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Purpose: Transperineal (TP) multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (TBx) has been shown to detect more clinically significant (cs) prostate cancer (PCa) than standard template biopsies (SBx). Current data supports the inclusion of both TBx and SBx in obtaining an optimal csPCa detection rate. We compared csPCa detection rates in patients with different prostate volumes to examine the benefit of performing TBx in smaller prostates through the TP approach., Methods: We identified all men who with suspicious lesions on mpMRI and underwent TP TBx (3-core) and concomitant SBx (20-core) in our single hospital from September 2019 to February 2021. Clinical, MRI and biopsy pathological characteristics were evaluated and compared between TBx and SBx. Grade group 2 or greater prostate adenocarcinoma was defined as csPCa., Results: Three hundred and one (n = 301) men were included. The median prostate volume by MRI was 45 ml. The patients were divided by prostate volume into three groups: ≤30ml group (19.9%), >30 to ≤45 ml group (31.3%) and >45ml group (48.8%). Patients in the ≤30ml group showed significantly higher frequency of combined (both TBx and/or SBx) csPCa detection rate (65.0%) than patients in the >45ml group (39.5%) but similar frequency to the >30 to ≤45 ml group (54.2%,). By TBx only (55.0% vs 27.9%) or by SBx only (56.7% vs. 34.0%), patients in the ≤30ml group consistently showed significantly higher rates of csPCa detection than patients in the >45 ml group. In the ≤30ml group, the detection rate of csPCa was comparable by TBx, SBx or when combined. Four of 6 csPCa cases missed by TBx but detected by SBx were present at the base location., Conclusion: Our data suggest that performing TBx with limited additional cores may potentially achieve the same csPCa detection rate as the combined SBx and TBx in smaller prostates., Competing Interests: Conflict of interest The authors declare no conflict of interest, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To examine associations between adverse childhood experiences (ACEs) and age-specific insufficient sleep duration (ISD) in American youth., Methods: Data from the 2016-2017 National Survey of Children's Health, a sample of 46,209 youth ages 6 to 17 were analyzed. The main outcome was sleep duration that did not meet the recent recommendations of the American Academy of Sleep Medicine. Nine types of ACEs, as well as a cumulative count of ACEs, were examined as independent variables in unadjusted and adjusted logistic regression models., Results: Approximately half of U.S. children and adolescents (ages 6-17) experienced at least one ACE and a third did not get sufficient sleep. Among those exposed to any ACE, 40.3% had ISD. Seven of the 9 ACEs examined were significantly associated with a 20% to 60% increase in odds of not getting sufficient sleep (adjusted ORs between 1.2 and 1.6). Children exposed to 2 or more ACEs were nearly twice as likely as those exposed to no ACE to have ISD (adjusted OR = 1.7, 95% CI: 1.5-1.9). Moreover, each individual ACE, except parental death was significantly associated with more than 1 hour less sleep than recommended., Conclusions: This study reports the association of specific and cumulative ACEs with ISD in a nationally representative sample of American youth. The study findings underscore the importance of screening for both ACEs and insufficient sleep during primary care encounters and addressing potential sleep problems in those exposed to ACEs., (Copyright © 2022 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Ribose-5-phosphate isomerase A (RPIA) regulates tumorigenesis in liver and colorectal cancer. However, the role of RPIA in lung cancer remains obscure. Here we report that the suppression of RPIA diminishes cellular proliferation and activates autophagy, apoptosis, and cellular senescence in lung cancer cells. First, we detected that RPIA protein was increased in the human lung cancer versus adjust normal tissue via tissue array. Next, the knockdown of RPIA in lung cancer cells displayed autophagic vacuoles, enhanced acridine orange staining, GFP-LC3 punctae, accumulated autophagosomes, and showed elevated levels of LC3-II and reduced levels of p62, together suggesting that the suppression of RPIA stimulates autophagy in lung cancer cells. In addition, decreased RPIA expression induced apoptosis by increasing levels of Bax, cleaved PARP and caspase-3 and apoptotic cells. Moreover, RPIA knockdown triggered cellular senescence and increased p53 and p21 levels in lung cancer cells. Importantly, RPIA knockdown elevated reactive oxygen species (ROS) levels. Treatment of ROS scavenger N-acetyl-L-cysteine (NAC) reverts the activation of autophagy, apoptosis and cellular senescence by RPIA knockdown in lung cancer cells. In conclusion, RPIA knockdown induces ROS levels to activate autophagy, apoptosis, and cellular senescence in lung cancer cells. Our study sheds new light on RPIA suppression in lung cancer therapy.

Background: Disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate and azathioprine, are commonly used to treat rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Blood-test safety monitoring is mainly undertaken in primary care. Normal blood results are common., Aim: To determine the frequency and associations of persistently normal blood tests in patients with RA prescribed methotrexate, and patients with IBD prescribed azathioprine., Design and Setting: Two-year retrospective study of a cohort taken from an electronic pseudonymised primary care/laboratory database covering >1.4 million patients across Hampshire, UK., Method: Patients with RA and IBD, and associated methotrexate and azathioprine prescriptions, respectively, were identified. Tests and test thresholds recommended by the National Institute for Health and Care Excellence were applied. Persistent normality was defined as no abnormalities of any tests nor alanine aminotransferase (ALT), white blood count (WBC), neutrophils, and estimated glomerular filtration rate (eGFR) individually. Logistic regression was used to identify associations with test normality., Results: Of 702 265 adults, 7102 had RA and 8597 had IBD. In total, 3001 (42.3%) patients with RA were prescribed methotrexate and 1162 (13.5%) patients with IBD were prescribed azathioprine; persistently normal tests occurred in 1585 (52.8%) and 657 (56.5%) of the populations, respectively. In patients with RA on methotrexate, 585 (19.5%) had eGFR, 219 (7.3%) ALT, 217 (7.2%) WBC, and 202 (6.7%) neutrophil abnormalities. In patients with IBD on azathioprine, 138 (11.9%) had WBC, 88 (7.6%) eGFR, 72 (6.2%) ALT, and 65 (5.6%) neutrophil abnormalities. Those least likely to have persistent test normality were older and/or had comorbidities., Conclusion: Persistent test normality is common when monitoring these DMARDs, with few hepatic or haematological abnormalities. More stratified monitoring approaches should be explored., (© The Authors.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pain and inflammation. NSAID complications include acute kidney injury (AKI), causing burden to patients and health services through increased morbidity, mortality, and hospital admissions., Aim: To measure the extent of NSAID prescribing in an adult population, the degree to which patients with potential higher risk of AKI were exposed to NSAIDs, and to quantify their risk of AKI., Design & Setting: Retrospective 2-year closed-cohort study., Method: A retrospective cohort of adults was identified from a pseudonymised electronic primary care database in Hampshire, UK. The cohort had clinical information, prescribing data, and complete GP- and hospital-ordered biochemistry data. NSAID exposure (minimum one prescription in a 2-month period) was categorised as never, intermittent, and continuous, and first AKI using the national AKI e-alert algorithm. Descriptive statistics and logistic regression were used to explore NSAID prescribing patterns and AKI risk., Results: The baseline population was 702 265. NSAID prescription fell from 19 364 (2.8%) to 16 251 (2.4%) over 2 years. NSAID prescribing was positively associated with older age, female sex, greater socioeconomic deprivation, and certain comorbidities (diabetes, hypertension, osteoarthritis, and rheumatoid arthritis) and negatively with cardiovascular disease (CVD) and heart failure. Among those prescribed NSAIDs, AKI was associated with older age, greater deprivation, chronic kidney disease (CKD), CVD, heart failure, diabetes, and hypertension., Conclusion: Despite generally good prescribing practice, NSAID prescribing was identified in some people at higher risk of AKI (for example, patients with CKD and older) for whom medication review and NSAID deprescribing should be considered., (Copyright © 2022, The Authors.)

Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1-CDK2 interface inhibitors were used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with taxol treatment, these two inhibitors can advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by taxol in TNBC cells, thereby improving sensitivity to taxol in these cell lines. Importantly, the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. Overall, the resistance to the anti-proliferative effects induced by taxol can be significantly reduced by the combined treatment with selective CRIF1-CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment.

Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD + )-dependent histone deacetylases. Since SIRTs have different subcellular locations and different preferences for deacylation activity, SIRTs are not only highly gaining significance in biological functions but also implications in human diseases. Therefore, it is valuable to establish a high-throughput screening method for the rapid and accurate discovery of SIRT modulators. In this study, we designed and synthesized small molecules 4a-d as fluorogenic probes based on the different lysine substrates of SIRTs, which can be recognized and catalyzed by SIRTs and then spontaneous intramolecular transesterification can give the fluorescence. We have undertaken a comprehensive study of these fluorogenic probes with different SIRTs for assay optimization, validation, kinetics, parameters, and applications of high-throughput screening formats. We envision that these probes will provide useful and powerful tools for the highly efficient discovery of more SIRT inhibitors.

Purpose: Transperineal (TP) prostate biopsy provides an effective approach to prostate cancer (PCa) detection. Although transrectal targeted biopsy has been well described, the specific advantage of the standard TP template or TP targeted biopsy using multiparametric (mp) magnetic resonance imaging (MRI)-ultrasound (US) fusion remains less understood and without consensus., Materials and Methods: We identified all men who underwent a transperineal standard 20-core template in addition to a targeted biopsy with mpMRI-US fusion-guided software from September 2019 to February 2021. We assessed and compared clinical, MRI and biopsy characteristics between standard TP template and fusion targeted biopsies., Results: A total of 301 men underwent TP fusion biopsy during the study period. Target lesions on MRI were sampled with 3 targeted cores per patient (IQR 3-4). The overall cancer detection rate was 74.1% and 63.5% by standard template and targeted biopsy, respectively, of which 52.5% and 59.7% were clinically significant (cs) PCa. Combined csPCa detection rate was 62.2%. Of 176 cases with a cancer diagnosis by both biopsy methods, 18.8% were upgraded with targeted biopsies while 18.2% were upgraded with template biopsies., Conclusions: In men with suspicious lesions on mpMRI, TP MRI fusion-guided biopsies combined with standard template provide a higher overall cancer detection rate and higher detection rate of csPCa than the standard template or targeted biopsy alone. In the setting of a suspicious mpMRI prostate lesion, targeted plus standard template should be included as part of the TP biopsy procedure.

Epithelial ovarian cancer, widely suggested as endocrine-related cancer, yields a low survival rate among patients. Despite intensive research for nearly a century, there have been no fundamental advances in treatment. The reductive 17β-HSD7 is a special enzyme possessing a remarkable dual activity in both the biosynthesis of the most potent estrogen estradiol and the inactivation of the most active androgen dihydrotestosterone. In the present study, we observed over-expression of 17β-HSD7 in EOC cells such as OVCAR-3 and SKOV-3, in agreement with integrative data analysis demonstrating overexpression of 17β-HSD7 in EOC tissues. After knocking down 17β-HSD7, SKOV-3 cell proliferation decreased by 29%, cell arrest in the G2/M phase increased by 25% with cyclin B1/Cdk1 inhibition. Inhibition of 17β-HSD7 in EOC cells triggered negative feedback of its expression, which further decreased the estradiol level to more than 60% under the experimental condition. Such inhibition increased the dihydrotestosterone level to many times higher and suppressed cell proliferation. Thus, 17β-HSD7 is demonstrated to be a promising target for the endeavor against the malignant ovarian cancer, a menace in human life. The targeting of such an enzyme thus provides exceptional scientific importance., Competing Interests: None., (AJCR Copyright © 2021.)

Objective: To analyze the pathogenic bacteria and epidemiological characteristics in children with respiratory tract infection in Tianjin area. Methods: Retrospective case analysis was performed on 2 392 hospitalized children in the wards of respiratory diseases, intensive care unit and special care ward of Tianjin Children's Hospital from June 2018 to May 2019. Thirteen pathogenic bacteria in deep sputum and bronchoalveolar lavage fluid samples were detected by loop-mediated isothermal amplification. The laboratory data and clinical characteristics of the infected children were analyzed, and the comparison between groups was performed by t test or χ 2 test. Results: Among 2 392 cases, 1 407 were males and 985 females. There was no significant difference in the detection rate between males and females (72.5% (1 020/1 407) vs .74.2% (731/985), χ 2 =0.87, P =0.35). A total of 1 751 strains and 12 kinds of positive respiratory pathogens were detected, with a detection rate of 73.2%. Among them, 913 (38.2%) strains were Mycoplasma pneumoniae (MP), 514 (21.5%) were Streptococcus pneumoniae (Sp), 381 (15.9%) were Methicillin-resistant Staphylococcus aureus (MRSA) and 279 (11.7%) were Hemophilus influenzae (Hi). There was significant difference in the detection rate of pathogens among different age groups (χ²=83.67, P< 0.01). The positive rate of alveolar lavage fluid group was higher than that of deep sputum fluid group [81.6% (614/752) vs. 69.3% (1 137/1 640), χ 2 =39.89, P <0.01]. The length of hospital stay of children infected with different pathogens was significantly different (all P <0.01). There was significant difference in duration of fever among children infected with different pathogens (χ²=228.69,103.56, 3.96, 27.38,24.50,41.66, all P <0.05). There were 63 (7.7%) cases of atelectasis, 260 (31.9%) cases of pleurisy and 120 (14.7%) cases of pleural effusion in MP children. Children with Sma were most likely to involve the heart system (2/9), and children with Eco infection had a higher incidence of complications such as those of blood (3/19), urinary (2/19), digestive systems(4/19), systemic inflammatory response syndrome and sepsis (1/19). Conclusions: The main bacterial pathogens of respiratory tract infection in children in Tianjin were MP, Sp, MRSA and Hi. It is suggested that clinicians should not only pay attention to the respiratory symptoms of children, but also pay attention to the complications caused by bacterial pathogen infection, so as to prevent the deterioration of the disease and improve the prognosis.

Perineural invasion (PNI) on biopsy is associated with adverse features in prostate cancer (PCa). Transrectal multiparametric magnetic resonance imaging (MRI)-targeted biopsy (TBx) has shown to detect higher presence of PNI than standard template biopsy (SBx). Transperineal biopsy provides effective cancer detection with lower complications than the transrectal approach. We compared PNI detection efficiency between SBx and TBx through transperineal approach. We identified patients with PCa who underwent transperineal TBx and concomitant standard 20-core template SBx from September 2019 to February 2021. Clinical, MRI imaging and biopsy characteristics were evaluated and compared between TBx and SBx. Two hundred thirty-eight patients with PCa underwent concomitant transperineal SBx and TBx procedures. Combined PNI+ (SBxPNI+ and/or TBxPNI+) was identified in 77 of 238 (32.4%) patients. SBx detected 23.9% PNI-positive patients and TBx detected 19.3% PNI-positive patients of all patients with PCa. Patients with PNI were with significantly different clinicopathological characteristics than patients without PNI. Although significantly more positive PCa cores and higher positive PCa core rate were found in the SBx method, patients with SBxPNI+ only shared similar features as TBxPNI+only patients. Of 176 cases with both SBxPCa and TBxPCa, TBx could detect 19 (15.1%) more PNI cases than SBx while SBx could detect 24 (18.3%) more PNI cases than TBx. Multiparametric MRI fusion-targeted biopsy in combination with template biopsy through transperineal approach achieved PNI detection rate over 30% of PCa cases. The increased PNI detection may improve the model to select active surveillance candidates in clinical practice., (Copyright © 2021. Published by Elsevier Inc.)

