Interpretable deep residual network uncovers nucleosome positioning and associated features.

Nucleosomes represent elementary building units of eukaryotic chromosomes and consist of DNA wrapped around a histone octamer flanked by linker DNA segments. Nucleosomes are central in epigenetic pathways and their genomic positioning is associated with regulation of gene expression, DNA replication, DNA methylation and DNA repair, among other functions. Building on prior discoveries that DNA sequences noticeably affect nucleosome positioning, our objective is to identify nucleosome positions and related features across entire genome. Here, we introduce an interpretable framework based on the concepts of deep residual networks (NuPoSe). Trained on high-coverage human experimental MNase-seq data, NuPoSe is able to learn sequence and structural patterns associated with nucleosome organization in human genome. NuPoSe can be also applied to unseen data from different organisms and cell types. Our findings point to 43 informative features, most of them constitute tri-nucleotides, di-nucleotides and one tetra-nucleotide. Most features are significantly associated with the nucleosomal structural characteristics, namely, periodicity of nucleosomal DNA and its location with respect to a histone octamer. Importantly, we show that features derived from the 27 bp linker DNA flanking nucleosomes contribute up to 10% to the quality of the prediction model. This, along with the comprehensive training sets, deep-learning architecture, and feature selection method, may contribute to the NuPoSe's 80-89% classification accuracy on different independent datasets.

Bivalent chromatin accommodates survivin and BRG1/SWI complex to activate DNA damage response in CD4+ cells.

BACKGROUND: Bivalent regions of chromatin (BvCR) are characterized by trimethylated lysine 4 (H3K4me3) and lysine 27 on histone H3 (H3K27me3) deposition which aid gene expression control during cell differentiation. The role of BvCR in post-transcriptional DNA damage response remains unidentified. Oncoprotein survivin binds chromatin and mediates IFNγ effects in CD4+ cells. In this study, we explored the role of BvCR in DNA damage response of autoimmune CD4+ cells in rheumatoid arthritis (RA). METHODS: We performed deep sequencing of the chromatin bound to survivin, H3K4me3, H3K27me3, and H3K27ac, in human CD4+ cells and identified BvCR, which possessed all three histone H3 modifications. Protein partners of survivin on chromatin were predicted by integration of motif enrichment analysis, computational machine-learning, and structural modeling, and validated experimentally by mass spectrometry and peptide binding array. Survivin-dependent change in BvCR and transcription of genes controlled by the BvCR was studied in CD4+ cells treated with survivin inhibitor, which revealed survivin-dependent biological processes. Finally, the survivin-dependent processes were mapped to the transcriptome of CD4+ cells in blood and in synovial tissue of RA patients and the effect of modern immunomodulating drugs on these processes was explored. RESULTS: We identified that BvCR dominated by H3K4me3 (H3K4me3-BvCR) accommodated survivin within cis-regulatory elements of the genes controlling DNA damage. Inhibition of survivin or JAK-STAT signaling enhanced H3K4me3-BvCR dominance, which improved DNA damage recognition and arrested cell cycle progression in cultured CD4+ cells. Specifically, BvCR accommodating survivin aided sequence-specific anchoring of the BRG1/SWI chromatin-remodeling complex coordinating DNA damage response. Mapping survivin interactome to BRG1/SWI complex demonstrated interaction of survivin with the subunits anchoring the complex to chromatin. Co-expression of BRG1, survivin and IFNγ in CD4+ cells rendered complete deregulation of DNA damage response in RA. Such cells possessed strong ability of homing to RA joints. Immunomodulating drugs inhibited the anchoring subunits of BRG1/SWI complex, which affected arthritogenic profile of CD4+ cells. CONCLUSIONS: BvCR execute DNA damage control to maintain genome fidelity in IFN-activated CD4+ cells. Survivin anchors the BRG1/SWI complex to BvCR to repress DNA damage response. These results offer a platform for therapeutic interventions targeting survivin and BRG1/SWI complex in autoimmunity.

Mucinous histology is a negative predictor of neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

DNA methylation cues in nucleosome geometry, stability and unwrapping.

