus of Fusarium sp. CPCC 401218, and its pharmacological activity has never been reported before. In this study, the potential of C8 as an anti-hepatic fibrosis agent was investigated. In human hepatic stellate cell (HSC) line LX-2, C8 suppressed the increased expression of COL1A1 and α-SMA induced by TGFβ1, which indicated that C8 could repress the activation of HSCs. In bile duct ligated rats, C8 administration (100 mg/kg, i.p.) markedly attenuated liver injury, fibrosis, and inflammation, and suppressed the expression of the macrophage surface marker F4/80. In terms of mechanism, C8 treatment blocked the activation of the NLRP3 inflammasome, which was stimulated by LPS and nigericin in bone marrow-derived macrophages (BMDMs) and companied by the release of active IL-1β. In addition, the activation of LX-2 cells induced by IL-1β released from BMDMs was also inhibited after C8 administration, which indicated that C8 repressed HSCs activation by inhibiting the activation of NLRP3 inflammasome in macrophages. Furthermore, C8 exhibited the effects of anti-fibrosis and inhibiting the expression of NLRP3 inflammasome in non-alcoholic steatohepatitis (NASH) mice. Finally, C8 can be commendably absorbed in vivo and was safe for mice at the concentration of 1000 mg/kg (p.o.). In summary, our study reveals that C8 ameliorates HSCs activation and liver fibrosis in cholestasis rats and NASH mice by inhibiting NLRP3 inflammasome in macrophages, and C8 might be a safe and effective candidate for the treatment of liver fibrosis.

Background Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease. The cellular glucose metabolism of fibroblast‐like synoviocytes (FLSs) of RA has been revealed to be essential to the pathogenesis and development of RA. To date, the precise roles and molecular mechanisms of long noncoding RNA TUG1 in RA have not been elucidated. Methods TUG1 and miR‐34a‐5p were detected by qRT‐PCR. Interactions between lncRNA‐miRNA and miRNA‐mRNA were validated by RNA pull‐down assay and luciferase assay. The glucose metabolism was evaluated by glucose uptake and extracellular acidification rate (ECAR). Cell viability was determined by MTT assay and Annexin V assay. Results TUG1 expression was significantly upregulated in synovial fibroblast‐like synoviocytes (FLSs) compared with normal FLSs. Functional assays uncovered that silence of TUG1 suppressed FLSs‐RA invasion, migration, glucose metabolism, and increased apoptosis. Bioinformatics analysis indicated that TUG1 interacted with miR‐34a‐5p. RNA pull‐down assay and luciferase assay validated that TUG1 sponged miR‐34a‐5p in FLSs‐RA. Overexpression of miR‐34a‐5p effectively inhibited glucose metabolism of FLSs‐RA. Furthermore, the glucose metabolism of FLSs‐RA was significantly elevated compared with normal FLSs. The glucose metabolism enzyme, LDHA, was directly targeted by miR‐34a‐5p in FLSs. Rescue experiments validated that the miR‐34a‐5p‐inhibited glucose metabolism of FLSs‐RA was through targeting LDHA. Finally, we showed restoration of miR‐34a‐5p in TUG1‐overexpressing FLSs‐RA successfully overcame the TUG1‐promoted glucose metabolism and apoptosis resistance via targeting LDHA. Conclusion The present study uncovered critical roles and molecular mechanisms underlying the TUG1‐mediated glucose metabolism and apoptosis of FLSs‐RA through modulating the miR‐34a‐5p‐LDHA pathway in fibroblast‐like synoviocytes of rheumatoid arthritis., Our conclusions uncover critical roles and molecular mechanisms of the TUG1‐mediated glucose metabolism and apoptosis of FLSs‐RA through modulating the miR‐34a‐5p‐LDHA pathway in RA patients, suggesting that targeting TUG1 could be an effective therapeutic approach to suppress the proliferation of FLSs for rheumatoid arthritis treatment.

Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor β1 (TGFβ1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.

