Search

Waldenström macroglobulinemia (WM) is a rare, indolent lymphoma, that predominately affects the elderly. We report the outcomes of young WM patients, evaluated over five decades, compared to their older counterparts, matched for the time of diagnosis. Between January 1, 1960 and October 31, 2013, 140 (11.8%) WM patients were ≤50 years of age at diagnosis in our database, and their estimated 10-year overall survival (OS) was 74%, with death attributable to WM in a higher proportion of patients compared to their older (≥65 years) counterparts (91% vs. 58%, p = .0001). Young patients were grouped into three cohorts based on the timing of the initiation of therapy: Group 1 (1960-1977, n = 12), Group 2 (1978-1995, n = 48), and Group 3 (1996-2013, n = 74). Among young patients, there was no disease-specific survival (DSS) difference across the three periods, [median DSS at 13 years (95% CI 5-23), 16 years (95% CI 14-22), and 15 years (95% CI 10-NR; p = .41), respectively]. However, DSS for the older cohort incrementally improved (Group 1, median 5.2 years, Group 2: 9.6 years, Group 3: 12 years; p = .05) over these periods. The estimated average years-of-life lost for the young cohort was 11.2 years from diagnosis, based on the expected survival for a normal age- and sex-matched population. Despite a protracted disease course, nearly all young patients succumb to their disease. In contrast to the improved survival of the elderly patient population, the evolving treatment strategies in WM have not impacted the outcome of young patients; however, the impact of Bruton tyrosine kinase inhibitors on this unique patient population remains to be determined.

Rapeseed peptide, extracted from rapeseed protein, is known to have a variety of biological activities. In this study, the anti-proliferation effect and molecular mechanism of rapeseed peptide on HepG2 cells were investigated.In vitro anticancer experiments showed that the rapeseed peptide NDGNQPL could inhibit HepG2 cell proliferation in a concentration-dependent manner [half maximal inhibitory concentration (ICThe current results indicate that the rapeseed-derived NDGNQPL peptide has the potential to inhibit the proliferation of HepG2 cells and promote human health. © 2022 Society of Chemical Industry.

Rice production is threatened by multiple pathogens. Breeding cultivars with broad-spectrum disease resistance is necessary to maintain and improve crop production. Previously we found that overexpression of miR160a enhanced rice blast disease resistance. However, it is unclear whether miR160a also regulates resistance against other pathogens, and what the downstream signaling pathways are. Here, we demonstrate that miR160a positively regulates broad-spectrum resistance against the causative agents of blast, leaf blight and sheath blight in rice. Mutations of miR160a-targeted Auxin Response Factors result in different alteration of resistance conferred by miR160a. miR160a enhances disease resistance partially by suppressing ARF8, as mutation of ARF8 in MIM160 background partially restores the compromised resistance resulting from MIM160. ARF8 protein binds directly to the promoter and suppresses the expression of WRKY45, which acts as a positive regulator of rice immunity. Mutation of WRKY45 compromises the enhanced blast resistance and bacterial leaf blight resistance conferred by arf8 mutant. Overall, our results reveal that a microRNA coordinates rice broad-spectrum disease resistance by suppressing multiple target genes that play different roles in disease resistance, and uncover a new regulatory pathway mediated by the miR160a-ARF8 module. These findings provide new resources to potentially improve disease resistance for breeding in rice.

Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN. We retrospectively analyzed 378 t-MN patients, of which 96 (25.4%, 47 therapy-related acute myeloid leukemia, 1 therapy-related chronic myelomonocytic leukemia, 48 therapy-related myelodysplastic syndrome) received venetoclax. Median interval from t-MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7-12) months, and patients received a median of 3 (IQR 1-4) cycles. The composite complete remission (CRc) rate, median progression-free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53-status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53-mutated clone. In a propensity-matched analysis, the use of venetoclax-based regimen as the first-line therapy was associated with a superior survival compared to hypomethylating agent (HMA)-based first-line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t-MN phenotypes.

The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter syndrome (RS), a rare event with dismal prognosis. In this study, we conducted whole-genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 patients recruited into a clinical trial (CHOP-O). We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumor necrosis factor receptor–associated factor 3 (TRAF3). In the noncoding genome, we discovered activation-induced cytidine deaminase–related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune-regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2, and TRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal deconvolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal-expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study. This trial was registered at www.clinicaltrials.gov as #NCT03899337.

Patients with asymptomatic/smouldering Waldenstrom macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2 -microglobulin (β2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.

