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BACKGROUND Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a relatively rare and aggressive neoplasm. High-dose methotrexate (HD-MTX) is an effective regimen for the treatment of PCNS-DLBCL, but MTX-related toxicity remains a problem. The aim of this analysis study was to investigate the influence of the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism on HD-MTX-related toxicity in patients with PCNS-DLBCL. MATERIAL/METHODS A prospective, observational study was conducted to analyze 148 MTX courses in 32 patients with PCNS-DLBCL. RESULTS The delayed MTX clearance was observed in 53 cycles (35.8%). The patients carrying the homozygous variant genotype had a higher risk of developing nephrotoxicity than those carrying the wild-type genotype (odds ratio [OR] 13.08; 95% confidence interval [CI], 1.65-103.86; P = .002) or heterozygous variant genotype (OR 8.43; 95% CI, 2.31-30.70; P < .001). Significant differences were observed in hepatotoxicity (OR 9.33; 95% CI, 2.54-34.27; P < .001) and hematologic toxicity (OR 3.09; 95% CI, 1.18-8.07; P = .024) in addition to nephrotoxicity between the homozygous variant genotype and the wild-type genotype. CONCLUSION The homozygous mutation of C to T at nucleotide 677 increases the risk on HD-MTX-related toxicity. The MTHFR C677T polymorphism can be used to predict HD-MTX-related toxicity for patients with PCNS-DLBCL.

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

Owing to the complexity of the sheet pile wall with a relieving platform, there are a large number of factors that affect the mechanical and deformation characteristics of the wall structure. Moreover, studying the influencing factors on the deformation of the retaining wall is beneficial in the selection of design parameters and deformation control. 28 groups of test models of the retaining wall structure are designed to analyze the effect on the deformation of rib pillars and determine the reasonable width and buried depth of the unloading board in this paper. The tests are conducted with and without the unloading board, and different widths and buried depths of the unloading board are also considered. The findings show that, without the external load, the reasonable board width and buried depth are 0.70 times and 0.53 times the wall height. With the external load, the reasonable board width is 0.35 times the wall height, and the large board width cannot effectively reduce the deformation of rib pillars, and the reasonable board width is 0.60 times the wall height. When both the external load and board width are relatively small, the reasonable buried depth is 0.53 times the wall height. However, when the external load is large, the reasonable buried depth is 0.70 times the wall height. The results also show that the setting of the unloading board effectively suppresses the deformation of rib pillars and controls the maximum deformation within an allowable range of the specification.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Rnd3, a Rho GTPase, is involved in the inhibition of actin cytoskeleton dynamics through the Rho kinase-dependent signaling pathway. We previously demonstrated that mice with genetic deletion of Rnd3 developed a markedly larger brain compared with wild-type mice. Here, we demonstrate that Rnd3 knockout mice developed an enlarged subventricular zone, and we identify a novel role for Rnd3 as an inhibitor of Notch signaling in neural stem cells. Rnd3 deficiency, both in vivo and in vitro, resulted in increased levels of Notch intracellular domain protein. This led to enhanced Notch signaling and promotion of aberrant neural stem cell growth, thereby resulting in a larger subventricular zone and a markedly larger brain. Inhibition of Notch activity abrogated this aberrant neural stem cell growth.

