The Impact of Body Mass Index Upon the Efficacy of Adalimumab in Hidradenitis Suppurativa.

Elevated BMI in Hidradenitis Suppurativa is associated with decreased response to Adalimumab therapy. BMI is proposed to segregate distinct disease subtypes. It remains unresolved whether a threshold BMI exists above which increased dosages may provide clinical benefit. Individual patient data from 578 PIONEER Phase 3 participants were analyzed. Descriptive, multivariable regression analysis and receiver operating characteristic (ROC) curves were calculated to assess the relationship between BMI and clinical outcome measures using R v3.5.3. Participants in the overweight and obese BMI category had reduced odds (58 and 67%, respectively) of achieving HiSCR [OR = 0.42 (95%CI -0.19, 0.91) p = 0.03], [OR = 0.33 (95%CI 0.16, 0.67) p = 0.002] compared to participants with BMI < 25. Reduction in AN count and IHS4 score was not significantly associated. ROC analysis did not reveal any cut off value predictive of treatment outcome. No correlation between BMI and baseline disease activity or covariate interactions were identified. These findings suggest BMI is a significant covariate in the setting of lower baseline disease activity, supporting the concept of disease heterogeneity and differential therapeutic response to Adalimumab.

Dermal tunnels influence time to clinical response and family history influences time to loss of clinical response in patients with hidradenitis suppurativa treated with adalimumab.

BACKGROUND: Clinical response in hidradenitis suppurativa (HS) is most commonly assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR) measure. Dermal tunnels, increased body mass index, smoking and antibiotic use significantly decrease the odds of achieving HiSCR. However, there are few data exploring if clinical features are also associated with length of time to achieve clinical response and/or time to lose clinical response. AIM: To explore whether variables associated with achievement of HiSCR are associated with time to achieve HiSCR and time to loss of HiSCR in patients with HS treated with adalimumab 40 mg weekly in the PIONEER open-label extension study. METHODS: Time-to-event analyses were performed to estimate time to achieve HiSCR and time to loss of HiSCR. The log rank test was used to compare cumulative incidence curves for a priori patient- and disease-associated factors. Cox regression analysis was performed to compare time-to-event outcomes in the presence of a priori variables. All statistical analyses were completed with R software (V3.5.3). RESULTS: Presence of dermal tunnels significantly increased the time to achieve HiSCR (median 32.6 vs. 14.3 weeks, P = 0.02) and the hazard ratio (HR) was significant after controlling for patient and disease factors (HR = 0.70, 95% CI 0.51-0.96, P = 0.03). A positive family history of HS significantly decreased the time to loss of HiSCR (median 11.4 vs. 18 weeks, P < 0.001) and remained significant in Cox regression analysis (HR = 2.01, 95% CI 1.40-2.88, P < 0.001). CONCLUSION: The presence of dermal tunnels significantly influences the odds of achieving HiSCR and the time to achieve HiSCR, while family history influences time to loss of HiSCR.

Malignancy and infection risk during adalimumab therapy in hidradenitis suppurativa.

BACKGROUND: The association of adalimumab therapy with malignancy and infection is established in other inflammatory diseases; however, rates of hidradenitis suppurativa (HS) are based on case reports or retrospective healthcare data and the effect of adalimumab therapy on these rates is unknown. Previously reported rates in the PIONEER OLE Phase 3 study reported on rates only in a subpopulation of 88 participants rather than the entire cohort. AIM: To quantify rates of malignancy and serious infection in all patients with HS treated with adalimumab 40 mg weekly. METHODS: Reanalysis was undertaken of individual patient data from the PIONEER 1, PIONEER 2 and PIONEER open-label extension Phase 3 trial data encompassing 591 unique patients with HS administered adalimumab 40 mg weekly without concurrent antibiotic exposure. Incidence rates of serious infection and malignancy were calculated. RESULTS: Incidence rates of serious infection and malignancy were 2.14 and 0.46 per 100 patient-years, respectively. Rates of infection and malignancy were comparable to those in other inflammatory conditions examined. CONCLUSION: Incidence of serious infection in patients with HS on adalimumab is comparable to those with psoriasis and inflammatory arthropathies, but the incidence of malignancy is increased. This may reflect disease-specific malignancy risk rather than an effect of adalimumab.

Transduction motif analysis of gastric cancer based on a human signaling network.

To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

Transduction motif analysis of gastric cancer based on a human signaling network

To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR, MAPK14, BCL2L1, KRT18, PTPN6, CASP3, TGFBR2, AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging.

OBJECTIVE: The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. METHODS: Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. RESULTS: Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4- subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status×APOEε4×Age) interaction-p-values=0.005 to 0.03]. INTERPRETATION: These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.