ObjectiveOur goal was to investigate the correlation between papillary thyroid carcinoma (PTC) characteristics on ultrasonography and metastases of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN). There is still no good method for clinicians to judge whether a patient needs LN-prRLN resection before surgery, and we also wanted to establish a new scoring system to determine whether patients with papillary thyroid carcinoma require LN-prRLN resection before surgery.Patients and MethodsThere were 482 patients with right or bilateral PTC who underwent thyroid gland resection from December 2015 to December 2017 recruited as study subjects. The relationship between the PTC characteristics on ultrasonography and the metastases of LN-prRLN was analyzed by univariate and logistic regression analyses. Based on the risk factors identified in univariate and logistic regression analysis, a nomogram-based LN-prRLN prediction model was established.ResultLN-prRLN were removed from all patients, of which 79 had LN-prRLN metastasis, with a metastasis rate of 16.39%. Multivariate logistic regression analysis revealed that LN-prRLN metastasis was closely related to sex, age, blood supply, larger tumors (> 1 cm) and capsular invasion. A risk prediction model has been established and fully verified. The calibration curve used to evaluate the nomogram shows that the consistency index was 0.75 ± 0.065.ConclusionPreoperative clinical data, such as sex, age, abundant blood supply, larger tumor (> 1 cm) and capsular invasion, are positively correlated with LN-prRLN metastasis. Our scoring system can help surgeons non-invasively determine which patients should undergo LN-prRLN resection before surgery. We recommend that LN-prRLN resection should be performed when the score is above 103.1.

Background Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease; cellular glutamine metabolism in fibroblast-like synoviocytes (FLSs) of RA was known to be essential for RA pathogenesis and progression. NEAT1, a long non-coding RNA, functions as an oncogene in diverse cancers. The exact roles and molecular mechanisms of NEAT1 in fibroblast-like synoviocytes (FLSs) of RA patients are unknown. Methods Expression of NEAT1 and miR-338-3p was measured by qRT-PCR. lncRNA-miRNA and miRNA-mRNA interactions were predicted from starBase and validated by RNA pull-down and luciferase assay. The glutamine metabolism of FLSs was evaluated by glutamine uptake and glutaminase activity. Cell death in FLSs in response to H2O2 was assessed by MTT and Annexin V assays. Results NEAT1 was significantly upregulated, and miR-338-3p was significantly downregulated in FLSs from RA patients compared to normal FLSs. Silencing of NEAT1 and overexpression of miR-338-3p suppressed glutamine metabolism in FLSs-RA and promoted H2O2-induced apoptosis. Bioinformatics analysis showed that NEAT1 sponges miR-338-3p to form competing endogenous RNA (ceRNAs), which was verified by RNA pull-down assay and luciferase assay FLSs-RA had an increased rate of glutamine metabolism compared to normal FLSs increased compared to normal FLSs. The results confirmed that GLS (Glutaminase), a key enzyme in glutamine metabolism, is a direct target of miR-338-3p in FLSs-RA. miR-338-3p inhibition of glutamine metabolism was verified by rescue experiments verified. Finally, restoration of miR-338-3p in FLSs-RA expressing NEAT1 overcomes NEAT1-promoted glutamine metabolism and resistance to apoptosis. Conclusions This study reveals the essential role and molecular targets of NEAT1-regulated glutamine metabolism and FLSs-RA dysfunction in fibroblast-like synoviocytes of RA and indicates that blocking the molecular pathway via non-coding RNAs may be beneficial for RA patients.

Granulocyte transfusions have long been used to bridge the time to neutrophil recovery in patients with neutropenia and severe infection. Recent randomized controlled trials did not prove a beneficial effect of granulocyte transfusions, but were likely underpowered and suffered from very heterogeneous study populations.We retrospectively reviewed data of all patients treated with granulocyte transfusions at our pediatric center from 2004 to 2019. To identify parameters that predict the success of granulocyte transfusions, we stratified patients in 3 groups. Patients in group 1 cleared their infection, whereas patients in group 2 succumbed to an infection in neutropenia despite granulocyte transfusions. A third group included all patients who died of causes that were not related to infection.We demonstrate that patients without respiratory or cardiocirculatory insufficiency are enriched in group 1 and more likely to benefit from granulocyte transfusions than patients who already require these intensive care measures. The effect of granulocyte transfusions correlates with the cell dose per body weight applied per time. With our standard twice weekly dosing, patients with a body weight below 40 kg are more likely to achieve a sufficient leukocyte increment and clear their infection in comparison to patients with a higher body weight.We suggest that future studies on the benefits of granulocyte transfusions stratify patients according to clinical risk factors that include the need for respiratory or cardiocirculatory support and strive for a sufficient dose density of granulocyte transfusions.