Human 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7), a special multifunctional enzyme, activates the estrogen estrone while inactivating the potent androgen dihydrotestosterone. Thus, this enzyme has become an ideal target for hormone-dependent breast cancer treatment, as its inhibition leads to estradiol reduction and dihydrotestosterone restoration. However, a particular concern has arisen related to an additional role in cholesterol biosynthesis, as inhibition of the enzyme may lead to undesirable side effects. Our findings demonstrate that the available enzyme inhibitors are non-competitive. Among these, many such as INH81, are specific toward sex-hormone conversion, whereas others represented by 4-bromo-ethynylestradiol, are more specific for zymosterone reduction occurring during cholesterol biosynthesis. The binding of non-competitive inhibitors does not affect the substrate binding on the enzyme. This is the first demonstration of non-competitive inhibitors acting selectively on different catalyses, thereby facilitating inhibitor uses for breast cancer treatment. We aim to quickly communicate the novel results., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cancer patients often exhibit chemotherapy-associated changes in serum lipid profiles, however, their prognostic value before and after adjuvant chemotherapy on survival among non-small-cell lung cancer (NSCLC) patients is unknown., Methods: NSCLC patients undergoing radical resection and subsequent adjuvant chemotherapy from 2013 to 2017 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Fasted serum lipid levels were measured before and after chemotherapy. The optimal lipid cut-off values at baseline and fluctuation were determined using X-tile™. The fluctuations in serum lipid levels and disease-free survival (DFS) were assessed., Results: Serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, apolipoprotein (Apo) A-I, and ApoB all significantly increased after adjuvant chemotherapy. X-tile determined 1.52 mmol/L of HDL-C and 0.74 g/L of ApoB as the optimal cut-off values before chemotherapy. Patients with HDL-C ≥ 1.52 mmol/L (median DFS: not reached vs. 26.30 months, P = 0.0005) and a decreased HDL-C level after adjuvant chemotherapy (median DFS: 80.43 vs. 26.12 months, P = 0.0204) had a longer DFS. An HDL-C level that increased by ≥ 0.32 mmol/L after chemotherapy indicated a worse DFS. A high baseline ApoB level were associated with a superior DFS. In the univariate analysis and the multivariate Cox analyses, a high baseline HDL-C level and a HDL-C reduction after adjuvant chemotherapy were independent indicators for superior DFS. High baseline HDL-C was related to N0-1 stage (χ 2  = 6.413, P = 0.011), and HDL-C fluctuation was significantly correlated with specific chemotherapy regimens (χ 2  = 5.002, P = 0.025)., Conclusions: Adjuvant chemotherapy increased various lipid levels in resected NSCLC patients. A higher HDL-C level before chemotherapy and a reduced HDL-C level after adjuvant chemotherapy were independent predictors of longer DFS in patients with curable NSCLC., (© 2021. The Author(s).)

Objectives: To study the expression of adipokines in children with primary nephrotic syndrome (PNS) before and after treatment and its correlation with blood lipids, as well as the role of adipokines in PNS children with hyperlipidemia., Methods: A total of 90 children who were diagnosed with incipient PNS or recurrence of PNS after corticosteroid withdrawal for more than 6 months were enrolled as subjects. Thirty children who underwent physical examination were enrolled as the control group. Venous blood samples were collected from the children in the control group and the children with PNS before corticosteroid therapy (active stage) and after urinary protein clearance following 4 weeks of corticosteroid therapy (remission stage). ELISA was used to measure the levels of adipokines. An automatic biochemical analyzer was used to measure blood lipid levels., Results: Compared with the control group, the children with PNS had a significantly lower level of omentin-1 in both active and remission stages, and their level of omentin-1 in the active stage was significantly lower than that in the remission stage ( P <0.001). For the children with PNS, the level of chemerin in the active stage was significantly higher than that in the remission stage, and the children with PNS in the active stage had a significantly higher level of chemerin than the control group ( P <0.001). For the children with PNS, atherogenic index of plasma, atherogenic coefficient (AC), castelli risk index-1 (CRI-1), castelli risk index-2 (CRI-2), and non-high-density lipoprotein in the active stage were significantly higher than those in the remission stage ( P <0.001), and these indices in the children with PNS in the active stage were significantly higher than those in the control group ( P <0.001). The children with PNS in the remission stage had significantly higher atherogenic index of plasma, AC, CRI-1, and non-high-density lipoprotein than the control group ( P <0.001). Compared with the control group, the children with PNS in the remission stage had significantly higher serum levels of total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, apolipoprotein B, and apolipoprotein A ( P <0.01). In the children with PNS, the ratio of omentin-1 before and after corticosteroid therapy was positively correlated with that of high-density lipoprotein, 24-hour urinary protein excretion, and high-density lipoprotein/apolipoprotein A before and after treatment, and it was negatively correlated with the ratio of AC and CRI-1 before and after treatment ( P <0.05). The PNS children with low omentin-1 levels in the active stage had significantly higher levels of CRI-1, CRI-2, AC, and apolipoprotein B/apolipoprotein A ratio than those with high omentin-1 levels ( P <0.05)., Conclusions: Omentin-1 may be associated with disease activity, dyslipidemia, and proteinuria in children with PNS. Blood lipid ratios may be more effective than traditional blood lipid parameters in monitoring early cardiovascular risk in children with PNS.

Background: Visceral pleural invasion (VPI) with PL1 or PL2 increases the T classification from T1 to T2 in non-small cell lung cancers (NSCLCs) ≤ 3 cm. We proposed a modified T classification based on VPI to guide adjuvant therapy., Research Question: Is it reasonable to upstage PL1-positive cases from T1 to T2 for NSCLCs ≤ 3 cm?, Study Design and Methods: In total, 1,055 patients with resected NSCLC were retrospectively included. Tumor sections were restained with hematoxylin and eosin stain and Victoria blue elastic stain for the elastic layer. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Subgroup analysis and a Cox proportional hazards model were used to further determine the impact of VPI on survival., Results: The extent of VPI was diagnosed as PL0 in 824 patients, PL1 in 133 patients, and PL2 in 98 patients. The 5-year DFS rates of patients with PL0, PL1, and PL2 were 62.6%, 60.2%, and 28.8% (P < .01), whereas the corresponding 5-year OS rates were 78.6%, 74.4%, and 50.0% (P < .01), respectively. As predicted, the DFS and OS of patients with PL2 were much worse than those of patients with PL0 (P < .01) and PL1 (P < .01). However, both the DFS and OS of patients with PL0 and PL1 were comparable (DFS: P = .198; OS: P = .150). For node-negative cases, the DFS and OS of patients with PL0 and PL1 were also comparable (DFS: P = .468; OS: P = .388), but patients with PL2 had much worse DFS and OS than patients with PL0 (P < .01) and PL1 (P < .01). Multivariable analyses suggested that PL2, together with node positivity and poor cell differentiation, was an independent adverse prognostic factor., Interpretation: In NSCLCs ≤ 3 cm, tumors with PL1 should remain defined as T1, not T2. Overtreatment by adjuvant chemotherapy in node-negative NSCLCs ≤ 3 cm might be avoided in PL1 cases., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Wnt signalling pathways have been the focus of intense research activity for decades due to their fundamental role in skeletal and dental development. Wntless, an exclusive chaperone protein for the exocytotis of Wnt ligands, was identified in 2006. In the last decade, the molecular biological studies of Wntless and its genetic studies in human and mice have highlighted the importance of this protein in mineralised tissues, including bone, cartilage and teeth. This article reviews recent developments and discrepancies in the role of Wntless in skeletal and dental development based on mutant phenotypes, as well as the underlying mechanism involved in its molecular and physiological regulation. We conclude that, though some controversial phenotypes exist due to different Cre line resources, Cre recombinase activity and detection time points, Wntless undeniably exerts a context- and stage-dependent regulatory function during the development and homeostasis of both skeletal and dental tissue.

The global spread of COVID-19 constitutes the most dangerous pandemic to emerge during the last one hundred years. About seventy-nine million infections and more than 1.7 million death have been reported to date, along with destruction of the global economy. With the uncertainty evolved by alarming level of genome mutations, coupled with likelihood of generating only a short lived immune response by the vaccine injections, the identification of antiviral drugs for direct therapy is the need of the hour. Strategies to inhibit virus infection and replication focus on targets such as the spike protein and non-structural proteins including the highly conserved RNA-dependent-RNA-polymerase, nucleotidyl-transferases, main protease and papain-like proteases. There is also an indirect option to target the host cell recognition systems such as angiotensin-converting enzyme 2 (ACE2), transmembrane protease, serine 2, host cell expressed CD147, and the host furin. A drug search strategy consensus in tandem with analysis of currently available information is extremely important for the rapid identification of anti-viral. An unprecedented display of cooperation among the scientific community regarding SARS-CoV-2 research has resulted in the accumulation of an enormous amount of literature that requires curation. Drug repurposing and drug combinations have drawn tremendous attention for rapid therapeutic application, while high throughput screening and virtual searches support de novo drug identification. Here, we examine how certain approved drugs targeting different viruses can play a role in combating this new virus and analyze how they demonstrate efficacy under clinical assessment. Suggestions on repurposing and de novo strategies are proposed to facilitate the fight against the COVID-19 pandemic., (Copyright © 2021. Published by Elsevier Masson SAS.)