Comparative data guiding initial therapy for Waldenstrom macroglobulinemia (WM), an infrequently encountered non-Hodgkin lymphoma, are sparse. We evaluated three commonly used frontline regimens: rituximab-bendamustine (R-Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment-naive patients with WM, seen at Mayo Clinic between 11/01/2000 and 10/31/2019. The median follow-up was 4.5 (95%CI: 4-5) years. The R-Benda (n=83) cohort demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n=92, ORR: 78%) or BDR (n=45, ORR: 84%) cohorts, p=0.003. Similarly, longer progression-free survival (PFS) was evident with R-Benda use [median 5.2 versus 4.3 (DRC) and 1.8 years (BDR), p=0.0003].The time-to-next therapy (TTNT) favored R-Benda [median, not-reached, versus 4.4 (DRC) and 2.6 years (BDR), p=0.0002). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p=0.77. In a subset analysis of 142 patients genotyped for MYD88L265P mutation, the ORR, PFS and TTNT were unaffected by the MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R-Benda are superior compared to DRC or BDR in treatment-naive patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88L265P mutation status. This article is protected by copyright. All rights reserved.

Objective To examine the longitudinal associations of fetal growth with adverse child growth outcomes and to assess whether maternal metabolic factors modify the associations. Design Prospective cohort study. Setting Born in Guangzhou Cohort Study, China. Population A total of 4818 mother–child pairs. Methods Fetal growth was assessed according to estimated fetal weight (EFW) from 22 weeks of gestation until birth and the measurement of the birthweight. Fetal growth Z‐scores were computed from random effects in the multilevel linear spline models to represent fetal size in early pregnancy (22 weeks of gestation) and growth in mid‐pregnancy (22–27 weeks of gestation), early third trimester (28–36 weeks of gestation) and late third trimester (≥37 weeks of gestation). Main outcome measures Z‐scores for childhood stunting, low weight, overweight or obesity, length/height for age (LAZ/HAZ), weight for age (WAZ) and body mass index for age (BMIZ) at the age of 3 years. Adjusted associations were examined using multiple Poisson or linear regression models. Results Increased Z‐scores of fetal size in early pregnancy and growth in mid‐pregnancy and early third trimester were associated with a higher risk of childhood overweight or obesity (risk ratios 1.25–1.45). Fetal growth in each period was negatively associated with stunting and low weight, with the strongest associations observed for fetal size in early pregnancy and growth in mid‐pregnancy. The results for continuous outcomes (LAZ/HAZ, WAZ and BMIZ) were similar. The associations of fetal growth with overweight or obesity in childhood were stronger among mothers who were underweight and who were overweight or obese than among mothers of normal weight. Conclusions Accelerated fetal growth before 37 weeks of gestation is associated with children who are overweight or obese, whereas the critical period for stunting and low weight occurs before 28 weeks of gestation. Tweetable abstract Fetal growth during different periods is differentially associated with childhood stunting, underweight and overweight or obesity.

Objectives To report our single-center experience of the management of children with prostatic utricle cysts. Methods We retrospectively analyzed 15 children who were incidentally found to have a prostatic utricle cyst and were admitted to our department between October 2013 and August 2020. Clinical characteristics and management were collected and catalogued. Results Recurrent genitourinary tract infections were the most frequent complaint, and two-thirds of patients also had hypospadias. A connection between the posterior urethra and the prostatic utricle cyst was found in all cases. Two patients directly had their progressively enlarging prostatic utricle cyst resected laparoscopically. Endoscopic techniques were used in 13 patients, two of whom underwent laparoscopic excision for repeated symptoms. The mean (range) follow-up period was 34.9 (2-82) months. No recurrences were observed in four patients who underwent prostatic utricle cyst excision and eight patients who received endoscopic treatment. Three patients had recurrent symptoms after endoscopic treatment and were managed by nonsurgical treatment. Conclusions Prostatic utricle cyst is a rare disease which can cause recurrent genitourinary tract infections. Extra attention should be paid to evaluation for prostatic utricle cyst in children with external genital anomalies. Retrograde urethrogram and magnetic resonance imaging are useful tools with which to distinguish prostatic utricle cyst from other cystic lesions that are located in the midline pelvis in male patients. Individualized treatment is appropriate when considering fertility preservation, recurrences and malignancy. Laparoscopic excision is feasible for symptomatic and large prostatic utricle cyst. Regular long-term monitoring is recommended for all patients with prostatic utricle cyst.