Cytosine methylation at the 5-carbon position is an essential DNA epigenetic mark in many eukaryotic organisms. Although countless structural and functional studies of cytosine methylation have been reported, our understanding of how it influences the nucleosome assembly, structure, and dynamics remains obscure. Here, we investigate the effects of cytosine methylation at CpG sites on nucleosome dynamics and stability. By applying long molecular dynamics simulations on several microsecond time scale, we generate extensive atomistic conformational ensembles of full nucleosomes. Our results reveal that methylation induces pronounced changes in geometry for both linker and nucleosomal DNA, leading to a more curved, under-twisted DNA, narrowing the adjacent minor grooves, and shifting the population equilibrium of sugar-phosphate backbone geometry. These DNA conformational changes are associated with a considerable enhancement of interactions between methylated DNA and the histone octamer, doubling the number of contacts at some key arginines. H2A and H3 tails play important roles in these interactions, especially for DNA methylated nucleosomes. This, in turn, prevents a spontaneous DNA unwrapping of 3-4 helical turns for the methylated nucleosome with truncated histone tails, otherwise observed in the unmethylated system on several microseconds time scale.

Concomitant extrahepatic autoimmune diseases do not compromise the long-term outcomes of primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) patients often have concomitant extrahepatic autoimmune (EHA) diseases including Sjögren's syndrome (SS), systemic sclerosis (SSc), rheumatoid arthritis (RA), and autoimmune thyroid disease. The present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese patients. METHODS: Medical records of PBC patients diagnosed in our institute were retrospectively reviewed. Patients were followed up by a standardized telephone interview. The endpoints were defined as liver-related death and/or liver transplantation. RESULTS: Totally 247 of the 985 (25.1%) PBC patients enrolled in the study had at least one concomitant EHA disease. Sjögren's syndrome (n = 140, 14.2%) was the most frequent one, followed by rheumatoid arthritis (RA) (n = 56, 5.7%) and Hashimoto's thyroiditis (n = 45, 4.6%). Patients with EHA diseases were more common in females (P < 0.001) and in those with a family history of autoimmune disease (P = 0.017). Overall, no differences were found between PBC patients with and without EHA diseases in terms of biochemical response rates to ursodeoxycholic acid, the incidence of hepatic events, or transplant-free survival. RA and EHA ≥ 2 were protective factors for hepatic events in univariate Cox analysis, but the results became insignificant in multivariate analysis. CONCLUSIONS: Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.

[Realization and Clinical Study of Robotic Technology in Cardiovascular Interventional Surgery].

The high incidence of cardiovascular diseases is a serious threat to human health, and endovascular surgery has become the standard treatment for most interventional cardiovascular diseases. The robotassisted endovascular surgery system further enhances surgeons' ability to perform minimally invasive endovascular procedures in interventional cardiology. This study presents a new robotic technique for coronary intervention from the perspective of clinical application. Aiming at clinical application scenarios, this scheme proposed an intuitive guide wire catheter mechanism design, which accurately and perfectly simulates the doctor's hand movements, realizes the positive and negative direction translation of the guide wire catheter, accurate torque control of the guide wire rotation and locking. The results of animal test showed that the R-OneTM has a high degree of dexterity, accuracy and stability,and meets the clinical needs.

Web 3DNA 2.0 for the analysis, visualization, and modeling of 3D nucleic acid structures.

Web 3DNA (w3DNA) 2.0 is a significantly enhanced version of the widely used w3DNA server for the analysis, visualization, and modeling of 3D nucleic-acid-containing structures. Since its initial release in 2009, the w3DNA server has continuously served the community by making commonly-used features of the 3DNA suite of command-line programs readily accessible. However, due to the lack of updates, w3DNA has clearly shown its age in terms of modern web technologies and it has long lagged behind further developments of 3DNA per se. The w3DNA 2.0 server presented here overcomes all known shortcomings of w3DNA while maintaining its battle-tested characteristics. Technically, w3DNA 2.0 implements a simple and intuitive interface (with sensible defaults) for increased usability, and it complies with HTML5 web standards for broad accessibility. Featurewise, w3DNA 2.0 employs the most recent version of 3DNA, enhanced with many new functionalities, including: the automatic handling of modified nucleotides; a set of 'simple' base-pair and step parameters for qualitative characterization of non-Watson-Crick double-helical structures; new structural parameters that integrate the rigid base plane and the backbone phosphate group, the two nucleic acid components most reliably determined with X-ray crystallography; in silico base mutations that preserve the backbone geometry; and a notably improved module for building models of single-stranded RNA, double-helical DNA, Pauling triplex, G-quadruplex, or DNA structures 'decorated' with proteins. The w3DNA 2.0 server is freely available, without registration, at http://web.x3dna.org.