Growth factor independence 1 (Gfi-1) has been widely studied for its anti-inflammatory and anti-apoptotic effects. However, whether Gfi-1 has similar effects on H9c2 cardiomyocytes has not yet been reported. In this study, we explored the effect of Gfi-1 on lipopolysaccharide (LPS)-induced inflammatory responses and apoptosis in H9c2 cells. We found that LPS induced the increased expression of TNF-α and IL-6 in the LPS group. After transfection of the Gfi-1 overexpression plasmid, the expression of TNF-α and IL-6 decreased significantly in the LPS + Gfi-1 group. Gfi-1 clearly blocked LPS-induced NF-κB, TNF-α, TNFR1, cleaved-caspase-3 and cleaved-caspase-8 expression and increased Gfi-1 and Bcl-xL expression in H9c2 cells. Similarly, compared with the LPS group, Gfi-1 significantly decreased the expression of cleaved-caspase3/8 and increased the expression of Bcl-xL in the LPS + Gfi-1 group, as verified by immunocytochemical analysis. Furthermore, Gfi-1 markedly inhibited LPS-induced H9c2 cardiomyocyte apoptosis in the LPS + Gfi-1 group, as determined by TEM, TUNEL and flow cytometry. Taken together, these results demonstrate that Gfi-1 may have protective effects against LPS-induced inflammatory responses and apoptosis in H9c2 cells. Gfi-1 may be a novel molecule for treating septic cardiomyopathy.

Functional exhaustion of immune cells is a defining characteristic of HIV-1 chronic infections, exhibiting dysregulation of cellular immune responses and expression of co-inhibitory receptors. Although the molecular mechanisms controlling immune-cell exhaustion retains largely unknown, immune checkpoint blockade strategy has shown inspiring potential to reinvigorate T cell functions in chronic infections. In this study, we investigated peripheral blood mononuclear cells (PBMCs) exhaustion markers from 109 chronic HIV-1-infected patients and found they correlated positively with microRNA-146a, which was inversely correlated with CD4+ T cell count. Intriguingly, ex vivo neutralization of miR-146a in PBMCs from chronic HIV-1 infection exhibited an elevated antiviral cytokines production as well as the expression of GZMB and perforin, while simultaneously, decreased the inhibitory receptors expression such as PD-1, CTLA-4, TIM-3 and LAG-3. These results highlight the importance of miR-146a to HIV-1 induced immune cell exhaustion, and uncover a novel layer of HIV/AIDS pathogenesis and provide potential targets for improved immune intervention.

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.

Background Both high and low prepregnancy body mass index (BMI) has been associated with small for gestational age births (SGA; birthweight below the population specific 10th centile for the gestational age), but results remain inconsistent. We examined the association between maternal BMI and SGA, and evaluated if the associations were modified by preterm birth (being born prior to 37 weeks) status. Methods A population-based cohort study was conducted in Wuhan, China from June 2011, to June 2013. Women who delivered a non-malformed livebirth (n = 76 695) were included using the Wuhan Maternal and Child Health Management Information System. Log-binomial regression models were used to analyse the associations between prepregnancy BMI, categorized using thresholds adapted to the Chinese population, and SGA. Stratified analyses were used to examine the relationship of prepregnancy BMI to preterm-SGA and term-SGA. Results Of the 76 695 live births, 3058 (4.0%) were delivered preterm. For babies born at term, prepregnancy underweight (

IMPORTANCE: Pityriasis rubra pilaris is a rare and disabling cutaneous disease that is frequently recalcitrant to conventional therapies and appears to involve interleukin (IL)-17 overexpression. OBJECTIVE: To investigate the clinical response and safety of ixekizumab in treating pityriasis rubra pilaris. DESIGN, SETTING, AND PARTICIPANTS: Single-arm, investigator-initiated trial conducted in adult patients with moderate to severe pityriasis rubra pilaris at a single-center academic university from June 2018 to January 2020. A total of 41 patients were screened, 12 were enrolled, and 11 completed the full duration of therapy. A referred, consecutive sample was used during participant selection. The treatment period and primary outcome occurred over 24 weeks with additional patient follow-up through 36 weeks. INTERVENTION: Subcutaneous administration of ixekizumab, a humanized IgG4 antibody that binds IL-17A, at the US Food and Drug Administration–approved dosing schedule for treatment of psoriasis for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in Psoriasis Area and Severity Index at 24 weeks. Secondary outcomes included change in affected body surface area, quality of life, induction of sustained remission, and association of improvement with CARD14 genetic variations and cutaneous cytokine expression. RESULTS: A total of 12 white patients (mean [SD] age, 49.8 [15.1] years; 8 male [67%]) were enrolled between June 2018 and April 2019, with 11 completing the full course of intervention. The mean (SEM) improvements in Psoriasis Area and Severity Index, affected body surface area, and Dermatology Life Quality Index were 15.2 (2.1) (P