BACKGROUND Although rapeseed protein isolate (RPI) possessed some good functional properties, the use of RPI as an ingredient in the food industry is restricted mainly due to its inferior gelation. The purpose of this study was to improve the heat-induced gel properties of RPI using double processes of acylation and additional transglutaminase catalysis. RESULTS Scanning electron microscopy showed that the gel formed by native RPI exhibited randomly aggregated particulate network structures whereas transglutaminase (TG)-assisted RPI gels significantly improved gelation properties. More importantly, the combined modifications of RPI using TG-assisted acylation can form a gel with unique percolating and small porous structure. Furthermore, TG-catalyzed 5% acylated RPI gel (100 U g-1 , protein basis) exhibited excellent gel properties in terms of gel strength, thermal stability, surface roughness and apparent viscosity compared to non-treated or single modification of RPI gel as determined by texture analyzer, atomic force microscopy and rheometer. Mechanistically, Fourier-transform infrared spectra and gel dissociation test revealed that TG-catalyzed acylation extensively unfolded the hydrophobic and sulfhydryl residues of RPI, in turn, reinforced re-assembly of protein molecules via hydrophobic interactions and disulfide bonds during gel formation. CONCLUSION Combined processes of acylation and additional TG catalysis improved the thermal gelation properties by altering inter- and intra-protein structures. Such sequential processes will provide a promising approach to improve the protein gelation that could be potentially applied in the food industry. © 2020 Society of Chemical Industry.

The role of long non‐coding RNAs (lncRNAs) in kidney diseases has been gradually discovered in recent years. LINC00963, as an lncRNA, was found to be involved in chronic renal failure. However, the role and molecular mechanisms of LINC00963 engaged in acute kidney injury (AKI) were still unclear. In this study, we established rat AKI models by ischaemia and reperfusion (I/R) treatment. Urea and creatinine levels were determined, and histological features of kidney tissues were examined following HE staining. CCK8 assay was chosen to assess the viability of hypoxia‐induced HK‐2 cells. Dual‐luciferase reporter gene assays were performed to verify the target relationship between LINC00963 and microRNA. The mRNA and protein levels were assayed by RT‐qPCR and Western blot, respectively. Annexin V‐FITC/PI and TUNEL staining were used to evaluate apoptosis. LINC00963 was highly expressed in the cell and rat models, and miR‐128‐3p was predicted and then verified as a target gene of LINC00963. Knockdown of LINC00963 reduced acute renal injury both in vitro and in vivo. LINC00963 activated the JAK2/STAT1 pathway to aggravate renal I/R injury. LINC00963 could target miR‐128‐3p to reduce G1 arrest and apoptosis through JAK2/STAT1 pathway to promote the progression of AKI.

Background Rice bran is a nutrient-dense and resource-rich byproduct produced from the rice milling. The limitation of rice bran utilization is mainly caused by oxidative deterioration. Improvement of stability to prolong rice bran shelf-life has thus become an urgent requirement. Results The present study aimed to determine the characteristics of infrared radiation heat treatment of rice bran (IRRB) and raw rice bran stored under different temperatures. The effects of heating and storage time on physicochemical, microbial, storage stability and structural properties were investigated. Additionally, the prediction model for the shelf-life of rice bran was established based on free fatty acids and the peroxide value by fitting the curve of bran lipid oxidation. The results obtained demonstrated that infrared radiation heating at 300 °C for 210 s resulted in decreased lipase activity and peroxidase activity of 73.05% and 81.50%, respectively. The free fatty acids and peroxide value of IRRB stored at 4 and 25 °C for 8 weeks were only reached at 2.35% and 3.17% and 2.53 and 3.64 meq kg-1 , respectively. The shelf-life prediction model showed the the shelf-life of infrared radiation-treated samples increased to 71.6 and 25.8 weeks under storage at 4 and 25 °C, respectively. Conclusion The stabilizing process could effectively suppress microbial growth and had no prominent effect on the physicochemical and microstructure properties of rice bran and, simultaneously, storage life was greatly extended. © 2020 Society of Chemical Industry.