Surgical hip dislocation for treatment of synovial chondromatosis of the hip.

PURPOSE: In the present study, we aimed to evaluate the clinical outcomes of surgical hip dislocation in patients with synovial chondromatosis (SC) of the hip. METHODS: Seven patients with primary SC of the hip treated with open synovectomy and removal of loose bodies by surgical hip dislocation from 2016 to 2019 were retrospectively reviewed. All patients had numerous and widespread loose bodies based on pre-operative images, including routine radiographs, CT, and MRI. The visual analog scale (VAS) score and Harris hip score (HHS) were collected and analyzed before and after surgery. The post-operative radiographs were reviewed to evaluate disease recurrence and osteoarthritis progression. RESULTS: The mean operative time was 61 minutes (range, 42-75 min). An average of 33 loose bodies in each patient (range, 16-67) was removed, and extra-articular pathology was found in one patient. Patients were followed up for a mean duration of 30 months (range, 18-42 months). The average VAS scores were decreased from 3.7 (range, 2-6) pre-operatively to 0.9 (range, 0-2) at the last follow-up, and the HHS was improved from 60.1 (range, 50-73) to 90.1 (range, 82-95). All results demonstrated significant improvements (P < 0.05). Post-operative radiographs showed no recurrence, osteoarthritis progression, or osteonecrosis of the femoral head in all hips. CONCLUSIONS: Surgical hip dislocation was a practical approach for managing both intra-articular and extra-articular pathologic lesions around the hip. It was an effective treatment for SC of the hip with short surgical time, good joint functions, a lower recurrence rate, and few complications.

The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.

The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune-cell-mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild-type (WT) mice after 4 wk of feeding on a methionine- and choline-deficient diet (MCD) or 16 wk of feeding on a high-fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD-fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non-CD8 cells or non-NK cells from WT mice, indicated that CD8 T-cell-derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin-deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow-derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.-Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.

Effects of Noncanonical Base Pairing on RNA Folding: Structural Context and Spatial Arrangements of G·A Pairs.

Noncanonical base pairs play important roles in assembling the three-dimensional structures critical to the diverse functions of RNA. These associations contribute to the looped segments that intersperse the canonical double-helical elements within folded, globular RNA molecules. They stitch together various structural elements, serve as recognition elements for other molecules, and act as sites of intrinsic stiffness or deformability. This work takes advantage of new software (DSSR) designed to streamline the analysis and annotation of RNA three-dimensional structures. The multiscale structural information gathered for individual molecules, combined with the growing number of unique, well-resolved RNA structures, makes it possible to examine the collective features deeply and to uncover previously unrecognized patterns of chain organization. Here we focus on a subset of noncanonical base pairs involving guanine and adenine and the links between their modes of association, secondary structural context, and contributions to tertiary folding. The rigorous descriptions of base-pair geometry that we employ facilitate characterization of recurrent geometric motifs and the structural settings in which these arrangements occur. Moreover, the numerical parameters hint at the natural motions of the interacting bases and the pathways likely to connect different spatial forms. We draw attention to higher-order multiplexes involving two or more G·A pairs and the roles these associations appear to play in bridging different secondary structural units. The collective data reveal pairing propensities in base organization, secondary structural context, and deformability and serve as a starting point for further multiscale investigations and/or simulations of RNA folding.

Prognosis of 732 ursodeoxycholic acid-treated patients with primary biliary cholangitis: A single center follow-up study from China.

BACKGROUND AND AIM: The impact of male sex and past hepatitis B virus (HBV) infection on survival of primary biliary cholangitis (PBC) are issues at discussion. The aim of the present study was to identify risk factors for transplant-free survival (TRS) in Chinese PBC patients who received ursodeoxycholic acid (UDCA), with special focus on the impact of male sex and past HBV infection. METHODS: We followed up PBC patients who received UDCA at our institute between January 2000 and December 2017 until their death, liver transplantation, or censored on April 1, 2018, by interview and review of medical records. We used Cox proportional hazards model and Kaplan-Meier method. RESULTS: Out of 976 PBC patients, 732 UDCA-treated patients (female : male = 6.2:1) with required clinical and laboratory data were enrolled in this study. The median follow-up period were 4.8 years (interquartile range: 2.8-7.1 years). The overall 5-, 10-, and 15-year TRS rates were 86.7% (95% CI: 83.8-88.1), 71.1% (95% CI: 65.0-77.2), and 59.2% (95% CI: 44.5-73.9), respectively. The survival was significantly worse for male patients and older patients (≥ 55 years) (log-rank test: P < 0.05 for both). On multivariate analysis, male sex, cirrhosis, serum bilirubin, and serum albumin were independent predictors for TRS. There was no significant difference in survivals between patients with (n = 167) and without (n = 219) past HBV infection (log-rank test: P = 0.293). CONCLUSIONS: In this large Chinese cohort of UDCA-treated PBC patients, male sex was associated with shorter survival, whereas past HBV infection was not associated with poorer outcome.