Objective: To investigate the effects and mechanism of eleutheroside E on the growth of human hypertrophic scar fibroblasts (Fbs). Methods: The experimental research method was used. The hypertrophic scar tissue was collected from 6 patients with hypertrophic scar (1 male and 5 females, aged 20 to 51 (37±8) years) admitted to General Hospital of Northern Theater Command, from October 2018 to March 2019. The third to seventh passages of human hypertrophic scar Fbs were cultured for later experiments. Cells were divided into normal saline group, 100 μmol/L eleutheroside E group, 200 μmol/L eleutheroside E group, and 400 μmol/L eleutheroside E group, and normal saline, eleutheroside E at the final molarity of 100, 200, and 400 μmol/L were added to cells in the corresponding groups. Cells were collected and divided into small interfering RNA (siRNA)-negative control alone group, siRNA-thrombospondin 1 (THBS1) alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group. Cells in siRNA-negative control alone group and siRNA-negative control + 400 μmol/L eleutheroside E group were transfected with siRNA-negative control, cells in siRNA-THBS1 alone group and siRNA-THBS1 + 400 μmol/L eleutheroside E group were transfected with siRNA-THBS1. At 24 h after transfection, cells in siRNA-negative control alone group and siRNA-THBS1 alone group were added with normal saline, and cells in siRNA-negative control + 400 μmol/L eleutheroside E group and siRNA-THBS1 + 400 μmol/L eleutheroside E group were added with eleutheroside E at the final molarity of 400 μmol/L. At 0 (immediately), 12, 24, 36, and 48 h after treatment, the cell proliferation activity (expressed as absorbance value) was detected by thiazolyl blue assay. Cells were divided into normal saline group, 200 μmol/L eleutheroside E group, 400 μmol/L eleutheroside E group, siRNA-negative control alone group, siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group. The corresponding treatments in each group were the same as before. At 24 h after treatment, the apoptosis was observed by Hoechst 33258 staining. Cells were collected and divided into normal saline group, 100 μmol/L eleutheroside E group, 200 μmol/L eleutheroside E group, 400 μmol/L eleutheroside E group, siRNA-negative control alone group, siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group. The corresponding treatments in each group were the same as before. At 24 h after treatment, the THBS1 protein level of cells was detected by Western blotting. The number of sample in each group was all 3 at each time point. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, independent sample t test, and Bonferroni correction. Results: At 0 h after treatment, the absorbance values of cells in normal saline group, 100 μmol/L eleutheroside E group, 200 μmol/L eleutheroside E group, and 400 μmol/L eleutheroside E group were similar ( P > 0.05). At 12, 24, 36, and 48 h after treatment, the absorbance values of cells in 100 μmol/L eleutheroside E group, 200 μmol/L eleutheroside E group, and 400 μmol/L eleutheroside E group were significantly lower than those of normal saline group ( t = 7.64, 28.94, 13.69, 5.87, 6.96, 22.83, 14.75, 11.52, 21.09, 20.15, 29.52, 23.12, P < 0.05 or P < 0.01). At 0 h after treatment, the absorbance values of cells in siRNA-negative control alone group, siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group were similar ( P > 0.05). At 12, 24, 36, and 48 h after treatment, the absorbance values of cells in siRNA-THBS1 alone group and siRNA-negative control + 400 μmol/L eleutheroside E group were significantly lower than those in siRNA-negative control alone group ( t = 7.14, 44.87, 20.67, 40.98, 9.26, 11.08, 15.33, 20.56, P < 0.05 or P < 0.01); the absorbance values of cells in siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group were similar ( P > 0.05). Compared with that in normal saline group, the numbers of apoptotic cells in 200 μmol/L eleutheroside E group and 400 μmol/L eleutheroside E group were increased at 24 h after treatment. At 24 h after treatment, compared with that in siRNA-negative control alone group, the numbers of apoptotic cells in siRNA-THBS1 alone group and siRNA-negative control + 400 μmol/L eleutheroside E group were increased, while the numbers of apoptotic cells in siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group were similar. At 24 h after treatment, the protein levels of THBS1 of cells in 100 μmol/L eleutheroside E group, 200 μmol/L eleutheroside E group, and 400 μmol/L eleutheroside E group (0.87±0.12, 0.38±0.07, 0.20±0.09) were significantly lower than 1.83±0.17 in normal saline group ( t = 16.61, 16.17, 17.29, P < 0.01). At 24 h after treatment, the protein levels of THBS1 of cells in siRNA-THBS1 alone group and siRNA-negative control + 400 μmol/L eleutheroside E group (0.61±0.07, 0.58±0.07) were significantly lower than 1.86±0.07 in siRNA-negative control alone group ( t = 71.06, 83.80, P < 0.01), and the protein levels of THBS1 of cells siRNA-THBS1 alone group, siRNA-negative control + 400 μmol/L eleutheroside E group, and siRNA-THBS1 + 400 μmol/L eleutheroside E group (0.63±0.11) were similar ( P > 0.05). Conclusions: Eleutheroside E can inhibit the growth of human hypertrophic scar Fbs by down-regulating the expression of THBS1.

Rapid tooling technology (RTT) provides an alternative approach to quickly provide wax injection molds for the required products since it can reduce the time to market compared with conventional machining approaches. Removing conformal cooling channels (CCCs) is the key technology for manufacturing injection mold fabricated by rapid tooling technology. In this study, three different kinds of materials were used to fabricate CCCs embedded in the injection mold. This work explores a technology for rapid development of injection mold with high cooling performance. It was found that wax is the most suitable material for making CCCs. An innovative method for fabricating a large intermediary mold with both high load and supporting capacities for manufacturing a large rapid tooling using polyurethane foam was demonstrated. A trend equation for predicting the usage amount of polyurethane foam was proposed. The production cost savings of about 50% can be obtained. An optimum conformal cooling channel design obtained by simulation is proposed. Three injection molds with different cooling channels for injection molding were fabricated by RTT. Reductions in the cooling time by about 89% was obtained. The variation of the results between the experiment and the simulation was investigated and analyzed.

COPD remains largely undiagnosed or is diagnosed late in the course of disease. We report findings of a specialist outreach programme to identify undiagnosed COPD in primary care. An electronic case-finding algorithm identified 1602 at-risk patients from 12 practices who were invited to attend the clinic. Three hundred and eighty-three (23.9%) responded and 288 were enrolled into the study. Forty-eight (16.6%) had undiagnosed mild and 28 (9.7%) had moderate airway obstruction, meeting spirometric diagnostic criteria for COPD. However, at 12 months only 8 suspected COPD patients (10.6%) had received a diagnostic label in their primary care record. This constituted 0.38% of the total patient population, as compared with 0.31% of control practices, p = 0.306. However, if all patients with airway obstruction received a coding of COPD, then the diagnosis rate in the intervention group would have risen by 0.84%. Despite the low take-up and diagnostic yield, this programme suggests that integrated case-finding strategies could improve COPD recognition.

This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To identify the potential indicators for higher-risk disease and poor outcome in younger prostate cancer (PCa) patients (age ≤ 50) who had undergone radical prostatectomy (RP) in the prostate-specific antigen (PSA) era., Materials and Methods: A total of 186 PCa cases of age ≤ 50 who underwent RP between 2003 and 2010 at our center were included for study. High-risk disease after RP was defined as cases with pre-PSA ≥ 20 ng/ml and/or Gleason score (GS) ≥ 4 + 3 and/or pT stage ≥ 3. The poor outcome group was defined as cases with biochemical recurrence (BCR) and/or metastasis (Mets) and/or all-cause death. Multivariate logistic regression models were performed to identify independent risk factors for both high-risk disease and poor outcome., Results: Among 186 younger PCa patients aged ≤ 50, 36 cases (19.5%) had high-risk disease and 24 cases (12.9%) had poor outcome. The presence of biopsy perineural invasion (BxPNI) was significantly associated with high-risk disease and showed a trend to correlate with worse outcome in univariate analysis. On multivariate logistic regression analysis, BxPNI was shown to be a significant independent risk factor with covariate of D'Amico for poor outcome ( p  = 0.047) and an independent risk factor with covariate of BxGPC for high-risk PCa excepting the variables to define high-risk disease ( p  = 0.013). Prognostically, cases with BxPNI showed a poor BCR-free survival in univariate analysis but did not reach significance ( p  = 0.063)., Conclusion: Our results show that BxPNI could be considered as a risk classification factor to identify the best candidates among younger PCa patients for further treatment and may also be used for developing active surveillance (AS) selection criteria for younger PCa patients.