Epipolythiodioxopiperazines from fungi: chemistry and bioactivities.

Epipolythiodioxopiperazines (ETPs), characterized by a unique bridged disulfide or polysulfide dioxopiperazine six-membered ring, occur in many fungi. Due to its broad spectra of bioactivities, ETPs have drawn wide attention in recent years. This review covers diverse natural sources that produce ETPs, the synthetic chemistry of ETPs and an overview of promising bioactivities exhibited by some well studied ETPs. The plausible biosynthetic hypotheses of ETPs and some new results on antitumor activity of ETPs are also reviewed.

Altered neurometabolites and motor integration in children exposed to methamphetamine in utero.

Methamphetamine (METH) is a neurotoxic drug. This study aimed to evaluate brain metabolite levels and cognitive function in young children with prenatal METH exposure. 101 children ages 3-4 years were evaluated with neuropsychological tests and underwent proton magnetic resonance spectroscopy ((1)H-MRS) without sedation. Complete datasets from 49 METH-exposed and 49 controls who completed the neuropsychological test battery, and 38 METH-exposed and 37 controls with high-quality MR spectra are reported here. Despite similar physical characteristics (including head circumference), global cognitive function (on Stanford-Binet), parental education, intelligence, mood, and socioeconomic status, METH-exposed children had higher total creatine (tCr: +7%, p=0.003), N-acetyl compounds (NA: +4.3%, p=0.004) and glutamate+glutamine (GLX: +9.6%, p=0.02) concentrations in the frontal white matter, but lower myoinositol (MI: -7%, p=0.01) and MI/tCr (-7.5%, p=0.03) in the thalamus, than control children. The higher frontal white matter NA in the METH-exposed children was due to the higher NA in the METH-exposed girls (+10.2%, p=0.003), but not the boys (+0.8%) compared to sex-matched controls. Furthermore, the METH-exposed children had poorer performance on a visual motor integration (VMI) task, which correlated with lower MI in the thalamus (r=0.26, p=0.03). The higher NA, tCr and GLX concentrations suggest higher neuronal density or cellular compactness in the white matter, especially in the girls, whereas the lower MI suggests lower glial content in the thalamus of these METH-expose children. These findings combined with their poorer performance on VMI also suggest accelerated but aberrant neuronal and glial development in these brain regions.

Microelectrical characterizations of junctions in solar cell devices by scanning Kelvin probe force microscopy.

Scanning Kelvin probe force microscopy was applied to the microelectrical characterizations of junctions in solar cell devices. Surface Fermi-level pinning effects on the surface potential measurement were avoided by applying a bias voltage (V(b)) to the device and taking the V(b)-induced potential and electric field changes. Two characterizations are presented: the first is a direct measurement of Bi-induced junction shift in GaInNAs(Bi) cells; the second is a junction-uniformity measurement in a-Si:H devices. In the first characterization, using Bi as a surfactant during the molecular beam epitaxy growth of GaInNAs(Bi) makes the epitaxial layer smoother. However, the electrical potential measurement exhibits a clear Bi-induced junction shift to the back side of the absorber layer, which results in significant device degradation. In the second characterization, the potential measurement reveals highly non-uniform electric field distributions across the n-i-p junction of a-Si:H devices; the electric field concentrates much more at both n/i and i/p interfaces than in the middle of the i-layer. This non-uniform electric field is due possibly to high defect concentrations at the interfaces. The potential measurements further showed a significant improvement in the electric field uniformity by depositing buffer layers at the interfaces, and this indeed improved the device performance.

Electrically benign behavior of grain boundaries in polycrystalline CuInSe2 films.

The classic grain-boundary (GB) model concludes that GBs in polycrystalline semiconductors create deep levels that are extremely harmful to optoelectronic applications. However, our first-principles density-functional theory calculations reveal that, surprisingly, GBs in CuInSe2 (CIS) do not follow the classic GB model: GBs in CIS do not create deep levels due to the large atomic relaxation in GB regions. Thus, unlike the classic GB model, GBs in CIS are electrically benign, which explains the long-standing puzzling fact that polycrystalline CIS solar cells with remarkable efficiency can be achieved without deliberate GB passivation. This benign electrical character of GBs in CIS is confirmed by our scanning Kelvin probe microscopy measurements on Cu(In,Ga)Se2 chalcopyrite films.

Scanning tunneling spectroscopy of Ag films: the effect of periodic versus quasiperiodic modulation.