Systematic review and meta-analysis on the incidence and prevalence of autoimmune hepatitis in Asian, European, and American population.

BACKGROUND AND AIM: Reported incidence and prevalence rates of autoimmune hepatitis (AIH) have been sparse and heterogeneous. The aim of this meta-analysis was to estimate the worldwide incidence and prevalence rates of AIH and reveal population difference. METHODS: Published articles on the epidemiology of AIH in PubMed, Embase, and Cochrane Library were systematically searched from inception to April 28, 2019. Two investigators independently reviewed these literatures and evaluated their quality. A random-effects model was used to pool the overall incidence and prevalence rates. The impact of population difference, gender, age, study period, study quality, diagnostic criteria, and study design was further analyzed with subgroup analysis and meta-regression. RESULTS: A total of 22 studies were included in the meta-analysis. The pooled worldwide annual incidence and prevalence of AIH were 1.37 (95% confidence interval [CI]: 0.95-1.80) and 17.44 (95% CI: 12.01-22.87) per 100 000 persons, respectively. Subgroup analysis showed that the pooled annual incidence for Asian, European, and American population was 1.31 (95% CI: 0.42-2.20), 1.37 (95% CI: 1.10-1.64), and 1.00 (95% CI: 0.44-1.56) per 100 000 persons, respectively; the pooled prevalence for Asian, European, and American population was 12.99 (95% CI: 2.05-23.92), 19.44 (95% CI: 15.63-23.24), and 22.80 (95% CI: -13.48 to 59.07) per 100 000 persons, respectively. In addition, higher incidence and prevalence rates were observed in women than men, and a higher prevalence rate was observed in elderly than young people. CONCLUSIONS: Autoimmune hepatitis is a rare disease, with a similar incidence worldwide and a higher prevalence in European and American than in Asian population.

Features of genomic organization in a nucleotide-resolution molecular model of the Escherichia coli chromosome.

We describe structural models of the Escherichia coli chromosome in which the positions of all 4.6 million nucleotides of each DNA strand are resolved. Models consistent with two basic chromosomal orientations, differing in their positioning of the origin of replication, have been constructed. In both types of model, the chromosome is partitioned into plectoneme-abundant and plectoneme-free regions, with plectoneme lengths and branching patterns matching experimental distributions, and with spatial distributions of highly-transcribed chromosomal regions matching recent experimental measurements of the distribution of RNA polymerases. Physical analysis of the models indicates that the effective persistence length of the DNA and relative contributions of twist and writhe to the chromosome's negative supercoiling are in good correspondence with experimental estimates. The models exhibit characteristics similar to those of 'fractal globules,' and even the most genomically-distant parts of the chromosome can be physically connected, through paths combining linear diffusion and inter-segmental transfer, by an average of only ∼10 000 bp. Finally, macrodomain structures and the spatial distributions of co-expressed genes are analyzed: the latter are shown to depend strongly on the overall orientation of the chromosome. We anticipate that the models will prove useful in exploring other static and dynamic features of the bacterial chromosome.

Does Prior Bariatric Surgery Improve Outcomes Following Total Joint Arthroplasty in the Morbidly Obese? A Meta-Analysis.