To assess the relationship between gestational weight gain (GWG) of twin-pregnancy women and twin birth weights, as well as to evaluate whether pre-pregnancy body mass index (BMI) influences this relationship. A cohort study was conducted in Wuhan, China, between 1/01/2011 and 8/31/2017. Women with twin pregnancies who delivered live and non-malformed twins were included (6,925 women and 13,850 infants), based on the Wuhan Maternal and Child Health Management Information System. Logistic regression models were employed to examine the association between GWG and paired small for gestational age (SGA, defined as birth weight

The aim of the present study was to explore the effects of annexin A1 (ANXA1) mimetic peptide AC2-26 on sepsis-induced cardiomyocyte apoptosis in vivo and in vitro and the underlying mechanisms. In the in vivo study, a rat septic model was established by the cecal ligation and puncture (CLP). The rats were divided into control group, sepsis group and AC2-26 group. The rats in the AC2-26 group were intraperitoneally injected with AC2-26 (1 mg/kg) 2 h before CLP, and those in the control group and sepsis group were injected with the same volume of normal saline. The myocardial tissue was examined by hematoxylin and eosin (HE) staining and transmission electron microscopy (TEM). Furthermore, myocardial apoptosis was measured by terminal dUTP nick end-labeling (TUNEL) assay. In the in vitro study, H9C2 cells were cultured and divided into three groups: control group, in which cells were only given the basic culture medium; LPS group, in which cells were treated with 10 μg/mL LPS; AC2-26 group, in which cells were treated with 0.5 μmol/L AC2-26 2 h before 10 μg/mL LPS was given. The apoptosis of H9C2 cells was detected by flow cytometry. The levels of lipoxin A4 receptor (LXA4), phosphoinositide-3-kinase (PI3K) and protein kinase B (PKB or AKT) protein were measured by Western blotting, the activity of NF-κB and the level of TNF-α by ELISA and the activities of caspase-3/8 by using the caspase activity kits. The in vivo study showed that the myocardial pathological damage and myocardial ultrastructural damage were significantly alleviated and the myocardial apoptosis significantly decreased in the AC2-26 group as compared with the sepsis group (P

The major metabolic feature of diabetes is hyperglycemia which has been linked to the diabetes inflammatory processes, and diabetes-related vulnerability to infection. In the present study, we assessed how glucose affected PBMCs in type I interferon (IFN) production and subsequent signaling. We found that the moderately elevated glucose promoted, and high glucose suppressed type I IFN production, respectively. Pre-exposure to high glucose rendered monocytes more sensitive to IFN-α stimulation with heightened signaling, whereas, instantaneous addition of high glucose did not exhibit such effect. Consistent with this finding, the mRNA levels of IFN-α-induced IRF-7 in PBMCs were positively correlated with HbA1c levels of diabetes patients. Additionally, we found that high glucose promoted the production of other proinflammatory cytokines/chemokines. This study suggests that hyperglycemia may affect the inflammatory process in diabetes via promoting proinflammatory cytokines, as well as the host defense against microbial infections through impeding type I IFN production and signaling.