Objective: The objective of this study was to evaluate the impact of the anterior/posterior status of positive surgical margin (PSM) on long-term outcomes after radical prostatectomy for prostate cancer., Patients and Methods: We included 391 consecutive PSM patients after radical prostatectomy between 1993 and 2007 excluding cases with multiple location PSM or lack of anterior/posterior status data. The oncologic impact of anterior-PSM and posterior-PSM were examined by Kaplan-Meier analysis and the Cox proportional hazards model., Results: There were 115 cases (29.4%) with apex-PSM, 257 cases (65.7%) with peripheral PSM, and 19 cases (4.9%) with bladder neck PSM. Among the 257 peripheral PSM cases, 58 cases (22.6%) were with anterior-PSM, 174 cases (67.7%) were with posterior-PSM, and 25 cases (9.7%) were with both anterior and posterior PSM. Over a median follow-up of 12.6 years, patients with anterior-PSM, especially those with low to intermediate Gleason score (≤7), showed a biochemical recurrence (BCR) prognosis similar to those with apex-PSM. In contrast, patients with posterior-PSM showed significantly higher BCR risk on both univariate and multivariate analyses when compared with those with apex-PSM. No impact on metastasis-free survival or overall survival was observed., Conclusions: In our study, we found that prostate cancer patients with anterior-PSM showed a more favorable BCR prognosis similar to those with apex-PSM when comparing to patients with posterior-PSM. Our study results may help physicians to choose different treatment options for patients diagnosed with different PSM status including considering further adjuvant treatment for patients with posterior-PSM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The surface modification of two-dimensional (2D) nanocontainers with versatile chemical functionalities offers enormous advantages in medicine owing to their altered physicochemical properties. In this study, we demonstrate the fabrication of surface-functionalized layered double hydroxides (LDHs) towards their use as effective intestinal bile acid sequestrants. To demonstrate these aspects, the LDHs are initially modified with an amino silane, N 1 -(3-trimethoxysilylpropyl) diethylenetriamine (LDHs-N3),which, on the one hand, subsequently used for the fabrication of the dendrimer by repetitive immobilization of ethylene diamine using methyl acrylate as a spacer. On the other hand, these surface-functionalized LDHs are wrapped with an anionic enteric co-polymer to not only prevent the degradation but also increase the stability of these 2D nanoplates in an acidic environment of the stomach to explore the in vivo efficacy. In vitro cholic acid adsorption results showed that these surface-functionalized LDHs displayed tremendous adsorption ability of bile salt. Consequently, the bile salt adsorption results in vivo in mice confirmed that the enteric polymer-coated diethylenetriamine silane-modified LDHs, resulting in the reduced cholesterol by 8.2% in the high fat diet-fed mice compared to that of the oil treatment group with augmented 28% of cholesterol, which gained weight by 6.7% in 4 weeks. Notably, the relative organ (liver and kidney) weight analysis and the tissue section of histology results indicated that the modified LDHs showed high biocompatibility in vivo. Together, our findings validate that these surface-functionalized 2D nanoplates have great potential as effective intestinal bile acid sequestrants., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Perineural invasion (PNI) after radical prostatectomy (RP) is a common feature of prostate cancer (PCa) and has been associated with unfavorable tumor characteristics. However, its prognostic relevance is controversial. In this study, we evaluated the impact of both PNI status (PNI+ versus PNI-) and quantified number of PNI focus on the long-term prognosis of biochemical recurrence (BCR) after RP. After reevaluating PNI of a total of 721 patients with localized PCa who underwent RP at our institution between 2000 and 2002, we examined associations between PNI status or PNI focus number and clinicopathological factors including tumor stage, Gleason score, margin status, tumor location, preoperative prostate specific antigen, age, prostate weight as well as BCR outcome. PNI was present in 530 of 721 cases (73.5%) of the RP specimens and was associated with more aggressive disease. BCR occurred in 19.4% of all patients within a median follow-up period of 8.5 years. PNI+ status was associated with poor BCR prognosis in univariate analysis but lost in multivariate analysis. Based on the number of PNI focus, PNI was further divided into 2 distinct group: PNI+ a (≤3) and PNI+ b (>3). In a multivariate Cox regression model, PNI+ b (>3) was identified as an independent BCR prognostic factor. Quantification of PNI focus number beside the dichotomized status recording will not only provide more detailed information but also be a novel prognostic indicator for risk stratification. Further external validation will be needed for an optimal cut-off value of the PNI focus number. Our findings will help further research on the relevance of PNI in the pretreatment setting and support ongoing efforts to understand its role of cancer progression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: With the rapid increase in younger age prostate cancer (PCa) patients, the impact of younger age on decision-making for PCa treatment needs to be revaluated in the new era., Materials and Methods: A systematic literature search was performed using PubMed, EMBASE, and Web of Science up to October 2019 to identify the eligible radical prostatectomy (RP) studies focusing on understanding the impact of age on clinicopathological features and oncological prognosis in patients with localized PCa in PSA era. Meta-analyses were conducted using available hazard ratios (HRs) from both univariate and multivariate analyses., Results: Twenty-six studies including 391 068 patients with RP treatments from the PSA era were included. Of these studies, age of 50 years old (age50) is the most commonly used cut-off age to separate the younger patient group (including either age < 50 or age ≤ 50) from the older patient group. In these studies, the incidence of younger patients varied between 2.6% and 16.6% with a median of 8.3%. Younger patients consistently showed more favorable clinicopathological features correlated with better BCR prognosis. Meta-analyses showed a 1.38-fold improved BCR survival of younger patients in multivariate analysis. Among the high-risk PCa patients, younger age was independently associated with worse oncological outcomes in multivariate analyses., Conclusion: In this study, we found younger age correlated with favorable clinicopathological characteristics and better BCR prognosis in low- to intermediate-risk patients. In high-risk group patients, younger patients often showed significantly worse oncological outcomes. Our study results suggest that age 50 could be used as a practical cut-off age to separate younger age patients from older age PCa patients., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Optical memory based on the electromagnetically induced transparency (EIT) in a double-[Formula: see text] atomic system provides a convenient way to convert the frequency, bandwidth or polarization of an optical pulse by storing it in one [Formula: see text] channel and retrieving it from another. This memory-based optical converter can be used to bridge the quantum nodes which have different physical properties in a quantum network. However, in real atoms, each energy level usually contains degenerate Zeeman states, which may lead to additional energy loss, as has been discussed in our recent theoretical paper (Tsai et al. in Phys. Rev. A 100, 063843). Here, we present an experimental study on the efficiency variation in the EIT-memory-based optical polarization conversion in cold cesium atoms under Zeeman-state optical pumping. The experimental results support the theoretical predictions. Our study provides quantitative knowledge and physical insight useful for practical implementation of an EIT-memory-based optical converter.