Objectives This study assessed risk adjustment performance of six comorbidity indices in two categories of comorbidity measures: diagnosis-based comorbidity indices and medication-based ones in patients with chronic obstructive pulmonary disease (COPD). Methods This was a population–based retrospective cohort study. Data used in this study were sourced from the Taiwan National Health Insurance Research Database. The study population comprised all patients who were hospitalized due to COPD for the first time in the target year of 2012. Each qualified patient was individually followed for one year starting from the index date to assess two outcomes of interest, medical expenditures within one year after discharge and in-hospital mortality of patients. To assess how well the added comorbidity measures would improve the fitted model, we calculated the log-likelihood ratio statistic G2. Subsequently, we compared risk adjustment performance of the comorbidity indices by using the Harrell c-statistic measure derived from multiple logistic regression models. Results Analytical results demonstrated that that comorbidity measures were significant predictors of medical expenditures and mortality of COPD patients. Specifically, in the category of diagnosis-based comorbidity indices the Elixhauser index was superior to other indices, while the RxRisk-V index was a stronger predictor in the framework of medication-based codes, for gauging both medical expenditures and in-hospital mortality by utilizing information from the index hospitalization only as well as the index and prior hospitalizations. Conclusions In conclusion, this work has ascertained that comorbidity indices are significant predictors of medical expenditures and mortality of COPD patients. Based on the study findings, we propose that when designing the payment schemes for patients with chronic diseases, the health authority should make adjustments in accordance with the burden of health care caused by comorbid conditions.

Background and aims Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. Approach and results We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4 -treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. Conclusions This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.

Integrin α11β1 is a collagen-binding integrin, which is receiving increasing attention in the context of wound healing and fibrosis. Although α11β1 integrin displays similar collagen specificity to α2β1 integrin, both integrins have distinct in vivo functions. In this context, the contribution of α11 subunit cytoplasmic tail interactions to diverse molecular signals and biological functions is largely unknown. In the current study, we have deleted the α11 cytoplasmic tail and studied the effect of this deletion on α11 integrin function. Compared to wild-type cells, C2C12 cells expressing tail-less α11 attached normally to collagen I, but formed fewer focal contacts. α11-tail-less cells furthermore displayed a reduced capacity to invade and reorganize a 3D collagen matrix and to proliferate. Analysis of cell signaling showed that FAK and ERK phosphorylation was reduced in cells expressing tail-less α11. Inhibition of ERK and FAK activation decreased α11-mediated cell proliferation, whereas α11-mediated cell invasion was FAK-dependent and occurred independently of ERK signaling. In summary, our data demonstrate that the integrin α11 cytoplasmic tail plays a central role in α11 integrin-specific functions, including FAK-dependent ERK activation to promote cell proliferation.

PURPOSE: Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS: MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS: The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m(2) (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08–3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m(2)) BMI (OR = 2.43, 95% CI 1.24–4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38–2.52, p = 0.96). CONCLUSIONS: Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+ tumors previously reported in Asian women.

Background In bowel obstruction and biliary pancreatitis, patients receive more expedient surgical care when admitted to surgical compared with medical services. This has not been studied in acute cholecystitis. Methods Retrospective analysis of clinical and cost data from July 2013 to September 2015 for patients with cholecystitis who underwent laparoscopic cholecystectomy in a tertiary care inpatient hospital. One hundred ninety lower-risk (Charlson-Deyo) patients were included. We assessed admitting service, length of stay (LOS), time from admission to surgery, time from surgery to discharge, number of imaging studies, and total cost. Results Patients admitted to surgical (n = 106) versus medical (n = 84) service had shorter mean LOS (1.4 days vs. 2.6 days), shorter time from admission to surgery (0.4 days vs. 0.8 days), and shorter time from surgery to discharge (0.8 days vs. 1.1 days). Surgical service patients had fewer CT (38% vs. 56%) and magnetic resonance imaging (MRI) (5% vs. 16%) studies. Cholangiography (30% vs. 25%) and endoscopic retrograde cholangiopancreatography (ERCP) (3 vs. 8%) rates were similar. Surgical service patients had 39% lower median total costs (US $7787 vs. US $12572). Conclusion Nonsurgical admissions of patients with cholecystitis are common, even among lower-risk patients. Routine admission to the surgical service should decrease LOS, resource utilization and costs. Level of evidence Therapeutic/care management, level IV.