Histological transformation in Waldenstrom macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high-grade lymphoma, with median time-to-transformation of 4.5 (range 0-21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non-transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1-23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time-to-transformation (HR 7.9 [95%CI: 2.3-27; P = .001]), with a 5-year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8-6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time-to-transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

The mitochondrial complexes are prone to sirtuin (Sirt)3-mediated deacetylation modification, which may determine cellular response to stimuli, such as oxidative stress. In this study, we show that the cytochrome c oxidase (COX)-1, a core catalytic subunit of mitochondrial complex IV, was acetylated and deactivated both in 2,2'-azobis(2-amidinopropane) dihydrochloride-treated NIH/3T3 cells and hydrogen peroxide-treated primary neuronal cells, correlating with apoptotic cell death induction by oxidative stress. Inhibition of Sirt3 by small interfering RNA or the inhibitor nicotinamide induced accumulation of acetylation of COX-1, reduced mitochondrial membrane potential, and increased cell apoptosis. In contrast, overexpression of Sirt3 enhanced deacetylation of COX-1 and inhibited oxidative stress-induced apoptotic cell death. Significantly, rats treated with ischemia/reperfusion injury, a typical oxidative stress-related disease, presented an inhibition of Sirt3-induced hyperacetylation of COX-1 in the brain tissues. Furthermore, K13, K264, K319, and K481 were identified as the acetylation sits of COX-1 in response to oxidative stress. In conclusion, COX-1 was discovered as a new deacetylation target of Sirt3, indicating that the Sirt3/COX-1 axis is a promising therapy target of stress-related diseases.-Tu, L.-F., Cao, L.-F., Zhang, Y.-H., Guo, Y.-L., Zhou, Y.-F., Lu, W.-Q., Zhang, T.-Z., Zhang, T., Zhang, G.-X., Kurihara, H., Li, Y.-F., He, R.-R. Sirt3-dependent deacetylation of COX-1 counteracts oxidative stress-induced cell apoptosis.

The aim of this study was to evaluate the clinical feasibility of non‐invasive prenatal testing (NIPT) to detect foetal copy number variations (CNVs). Next‐generation sequencing for detecting foetal copy number variations (CNVs) was performed on the collected samples from 161 pregnancies with ultrasound anomalies and negative NIPT results for aneuploidy. The performance of NIPT for detecting chromosome aberrations was calculated. The sensitivity and specificity of NIPT for detecting CNVs > 1 Mb were 83.33% and 99.34%; the PPV and negative predictive rate (NPV) were 90.91% and 98.68%. Non‐invasive prenatal testing can be performed to detect chromosomal aberrations in first trimester with high performance for CNVs, and occasional discordant cases are unavoidable.

In this paper, an indirect competitive enzyme‐linked immunosorbent assay (IC‐ELISA) has been developed and optimized to detect Hg(II) in tap water and lake water based on a monoclonal antibody (mAb‐A24). Some stabilizing additives (Gelatin, bovine serum albumin [BSA], polyvinyl alcohol [PVA], and polyvinyl pyrrolidone [PVP]) and surfactant (Tween‐20) have been investigated thoroughly in the optimization process. Under the optimal condition, the 50% half maximal inhibitory concentration (IC50) and limit of detection (LOD) were 1.68 and 0.079 ng/ml, respectively. These anti‐Hg mAbs also have some affinity with methyl mercury (CH3Hg) and with no cross‐reactivity with other thirteen metal ions. The developed method has shown satisfactory recovery of Hg(II), ranged between 91% and 116%, from tap water and lake water. Therefore, this immunoassay can be used to detect trace Hg(II) in environment water.

Type 2 diabetes mellitus (T2DM) is increasingly being recognized as an independent risk factor for the onset and progression of osteoarthritis (OA). Extensive studies have focused on the contribution of obesity (excessive mechanical stress), comorbidity frequently found in T2DM, to cartilage destruction during OA development. However, a little is known about how diabetes-related inflammation may affect the local cartilage in a diabetic objective. In the present study, we were able to establish a T2DM rat model using a combination of a low dose of streptozotocin with high-fat and high-sugar diet. Although the cartilage integrity was comparable between the control and T2DM groups, the expression of matrix metalloproteinases-13 (MMP-13) was significantly upregulated in T2DM, indicating the initiation of an early cascade of cartilage degeneration. In parallel, an obvious alteration of subchondral bone remodeling (inhibition of bone formation) was observed, as evidenced by the reduction of osterix-expressing positive cells. Moreover, we demonstrated that the expression of intercellular adhesion molecule-1 (ICAM-1) in the serum and synovium of T2DM rats was elevated, accompanied by an increase of synovitis score. We also noticed that the number of F4/80-positive macrophage cells was significantly increased in the T2DM group. Mechanistically, the expression of ICAM-1 in fibroblast-like synoviocytes can be triggered by glucose and interleukin-1β, which are the two important factors within the joint of T2DM. Given that MMP-13 expression was significantly upregulated in the T2DM cartilage, and that ICAM-1-mediated filtration of macrophage was associated with synovitis, we propose that ICAM-1 is essential for triggering a vicious cycle of inflammation within the joint, which together subsequently drivers the cartilage degradation.

Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti-neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages.

Engineering electronic properties by elemental doping is a direct strategy to design efficient catalysts towards CO2 electroreduction. Atomically thin SnS2 nanosheets were modified by Ni doping for efficient electroreduction of CO2 . The introduction of Ni into SnS2 nanosheets significantly enhanced the current density and Faradaic efficiency for carbonaceous product relative to pristine SnS2 nanosheets. When the Ni content was 5 atm %, the Ni-doped SnS2 nanosheets achieved a remarkable Faradaic efficiency of 93 % for carbonaceous product with a current density of 19.6 mA cm-2 at -0.9 V vs. RHE. A mechanistic study revealed that the Ni doping gave rise to a defect level and lowered the work function of SnS2 nanosheets, resulting in the promoted CO2 activation and thus improved performance in CO2 electroreduction.

Objective To assess potential risk factors in identifying women at risk for gestational diabetes mellitus (GDM). Methods The present study included data collected as part of a prospective cohort study, and included women with singleton pregnancies who underwent initial prenatal examination at a tertiary women and children's hospital in Guangzhou, China between February 1, 2012, and December 31, 2015. Maternal characteristics and medical history were investigated to evaluate associations with GDM. A risk factor scoring system for the prediction of GDM was generated using logistic regression. Results Overall, 1129 (13.5%) of 8381 women were diagnosed with GDM. Women older than 35 years had a 3.95‐fold increased risk of GDM (95% confidence interval 2.80–5.58) compared with women aged 16–25 years; obese women had a 6.54‐fold higher risk (95% confidence interval 3.50–12.23) compared with underweight women. A risk scoring system was established based on age, body mass index, family history of diabetes, weight gain, and history of GDM. Screening for women with a score of 12 or more would have reduced the number undergoing oral glucose tolerance testing by 2131 (25.4%) patients with a sensitivity of 87% for GDM detection. Conclusion The assessment of risk factors for GDM could provide a foundation for improving risk‐based screening strategies in this and similar populations.

Background Epidermolytic palmoplantar keratoderma (EPPK) is characterized by hyperkeratotic lesions on palms and soles. The disorder is caused by mutations of keratin 9 (KRT9) or KRT1 gene. Methods Epidermolytic palmoplantar keratoderma was diagnosed by physical examination and histopathological analysis in a five‐generation Chinese family. Mutation was screened by Sanger sequencing. The palmar expression of multiple cytokeratins were analyzed by tape‐stripping and Real‐time PCR. Literatures of EPPK with additional symptoms were reviewed. Results Affected family members showed diffuse palmoplantar keratosis, with knuckle pads, friction‐related lesions and a novel additional symptom of palmar constriction. A heterozygous mutation of c.T491C (p.L164P) of KRT9 was found within the helix initiation motif. The hydrophobic effect was decreased and the initiation of coiled‐coil conformation was delayed. The KRT16/KRT6 expression were significantly increased in the patients, especially on the right, indicating activation of stress‐response and wound‐healing cytokeratins. There were also increased KRT9/KRT2, unchanged KRT10/KRT1, and undetectable KRT14/KRT5 expression. The genetic and phenotypic heterogeneity of EPPK with additional symptoms were summarized by literature review. Conclusion The p.L164P mutation of KRT9 caused EPPK with a novel symptom of palmar constriction. The expression of multiple cytokeratins was altered in EPPK patients.

Shikonin, a natural naphthoquinone compound derived from the herb Lithospermum erythrorhizon, is widely used for its various pharmacological activities. However, its potential interactions with other medications by inhibiting human carboxylesterases 2 (hCE2) remain unknown. In this study, the inhibitory effects of shikonin on the activity of hCE2 in human liver microsomes are investigated by using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN), and CPT-11 as substrates of hCE2. The results demonstrate that shikonin significantly inhibits the activity of hCE2 when FD and NCEN are used as substrates, whereas the half inhibition concentration value of shikonin increased by 5-30 times when CPT-11 was used as the substrate. The inhibition types of shikonin against hCE2 activity reflected by 3 substrates were all best fit to noncompetitive manners. In addition, shikonin was found to distinctly suppress endogenous hCE2 activity, characterized with attenuated fluorescence. Furthermore, for drugs metabolized by hCE2 with the similar binding sites with FD or NCEN, the estimated magnitudes of area under the curve variation were approximately 9-357% in the presence of shikonin. Also, the area under the curve of CPT-11 could be increased by 1-14% following administration of shikonin. These findings have clear clinical implications for the combination of shikonin and hCE2-metabolizing prodrugs.