ObjectiveAlthough vomiting in the first trimester has been reported to be associated with preterm birth (PTB), findings supporting this association remain inconsistent. Our aim was to assess the association between vomiting and PTB, as well as evaluate if the association is modified by pre-pregnancy body mass index (BMI).DesignA retrospective cohort study.SettingWuhan, a central city of China.ParticipantsA total of 317 463 pregnant women who had a live, singleton newborn from 1 January 2010 to 23 May 2016 were enrolled in our study.Main outcome measurePTB was defined as gestational age ResultsOf the 317 463 pregnant women, 29.88% (94 857) experienced vomiting in the first trimester and 5.00% (15 889) experienced a PTB. Vomiting in the first trimester increased the risk for PTB and the multivariable adjusted OR was 1.05 (95% CI 1.02 to 1.09). In the stratified analyses, the association of vomiting in the first trimester was significant among underweight women (adjusted OR=1.08, 95% CI 1.04 to 1.17) and normal pre-pregnancy BMI women (adjusted OR=1.06, 95% CI 1.02 to 1.11), but not in overweight women (adjusted OR=1.01, 95% CI 0.90 to 1.14) and obese women (adjusted OR=0.93, 95% CI 0.73 to 1.19).ConclusionsOur study indicates that vomiting in the first trimester was associated with PTB. Additionally, women with underweight and normal pre-pregnancy BMI who experienced vomiting are more likely to have a PTB.

Supplemental Data Supplemental Data include five figures and three tables and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2017.05.003. Supplemental Data Document S1. Figures S1–S5 and Tables S1–S3 Download Document S2. Article plus Supplemental Data Download Web Resources 1000 Genomes, http://www.internationalgenome.org/ ANNOVAR, http://annovar.openbioinformatics.org/en/latest/ BWA-MEM, http://bio-bwa.sourceforge.net/index.shtml Database of Genomic Variants, http://dgv.tcag.ca/dgv/app/home dbSNP, https://www.ncbi.nlm.nih.gov/projects/SNP/ Exome Aggregation Consortium (ExAC) Browser, http://exac.broadinstitute.org/ ExonPrimer, https://ihg.helmholtz-muenchen.de/ihg/ExonPrimer.html GenBank, https://www.ncbi.nlm.nih.gov/genbank/ Genome Analysis Toolkit (GATK), https://software.broadinstitute.org/gatk/ Integrative Genomics Viewer (IGV), http://software.broadinstitute.org/software/igv/ OMIM, https://www.omim.org/ SNPmasker, http://bioinfo.ebc.ee/snpmasker/ UCSC Genome Browser, https://genome.ucsc.edu/index.html Variant Effect Predictor, http://useast.ensembl.org/info/docs/tools/vep/index.html The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet. Although exome sequencing revealed several of the KDSR mutations, we employed genome sequencing to discover a pathogenic 346 kb inversion in multiple probands, and cDNA sequencing and a splicing assay established that two mutations, including a recurrent silent third base change, cause exon skipping. Immunohistochemistry and yeast complementation studies demonstrated that the mutations cause defects in KDSR function. Systemic isotretinoin therapy has achieved nearly complete resolution in the two probands in whom it has been applied, consistent with the effects of retinoic acid on alternative pathways for ceramide generation.

IFAP syndrome is a rare autosomal recessive X-linked disease characterized by the triad of alopecia universalis, severe photophobia, and follicular ichthyosis. It is caused by loss of function of the gene MBTPS2. Its severity varies and there are only a few reports in the literature. We present a patient with characteristic clinical features and a mutation not previously reported.

Epidermal keratinocytes are particularly suitable candidates for in situ gene correction. Intraperitoneal administration of a triplex-forming oligonucleotide (TFO) was previously shown to introduce DNA base changes in a reporter gene in skin, without identifying which cells had been targeted. We extend those previous experiments using two triplex-forming molecules, a peptide nucleic acid–antennapedia (PNA-Antp), and a TFO (AG30), as well as two lines of transgenic mice that have the chromosomally integrated λsupFG1 shuttle-reporter transgene. Successful in vivo genomic modification occurs in the epidermis and dermis in CD1 transgenic mice following either intraperitoneal or intradermal delivery of the PNA-Antp conjugate. FITC-PNA-Antp accumulates in nuclei of keratinocytes, and, after intradermal delivery of the PNA-Antp, chromosomally modified, keratin 5–positive basal keratinocytes persist for at least 10 days. In hairless (SKH1) mice with the λsupFG1 transgene, intradermal delivery of the TFO, AG30, introduces gene modifications in both tail and back skin, and these chromosomal modifications persist in basal keratinocytes for 10 days. Hairless mice should facilitate comparison of various targeting agents and methods of delivery. Gene targeting by repeated local administration of oligonucleotides may prove clinically useful for judiciously selected disease-causing genes in the epidermis.