Background: Self-Management Support (SMS), refers to the actions taken by individuals to recognise and manage their own health. It is increasingly recognised that individuals with chronic obstructive pulmonary disease (COPD) require additional support with their Self-management. Emerging evidence suggests that the use of a social network intervention can improve health outcomes and increase quality of life. In order to understand the potential benefits of SMS in COPD, the GENIE (Generating Engagement in Network Support) SMS tool was implemented and evaluated in a COPD primary care context. The GENIE intervention is a social networking tool that consists of 3 parts; a concentric circle modelling to map existing social networks; a questions sections to elicit preferences for activities; a map of selected resources is then produced, aligned with the user's interests and suggestions for connections to existing network members and to new resources., Methods: A pilot, parallel, single blind, block randomised controlled trial. Patients with COPD ranging from mild-very severe were recruited. Participants provided written consent and were then randomised to either the intervention or usual care. The primary aim was to understand the clinical benefit through the analysis of health status, symptom burden and quality of life. The secondary outcome measure was health utilisation. NHS cost differences were reported between groups using the GENIE intervention over usual care., Results: The GENIE pilot results demonstrate maintenance in health status and clinical symptoms with a decrease in anxiety. An overall increase in quality of life was observed, these findings did not reach significance. A cost reduction was demonstrated in inpatient stay with no difference in primary care costs. Overall a cost reduction in NHS service utilisation was indicated in the intervention group., Conclusion: This pilot study indicated that using a social network intervention can encourage the development of new social connections and extend existing support networks for COPD patients. Increasing network support in this population is of benefit to both patients and NHS providers in terms of cost reductions and enhancing wellbeing. This broadens the understanding of possible new approaches to SMS in community COPD patients, which could now be investigated in a larger population over a longer period., Trial Registration: Clinical Trials.gov PRS National Library of Medicine. Protocol ID number: 19175, Clinical Trial ID: NCT02935452.

The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9%-98.1%) and lower identity among their Spike proteins (27%-77%). Thus, a 3D structural model of RdRp, NiRAN, non-structural protein 7 (nsp7), and nsp8 of SARS-CoV-2 was generated by modeling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors (Galidesivir, Favipiravir, and Penciclovir), which were recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirms their efficacy to inhibit viral RNA replication and provides an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.

Objective: The aim of this study was to explore the clinical significance of lncRNA-survival associated mitochondrial melanoma-specific oncogenic non-coding RNA (lncRNA-SAMMSON) in the development and clinicopathological parameters of gastric cancer (GC)., Patients and Methods: Tissue specimens were collected from GC patients who received treatment in our hospital. Real-time quantitative polymerase chain reaction (QRT-PCR) was used to determine lncRNA-SAMMSON expression. Small interfering RNA (siRNA) was transfected to suppress the expression of lncRNA-SAMMSON in vitro. Pearson's χ2-test  was used to investigate the interaction of lncRNA-SAMMSON with clinicopathological parameters of GC patients. Kaplan-Meier method and Log rank analysis were used to analyze the progression-free survival time and overall time of GC patients. Furthermore, transwell assay and wound healing assay were conducted to determine the invasion and migration abilities of GC cells, respectively., Results: QRT-PCR results showed that lncRNA-SAMMSON was abnormally overexpressed in GC tissues and cells (p<0.05). Pearson's χ2-test illustrated that clinical stage, distant metastasis and lymph node metastasis were closely related to lncRNA-SAMMSON expression in GC patients (p<0.05). Kaplan-Meier survival analysis represented that GC patients with high lncRNA-SAMMSON expression had significantly shorter progression-free survival time and overall survival time (p<0.05). Transwell assay and wound healing assay proved that inhibition of lncRNA-SAMMSON in GC cells dramatically reduced the invasion and migration abilities of GC cells, respectively (p<0.05)., Conclusions: LncRNA-SAMMSON played an important role in the development of GC, which might be regarded as a new target for the diagnosis and treatment of GC.

The heterofunctional lactone furo[3,4-b]pyridin-5(7H)-one (L 1 ) undergoes a coordination-induced ring-opening reaction with Zn(NO 3 ) 2  ⋅ 6H 2 O to yield the zwitterionic [Zn(L 1 ') 2 (H 2 O) 2 ] (1, L 1 '=2-(hydroxymethyl)nicotinate) with an uncoordinated carboxylate. The same reaction with Cd(NO 3 ) 2  ⋅ 4H 2 O provides a two-dimensional (2D) network of [Cd(L 1 ') 2 ] n (3) with the carboxylates coordinated to cadmium(II) propagating the assembly. The corresponding reactions of Zn(NO 3 ) 2  ⋅ 6H 2 O and Cd(NO 3 ) 2  ⋅ 4H 2 O with 2-(hydroxymethyl)isonicotinic acid (HL 2 ) generated zwitterionic [Zn(L 2 ) 2 (H 2 O) 2 ] (2) and a 2D network [Cd(L 2 ) 2 ] n ⋅nDMF (4, DMF=N,N'-dimethylformamide), respectively. Complexes 1-4 are weakly emissive, giving ligand-centered emissions at 409 nm (1), 412/436 nm (2), 404 nm (3), and 412/436 nm (4) in CHCl 3 solutions upon excitation at 330 nm. This work points to the potential of using 'hidden' functionalities widely found in small organic molecules and natural products for the construction of coordination complexes with new functionality and potential applications., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration-dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen-induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration-resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies., (© 2019 Wiley Periodicals, Inc.)

Androgen receptor (AR) signaling is essential for prostate cancer (PC) progression and treatment. Experiments have demonstrated that the intratumoral androgen levels are not affected by circulating androgen levels, but rather modulated by local steroid-converting enzyme activities. The expression modulation status of human steroid-converting enzymes and nuclear receptors are of great promise to identify novel therapeutic targets. Meta-analysis was performed with 9 cohorts (1093 specimens) from Gene Expression Omnibus, 16 cohorts (933 specimens) from Oncomine and the TCGA cohort (550 specimens). We found significant up regulation of 5α-reductase type 1 and type 3 in both primary and metastatic PC, together with the down regulation of AKR1C2 in primary PC, contributing to the high intratumoral DHT levels. The expression of AR in metastatic PC was up regulated, indicating the importance of AR signaling in the progression of this cancer. The down regulations of HSD11B1 and NR3C1 in primary and metastatic PC may diminish the anti-inflammation and anti-proliferation effects of glucocorticoids signaling. Furthermore, the decrease of progesterone receptor (PGR) expression in primary and metastatic PC was also observed, relieving the suppression effect of PGR on PC proliferation. The clinical evidences of the remarkable expression modulation of steroid-converting enzymes and receptors in PC may indicate novel combined treatment against this highly incident cancer., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Chronic stress has been known to impair the female reproductive function, but the mechanism remains to be further investigated. Chaiyu-Dixian Formula (CYDXF) has been reported to regulate human endocrine disorders clinically. However, whether this formula can affect chronic stress-induced ovarian follicular development is not clear., Aim of the Study: To examine effects of CYDXF on follicular development and explore possible mech anisms in a chronic unpredictable mild stress (CUMS) model., Materials and Methods: Adult female rats were randomly divided into 5 groups control group, CUMS group (saline treatment), CUMS+Estradiol (E 2 ) (0.1 mg/kg) group, CUMS+CYDXF (2.73 g/kg) group, and CUMS+CYDXF (5.46 g/kg) group. Body weights and behavioral tests were documented. Serum hormone levels were determined by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to detect the protein levels in the PI3K/Akt pathway and brain-derived neurotrophic factor (BDNF). The follicles were analyzed and classified according to their morphological characterization., Results: CYDXF relieved depression-like behaviors and ameliorated the abnormality in rat estrous cycle within the rat model of CUMS. Moreover, CYDXF could regulate endocrine disorders, increase the proportion of antral follicles as well as decrease the proportion of follicular atresia, which suggested that CYDXF could alleviate abnormal follicular development and improve overall ovarian function. Furthermore, CYDXF also activated the BDNF-mediated PI3K/Akt signaling pathway., Conclusions: CYDXF (at dose of both 2.73 and 5.46 g/kg) attenuated chronic stress-induced abnormal ovarian follicular development by relieving depression-like behaviors and improving ovarian function through partly the regulation of the BDNF-mediated PI3K/Akt pathway., (Copyright © 2020 Xu, Lin, Gong, Huo, Zhao, Zhu and Xi.)

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of factors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed reduced metabolic function and increased inflammatory activation. These data suggest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency, can exacerbate demyelinating disease by loss of metabolic support and increase in the inflammatory environment., (© 2019 Wiley Periodicals, Inc.)