BACKGROUND: There remains a controversy regarding the risks in subsequent total joint arthroplasty (TJA) with and without previous bariatric surgery (BS). We performed a meta-analysis based on the current evidence-based study to determine the influences of prior BS on the short-term and long-term outcomes following TJA. METHODS: From the inception to July 2018, the EMBASE, PubMed, Web of Science, and Cochrane Library electronic databases were searched for all relevant English language trials. The primary outcome measures were complications and revision, whereas the secondary outcomes included length of stay and operative time. Short-term follow-up was defined as that from hospital discharge to 90 days, and long-term follow-up was defined as more than 1 year. RESULTS: A total of 9 studies with 38,728 patients were included. Overall, medical comorbidities were higher in the BS group compared with the control morbid obesity group before TJA. Our meta-analysis revealed that BS prior to TJA was associated with reduced short-term medical complications, length of stay, and operative time. However, BS did not reduce the short-term risks for superficial wound infection or venous thromboembolism, and the long-term risks for dislocation, periprosthetic infection, periprosthetic fracture, and revision. Subgroup analysis identified a significant reduction in the risk of short-term periprosthetic infection in the BS group after total knee arthroplasty, but not after total hip arthroplasty. CONCLUSION: BS prior to TJA was associated with partially improved short-term outcomes after TJA. However, BS did not improve the risks for long-term outcomes. Limited by relatively higher comorbidities burden, the short-term benefits of BS should be further revealed by high-quality, controlled study in the future.

Associations between patient clinical characteristics and the presence of cytomegalovirus DNA in the bronchoalveolar lavage fluid of children with recurrent wheezing.

BACKGROUND: This study aimed to investigate the occurrence of Cytomegalovirus (CMV) DNA in the Bronchoalveolar lavage fluid (BALF) of children with recurrent wheezing and to identify associations with certain patient clinical characteristics. METHODS: In this cross-sectional study, pediatric patients (age < 36 months) admitted to Soochow University Hospital with recurrent wheezing (≥ 4 episodes of wheezing per year) were enrolled in the study. Cytomegalovirus DNA from their BALF was detected by real-time PCR. Subpopulations of blood immunoglobulins and T lymphocytes were quantified. The clinical characteristics of patients with and without BALF CMV DNA were compared. Comparisons of non-normally distributed continuous variables between groups were made using the Mann-Whitney U-test. Comparisons of frequency distributions were made using the Chi-squared test. Spearman's rank correlation coefficient was used to evaluate correlations between the number of CMV DNA copies and continuous variables. RESULTS: A total of 111 patients aged 4 to 36 months (median 14.0 (IQR 8.0-22.0) months) were enrolled on to the study. Cytomegalovirus DNA was detected in 51.4% of patients (n = 111) with recurrent wheeze and was more prevalent among those aged 12 to 36 months with a positive modified asthma predictive index (mAPI) (n = 38, median 23.5 (IQR 19.7-31.2) months) than in those of the same age group with a negative mAPI (n = 25, median 15.0 (IQR 13.0-19.0) months) (57.9% vs. 20.0%, p = 0.003). Bronchoalveolar lavage fluid CMV DNA copy number [median 7560 (IQR 1200-71,150) copies/mL] was positively correlated with the duration of hospitalization (r = 0.33, p = 0.013), and negatively correlated with patient age (r = - 0.41, p = 0.002) and the percentage of BALF eosinophils (r = - 0.38, p = 0.004). CONCLUSIONS: CMV infection or reactivation in children with recurrent wheeze is associated with certain clinical characteristics, including younger age and lower levels of BALF eosinophils. Higher CMV DNA copy numbers were associated with a longer duration of hospitalization. Further studies are needed to address whether specific antiviral treatment could be beneficial for BALF CMV positive patients.

Retrospective Analysis of Thyroid Nodules: Thyroid Cancer Risk Factors in Suzhou, China.

BACKGROUND: Thyroid nodules are common, frequently discovered in clinical practice and the incidence has increased in recent decades. They are clinically important primarily due to their malignant potential, because 2 to 5% are malignant. Correct identification of the malignancy in thyroid nodules is a diagnostic challenge, leading to potentially unnecessary surgery in patients for whom final histology is benign. Because there is no accurate preoperative detection, it is very important to predict the risk of malignancy in patients with nodular thyroid disease. METHODS: The medical records of 405 patients who underwent surgery for nodular thyroid disease were retrospectively reviewed. Then clinical parameters and preoperative serum markers were compared between benign thyroid nodular disease and thyroid cancer groups. RESULTS: Younger than 40 years (OR 2.14, 95% CI 1.02 - 4.47, p = 0.044), preoperative TSH levels equal to or higher than 1.79 mIU/L (OR 1.76, 95% CI 1.05 - 2.95, p = 0.033), TgAb positivity (OR 2.59 95% CI 1.25 - 5.37, p = 0.01) and nodules less than or equal to 1 cm (OR 5.51, 95% CI 2.61 - 11.66, p < 0.001) were associated with increased risk of thyroid cancer in patients with thyroid nodules. CONCLUSIONS: The retrospective analysis suggests that younger patients with nodular thyroid disease cannot ignore the small size nodules, especially those with higher TSH levels and TgAb positivity.