This study is a nested case control study from a population-based cohort study conducted in Wuhan, China. The aim is to estimate the association between symptoms of depression during pregnancy (DDP), anxiety during pregnancy(ADP), and depression with anxiety during pregnancy (DADP) and low birth weight (LBW) and to examine the extent to which preterm birth (PTB) moderates these associations. Logistic regression analyses were used to model associations between DDP, ADP, and DADP and LBW. Models were stratified by the presence or absence of PTB to examine moderating effects. From the cohort study, 2853 had a LBW baby (cases); 5457 pregnant women served as controls. Women with DDP or ADP only were not at higher risk of having a LBW baby, but DADP was associated with increased risk of LBW (crude OR 1.41, 95% CI 1.17-1.70; adjusted OR 1.29, 95% CI 1.07-1.57), and the significant association was particularly evident between DADP and LBW in PTB, but not in full-term births. Our data suggests that DADP is related to an increased risk of LBW and that this association is most present in PTBs.

Objectives Few studies focus on the symptoms of common mental disorders during pregnancy (CMDP) and risk of preterm birth subtypes (PTB). The purpose of this study was to estimate the association between CMDP and PTB, and to examine whether or not the association between CMDP and PTB varies with the subtype of PTB in Chinese. Methods This population-based case control study, conducted in Wuhan, China, defined cases as every pregnant woman who had a PTB among all births in Wuhan, from June 10, 2011, to June 9, 2013. The same number of pregnant women who had term births was randomly selected as controls. The Electronic Perinatal Health Care Information System, a questionnaire designed for the study, provided data about the participants. Logistic regression analyses were used to model associations between CMDP and PTB, and to test associations between CMDP and two subtypes of PTB. Results The study recruited 8616 cases and an equal number of controls. We successfully collected maternal information on 6656 cases and controls for a response rate of 77.3 %. The incidence of PTB in Wuhan was 4.5 %. Spontaneous preterm births (SPTB) accounted for 60.1 %, and medically induced preterm births (IPTB) accounted for 39.9 % of preterm births. The prevalence rate of CMDP was 15.8 %. CMDP was slightly associated with PTB (crude OR 1.16, 95 % CI 1.01-1.32; adjusted OR 1.15, 95 % CI 1.00-1.32), further analyses showed CMDP was associated with IPTB (aOR 1.25, 95 % CI 1.04-1.50), but not with SPTB. Conclusion Our data suggest that CMDP is related to an increased risk of PTB, and that this association is primarily due to IPTB rather than SPTB.

Congenital ichthyosiform erythroderma is an autosomal recessive ichthyosis characterized by severe scaling and erythroderma. We report a family of three siblings who were all born with a collodion membrane and presented with diffuse scaling and pruritus. All three children subsequently developed chronic cutaneous dermatophyte infections requiring oral antifungals. One child developed superinfection with methicillin-resistant Staphylococcus aureus requiring antibiotics.

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

The accessibility of skin makes it an ideal target organ for nucleic acid-based therapeutics; however, effective patient-friendly delivery remains a major obstacle to clinical utility. A variety of limited and inefficient methods of delivering nucleic acids to keratinocytes have been demonstrated; further advances will require well-characterized reagents, rapid noninvasive assays of delivery, and well-developed skin model systems. Using intravital fluorescence and bioluminescence imaging and a standard set of reporter plasmids we demonstrate transfection of cells in mouse and human xenograft skin using intradermal injection and two microneedle array delivery systems. Reporter gene expression could be detected in individual keratinocytes, in real-time, in both mouse skin as well as human skin xenografts. These studies revealed that non-invasive intravital imaging can be used as a guide for developing gene delivery tools, establishing a benchmark for comparative testing of nucleic acid skin delivery technologies.

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.