In spite of the significant progress of estrogen-dependent breast cancer (BC) treatment, aromatase inhibitor resistance is a major problem limiting the clinical benefit of this frontier endocrine-therapy. The aim of this study was to determine the differential expression of steroid-converting enzymes between tumor and adjacent normal tissues, as well as their correlation in modulating intratumoral steroid-hormone levels in post-menopausal estrogen-dependent BC. RNA sequencing dataset (n = 1097) of The-Cancer-Genome-Atlas (Breast Invasive Carcinoma) retrieved through the data portal of Genomic Data Commons was used for differential expressions and expression correlation analyses by Mann-Whitney U and Spearman's rank test, respectively. The results showed significant up-regulation of 17β-HSD7 (2.50-fold, p < 0.0001) in BC, supporting its effect in sex-hormone control. Besides, suppression of 11β-HSD1 expression (-8.29-fold, p < 0.0001) and elevation of 11β-HSD2 expression (2.04-fold, p < 0.0001) provide a low glucocorticoid environment diminishing BC anti-proliferation. Furthermore, 3α-HSDs were down-regulated (-1.59-fold, p < 0.01; -8.18-fold, p < 0.0001; -33.96-fold, p < 0.0001; -31.85-fold, p < 0.0001 for type 1-4, respectively), while 5α-reductases were up-regulated (1.41-fold, p < 0.0001; 2.85-fold, p < 0.0001; 1.70-fold, p < 0.0001 for type 1-3, respectively) in BC, reducing cell proliferation suppressers 4-pregnenes, increasing cell proliferation stimulators 5α-pregnanes. Expression analysis indicates significant correlations between 11β-HSD1 with 3α-HSD4 (r = 0.605, p < 0.0001) and 3α-HSD3 (r = 0.537, p < 0.0001). Significant expression correlations between 3α-HSDs were also observed. Our results systematically present the regulation of steroid-converting enzymes and their roles in modulating the intratumoral steroid-hormone levels in BC with a vivid 3D-schema, supporting novel therapy targeting the reductive 17β-HSD7 and proposing a new combined therapy targeting 11β-HSD2 and 17β-HSD7., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Urothelial carcinoma with squamous differentiation (UCSD) is the most common histologic variant in bladder cancer (BCa). Previously, some studies have linked the presence of UCSD with the risk of worse survival outcomes in BCa patients. However, such association is still controversial. In this study, we performed a meta-analysis to clarify the clinicopathological characteristics and to further investigate the prognostic value of UCSD in BCa., Methods: A systematic literature search was performed in electronic databases including PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Data until October 2018. Subgroup analyses were performed according to different treatments and study outcomes., Results: Total of 13,284 patients were enrolled in 19 studies which were included in this meta-analysis. The percentage of female patients with UCSD was significantly higher than those with pure urothelial carcinoma. UCSD was correlated with tumor stage T3/T4, tumor grade 3, positive surgical margin, and lymph node involvement. Moreover, the recurrence rate was higher in patients with UCSD after surgery. UCSD was associated with poorer disease-free survival (DFS). No significant difference of cancer-specific survival (CSS) or overall survival (OS) was found on multivariable analysis between the two groups., Conclusions: Our study demonstrated that UCSD in BCa was associated not only with unfavorable clinicopathological features, but also with high risk of recurrence and poorer prognosis for DFS. However, UCSD is not independently significant for CSS and OS. Well-designed randomized study with larger sample size is warranted to verify the findings and to further explore the role of UCSD in BCa.

Understanding the interaction mechanism of proteins and nucleic acids is one of the most fundamental problems for genome editing with engineered nucleases. Due to some limitations of experimental investigations, computational methods have played an important role in obtaining the knowledge of protein-nucleic acid interaction. Over the past few years, dozens of computational tools have been used for identification of nucleic acid binding site for site-specific proteins and design of site-specific nucleases because of their significant advantages in genome editing. Here, we review existing widely-used computational tools for target prediction of site-specific proteins as well as off-target prediction of site-specific nucleases. This article provides a list of on-line prediction tools according to their features followed by the description of computational methods used by these tools, which range from various sequence mapping algorithms (like Bowtie, FetchGWI and BLAST) to different machine learning methods (such as Support Vector Machine, hidden Markov models, Random Forest, elastic network and deep neural networks). We also make suggestions on the further development in improving the accuracy of prediction methods. This survey will provide a reference guide for computational biologists working in the field of genome editing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aims: Probiotics was considered as a potential therapy for nonalcoholic fatty liver disease (NAFLD) without approval and comprehensive assessment in recent years, which call for a meta-analysis., Methods: We performed electronic and manual searches including English and Chinese databases published before April 2019, with the use of mesh term and free text of "nonalcoholic fatty liver disease" and "probiotics." Clinical trials evaluating the efficacy of probiotic therapy in NAFLD patients were included according to the eligibility criteria. With the use of random effects models, clinical outcomes were presented as weighted mean difference (WMD) with 95% confidence interval (CI), while heterogeneity and meta-regression were also assessed., Results: 28 clinical trials enrolling 1555 criterion proven NAFLD patients with the use of probiotics from 4 to 28 weeks were included. Overall, probiotic therapy had beneficial effects on body mass index (WMD: -1.46, 95% CI: [-2.44, -0.48]), alanine aminotransferase (WMD: -13.40, 95% CI: [-17.03, -9.77]), aspartate transaminase (WMD: -13.54, 95% CI: [-17.86, -9.22]), gamma-glutamyl transpeptidase (WMD: -9.88, 95% CI: [-17.77, -1.99]), insulin (WMD: -1.32, 95% CI: [-2.43, -0.21]), homeostasis model assessment-insulin resistance (WMD: -0.42, 95% CI: [-0.73, -0.12]), and total cholesterol (WMD: -15.38, 95% CI: [-26.50, -4.25]), but not in fasting blood sugar, lipid profiles, or tumor necrosis factor-alpha., Conclusion: The systematic review and meta-analysis support that probiotics are superior to placebo in NAFLD patients and could be utilized as a common complementary therapeutic approach., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Meng-Wei Xiao et al.)

Breast cancer is a major cause of cancer-related death for women in western countries. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) play important roles in the last step of sex-hormone activation and the first step of sex-hormone inactivation. 17β-HSD2 is responsible for oxidizing the sex hormones. We used microarray technology to analyze the effect of 17β-HSD2 on the MCF-7 cell transcript profile after knocking down 17β-HSD2. Five hundred forty-two genes were regulated 1.5-fold or higher after treatment with 17β-HSD2 siRNA. Knocking down 17β-HSD2 interrupted nucleosome assembly. Pathway-Act-Network analysis showed that the MAPK and apoptosis signaling pathways were most regulated. In the gene-gene interaction network analysis, UGT2B15, which is involved in hormone metabolism, was the most regulated core gene. FOS, GREB1, and CXCL12 were the most regulated genes, and CXCL12 was related to tumor migration. Following 17β-HSD2 knock-down, the cell viability decreased to 75.9%. The S-phase percentage decreased by 19.4%, the Q2-phase percentage in cell apoptosis testing increased by 1.5 times, and cell migration decreased to 66.0%. These results were consistent with our gene chip analysis and indicated that 17β-HSD2 plays both hormone-dependent and hormone-independent enzymatic roles. In-depth investigations of this enzyme on the genomic level will help clarify its related molecular mechanisms., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma among adults. In some cases, DLBCL may seem similar to carcinoma cells, presenting a round, oval, or polygonal shape and clear nuclei. We found that the expression of P63 accounted for a considerable proportion of DLBCL cases. Under the circumstances, P63 expression may lead to a misdiagnosis, especially with a small biopsy. We aim to investigate the expression status and prognostic significance of P63 in a cohort of Chinese DLBCL patients., Methods: P63, ΔNP63(P40), P53 and Ki67 were detected by immunohistochemistry (IHC). A ROC curve was adopted to find the best cut-off value for positive P63/P53 expression and high Ki67 expression. We defined P53 as positive when ≥50% of the tumor cells showed staining. The relationship between P63 and P53/Ki67 expression was examined. Time-to-event endpoints were estimated according to the Kaplan-Meier method. Moreover, multivariate analyses were conducted to evaluate the prognostic factors in DLBCL., Results: Out of all the 159 DLBCL cases, 76 (47.8%) expressed P63 in the nuclei, while 41 (25.8%) were determined to have high expression by using a ROC cut-off value "≥6". Examination of the different P63 isoforms revealed that the ΔNP63(P40) was unclearly and weakly expressed in only 3 cases, showing a fuzzy yellow cytoplasm. P63 expression was not correlated with subtype (GCB or non-GCB) or P53 but was correlated with a high proliferative index (Ki67). Kaplan-Meier analyses revealed that P63 expression was correlated with overall survival, and P63 positive cases showed poor survival outcomes (P<0.05) in our cohort., Conclusions: ΔNP63(P40) is a useful marker in the differential diagnosis of poorly differentiated squamous cell carcinoma versus DLBCL in small needle biopsy. P63 may be involved in DLBCL tumor progression, and it is an unfavorable prognostic marker in DLBCL. A subgroup of P63 and P53 coexpression DLBCL patients with an extremely poor prognosis should be noted.