Clinical Outcomes of Gap Balancing vs Measured Resection in Total Knee Arthroplasty: A Systematic Review and Meta-Analysis Involving 2259 Subjects.

BACKGROUND: The argument on the clinical effects between gap balancing (GB) and measured resection (MR) in total knee arthroplasty remains to be resolved. A systematic review and meta-analysis was performed to investigate which technique in total knee arthroplasty has better clinical effect. METHODS: A total of 20 studies involving 2259 cases were included in the meta-analysis. The primary outcome measure was Knee Society Score (KSS), whereas the secondary outcomes included other function assessment systems (eg, range of motion, Western Ontario and McMaster University Osteoarthritis Index), radiological outcomes (eg, femoral component rotation, total outliers), revision rate, complications (eg, infection, loosening, instability), and surgical time. RESULTS: The GB technique was associated with statistically significant increases in the primary outcomes of KSS-function in 1 year. However, a mean difference of 2.12 points was below the minimal clinically important difference of 6 points. No differences were found in the analyses of KSS-knee and KSS-function in any other follow-up periods. Secondary outcome assessments showed significant decreased surgical time (mean difference, 16.18; P < .00001) for MR. Although statistically significant difference in favor of GB was identified in total outliers (risk ratio, 1.72, P = .0004), the 2 techniques were comparable in range of motion, Western Ontario and McMaster University Osteoarthritis Index, femoral component rotation, complications, and revision rate. CONCLUSION: We conclude that both techniques can result in equivalent results when done properly, and each surgeon must understand the strengths and weaknesses of each technique.

The role of LGR5 and ALDH1A1 in non-small cell lung cancer: Cancer progression and prognosis.

The Leucine rich repeat containing G protein coupled receptor 5 (LGR5), may be a candidate marker of non-small cell lung cancer (NSCLC) cells with stem cell-like properties. Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of NSCLC stem cell markers. To identify the relationship of LGR5 and ALDH1A1 in NSCLC, we analyzed the expression of LGR5 and ALDH1A1 in NSCLC samples, and determined their clinical significance. We performed quantitative RT-PCR for LGR5 and ALDH1A1 expression in 24 NSCLC patients, and showed that LGR5 and ALDH1A1 mRNA were frequently increased in NSCLC tissues in comparison to that in adjacent normal tissues (p = 0.0005 and p < 0.0001, respectively). Besides, the expression of LGR5 and ALDH1A1 mRNA has a significant correlation (r = 0.416, P = 0.0483). The expression of LGR5 and ALDH1A1 in 109 NSCLC tumors and 50 adjacent normal tissues were detected by immunohistochemistry. Positive LGR5 and ALDH1A1 expression was defined in 28.4% and 41.3% of the NSCLC tumors, respectively. Further analysis indicated that 24 of these LGR5⁺ (24/31) samples expressed ALDH1A1(r = 0.3883, p < 0.0001), we also found co-localization of LGR5 and ALDH1A1 in tumor tissue samples. LGR5 and ALDH1A1 expression was significantly associated with higher pathological TNM stage of the disease (stage I + II and III + IV) (P = 0.0311 and p = 0.0221, respectively), the co-expression of LGR5 and ALDH1A1 was associated with nodal status (p = 0.0424). High expression of LGR5 or ALDH1A1 was related to poor prognosis (P = 0.0125 and p = 0.0410, respectively), and NSCLC patients with co-expression of LGR5 and ALDH1A1 had a poorer prognosis than the others (P = 0.0011). Both of them can be an independent risk factor of a poorer prognosis (P = 0.016 and P = 0.024, respectively). The expression of LGR5 and ALDH1A1 were closely associated with the tumorigenicity, metastasis and poor prognosis of NSCLC, and LGR5⁺ cells in NSCLC were likely to be the cancer cells with stem cell-like properties due to the significant correlation between LGR5 and ALDH1A1.