Objectives: To investigate the association between biopsy perineural invasion (PNI) and oncological outcomes of prostate cancer (PCa) after radical prostatectomy (RP). Materials and methods: A systematic literature search was performed using PubMed, EMBASE and Web of Science up to December 2018 to identify the eligible studies that included localized PCa patients who underwent biopsy and subsequently RP as well as follow-up information. Meta-analyses were conducted using available hazard ratios (HRs) of biopsy PNI from both univariate and multivariate analyses. Results: Eighteen studies including 14,855 patients with treatment follow-up information were included in the current systematic review. The rate of biopsy PNI varied between 7.0% and 33.0%. Seven out of the 18 studies that demonstrated biopsy PNI were associated with adverse pathologic features. Thirteen out of the 18 studies showed biopsy PNI correlated significantly with higher rates of biochemical recurrence (BCR)/cancer progression status or worse prognostic outcomes. With pooled data based on four studies with available univariate analysis results and four studies with multivariate analysis, statistically significant associations were found between biopsy PNI and BCR with univariate analysis (HR = 2.05; 95% CI = 1.57-2.68; p  < 0.001) and with multivariate analysis (HR = 1.57; 95% CI = 1.28-1.93; p  < 0.001). Conclusion: Evidence from the included observational studies indicated that biopsy PNI was not only correlated with adverse pathologic characteristics but also with worse BCR prognosis of local PCa after RP. The status of biopsy PNI could serve as a promising risk-stratification factor to help the decision-making process, considering active surveillance (AS) or further treatment for PCa patients.

Reductive 17β-hydroxysteroid dehydrogenases (17β-HSDs) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) play crucial roles in respectively regulating steroids and glucocorticoids for the progression of hormone-dependent breast cancer. Most studies focused on the function and individual regulation of these enzymes. However, mutual regulation of these enzymes and the induced modulation on the estrogen and androgen receptors for breast cancer promotion are not yet clear. In this study, MCF-7 and T47D cells were treated with inhibitors of 17β-HSD1, 17β-HSD7, aromatase or steroid sulfatase (STS), then mRNA levels of 17β-HSD7, STS, 11β-HSD 2, estrogen receptors α (ERα) and androgen receptor (AR) were determined by Q-PCR. ER negative cell line MDA-MB-231 was used as a negative control. Our results demonstrate that 17β-HSD7, STS and 11β-HSD2 are all regulated by the same estrogen estradiol via ERα. When the gene of ERα (ESR1) was knocked down, there was no longer significant mutual regulation of these enzymes. Our results demonstrate that important steroidogenic enzymes transcriptionally regulated by ERα, can be mutually closely correlated. Inhibition of one of them can reduce the expression of another, thereby amplifying the role of the inhibition. Furthermore, inhibition of 17β-HSD7 increases the expression of AR gene which is considered as a marker for better prognosis in ER + breast cancer, while maintaining ERα level. Thus, our mechanistic finding provides a base for further improving the endocrine therapy of ER + breast cancer, e.g., for selecting the target steroid enzymes, and for the combined targeting of human 17β-HSD7 and ERα., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We previously showed LKE (lanthionine ketimine ester) reduces disease in the EAE model of multiple sclerosis, however whether LKE affects oligodendrocytes (OLGs) was not tested. In OLG progenitor cells (OPCs), LKE increased process number and area, but not PDGF-receptor-alpha expressing cells. In contrast, PDGF increased OPC numbers, but reduced process number and area. LKE increased collapsin response mediator protein-2 (CRMP2) expression, an LKE target, and CRMP2-expressing OLGs expressed myelin basic protein. LKE increased markers of OPC maturation, while PDGF, but not LKE, increased Sox2 expression. Our findings suggest that effects on OPCs may contribute to LKE beneficial actions in EAE., (Published by Elsevier B.V.)

Objective: To investigate the oncological impact of incidental prostate cancer (iPCa) found during radical cystoprostatectomy (RCP) on overall survival (OS) prognosis of urothelial carcinoma of the bladder (BCa)., Patients and Methods: A total of 122 RCP cases resected between 2002 and 2012 at our center were included for study. Survival of BCa patient was compared using the Kaplan-Meier method and the log-rank test. Cox proportional hazards regression models were used to analyze the impact of iPCa on the 5-year overall mortality of BCa patients after RCP., Results: Among the 122 BCa cases that underwent RCP, 38 cases (31.1%) had iPCa, in which, 17 cases (44.7%) were identified as clinically significant iPCa (csPCa). BCa patients with iPCa were older (71 vs 64 years, p = 0.004) and had higher preoperative PSA level (3.1 ng/mL vs 1.4 ng/mL, p = 0.017) when compared to those without iPCa. Cases with iPCa showed a more favorable 5-year OS than cases without iPCa, although this difference did not reach statistical significance (p = 0.219). When excluding the higher risk cases with Gleason score (GS) ≥ 4 + 3 and/or preoperative PSA > 10 ng/mL, BCa patients with iPCa showed a significantly longer OS than cases without iPCa on univariate analysis (p = 0.044), but not on multivariate analysis (p = 0.125)., Conclusion: Our results demonstrated that the frequent findings of low-risk iPCa in BCa patients could indicate the potential possibility of shared pathogenesis pathways between iPCa and BCa. Future study with a larger cohort is warranted to validate this result.

Circulating EBV-DNA is an accurate biomarker of tumor load in extranodal natural killer (NK)/T cell lymphoma (ENKTL); however, its role in patients treated with P-GEMOX has not been evaluated. In this study, we examined plasma EBV-DNA of 99 patients at different time points by real-time quantitative polymerase chain reaction. Multivariate analysis revealed that ECOG PS score, response rate, and post-treatment EBV-DNA level were independent predictors of progression-free survival (PFS) and overall survival (OS). Positive post-treatment plasma EBV-DNA was associated with poor OS in ENKTL patients. The 3-year OS for patients with positive pre-, interim-, post-treatment EBV-DNA was significantly lower than that for patients with negative EBV-DNA; the values were 70.2% vs. 93.9% ( p  = .022), 53.8% vs. 99.1% ( p  < .001), and 40.6% vs. 91.8% ( p  < .001), respectively. We conclude that monitoring dynamic changes in plasma EBV-DNA in ENKTL patients treated with P-GEMOX could predict important outcomes such as OS.

Background: Increased drug overdose deaths have become a serious public health problem. Primary care providers prescribe about 50% all opioid medications. This study examined opioids prescribing during primary visits to patients with a pain-depression dyad and patient demographic characteristics associated with opioids prescribing., Method: This study analyzed data from the 2014 to 2015 National Ambulatory Medical Care Survey and included primary care visits by adult patients (aged 18 years or older) with noncancer pain., Results: An opioid medication was prescribed in 26.4% (95% CI, 22.6% to 30.6%) of the primary care visits by patients with noncancer pain. Opioid medications were more likely to be prescribed during visits by patients with a pain and depression dyad (adjusted odds ratios [AOR] = 1.8; 95% CI, 1.4 to 2.4). Narcotic analgesics were more likely to be prescribed during visits by patients aged 46 to 64 years; by male patients or non-Hispanic white patients., Discussion/conclusions: Pain-depression dyad is associated with higher odds of opioids prescribing during primary care visits. Future studies are needed to understand the complexity of these factors and identify effective strategies to prevent opioids addiction and overdose among patients with pain and depression., Competing Interests: Conflict of interest: none declared., (© Copyright 2019 by the American Board of Family Medicine.)