By using scanning tunneling spectroscopy to probe a silver thin film that contains both periodic and quasiperiodic modulation, and by using Fourier analysis, we unravel the influences of individual Fourier components of the scattering potential (periodic versus quasiperiodic) on the electronic structure of a one-dimensional quasiperiodically modulated thin Ag film. Along the periodically modulated direction, a Bragg reflection-induced energy gap is observed in k space. On the other hand, the exotic E vs k spectrum with many minigaps was observed along the quasiperiodic direction.

Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study.

The objective of this study was to determine objective response and overall survival (OS) and progression-free survival (PFS) following cisplatin plus tirapazamine treatment in eligible consenting patients with metastatic or recurrent squamous or adenosquamous carcinoma of the cervix. Treatment consisted of intravenous tirapazamine, 260 mg/m(2), followed by cisplatin, 75 mg/m(2), every 21 days for six cycles. Of 56 registered cases, 52 were evaluable for toxicity. There were six grade 4 toxicities (anemia [three], dyspnea [one], neutropenia/granulocytopenia [one], and dehydration [one]). Fifty-three patients were evaluable for response, OS, and PFS. The 6-month OS rate was 56.6% (95% CI 43.3-69.9%). The objective response rate was 32.1% (4 complete [2 confirmed and 2 unconfirmed] and 13 partial [8 confirmed and 5 unconfirmed]). Higher response rates (16/34 [47.1%] vs 1/19 [5.3%], P= 0.0018) were observed in patients who had not previously received radiation-sensitizing chemotherapy, as were OS and PFS (13.9 vs 4.0 months, P < 0.0001; 5.3 vs 1.8 months, P= 0.01). The OS was considered too low to warrant further testing in this disease setting. Despite this, tirapazamine plus cisplatin was active in patients who had not received cisplatin previously. Prior use of radiosensitizing chemotherapy impacted response and survival significantly and should be considered in future clinical trials.

Building Pb nanomesas with atomic-layer precision.

We demonstrate a novel scheme for manipulating metallic nanostructures involving a macroscopic number of atoms, yet with precise control in their local structures. The scheme entails a two-step process: (a) a triggering step using a scanning tunneling microscope, followed by (b) self-driven and self-limiting mass-transfer process. By using this scheme, we construct Pb nanomesas on Si(111) substrates whose thickness can be controlled with atomic-layer precision. The kinetic barrier for the mass transfer and the underlying mechanism behind this novel manipulation are determined.

[TFAR19 enhances the opening of permeability transition pore in the mitochondrial membrane of mice liver].

TFAR19 TF-1 cell apoptosis related gene 19 is a novel apoptosis-related gene cloned from human leukemia cell line TF-1 cells undergoing apoptosis in 1999 (accession number AF014955 in GenBank). The human TFAR19 encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. TFAR19 exhibits a ubiquitous expression pattern and its expression is upregulated in tumor cells undergoing apoptosis. Overexpression of TFAR19 could enhance apoptosis of some tumor cells induced by growth factor withdrawal or serum deprivation. But the exact mechanism of TFAR19 is unclear. Mitochondria not only provides energy for the cell, but also plays a critical role on cell death or survival. The release of apoptosis promoting factor, such as cytochrome c from mitochondria, resulted by the damage of mitochondrial membrane integrity, is the key factor controlling apoptosis. The permeability transition pore (PTP) of mitochondria is a protein complex located between the mitochondrial membranes, and it plays an important role in regulating the integrity of mitochondrial membrane. In this study, the effect of recombinant TFAR19 on isolated mitochondrial PTP, membrane potential, and release of cytochrome c was investigated in vitro. The results indicated that recombinant TFAR19 facilitated the isolated mitochondrial PTP opening, decreased the membrane potential, and promoted the release of cytochrome c. The effect of TFAR19 on mitochondria is implemented by opening the mitochondrial PTP. Experimental results implicate that TFAR19 may positively feedback apoptosis signal of mitochondria, forming a positive loop to promote apoptosis.

Quantitative determination of the metastability of flat Ag overlayers on GaAs(110).

Atomically flat ultrathin Ag films on GaAs(110) can be formed through a kinetic pathway. However, such films are metastable and will transform to 3D islands upon high temperature annealing. Using scanning tunneling microscopy, we have measured quantitatively the layer-resolved metastability of flat Ag overlayers as they evolve toward their stable state, and deduced the corresponding kinetic barrier the system has to overcome in reaching the stable state. These results indicate that the metastability of the Ag overlayer is defined by the quantum nature of the conduction electrons confined within the overlayer.

Molecular similarity of Drosophila melanogaster alcohol dehydrogenase thermostable alleles from populations on different continents.

Allele specific oligonucleotide probes have been used to show that DNA, amplified by the polymerase chain reaction, from eleven thermostable Adh alleles extracted from populations on different continents contains the triplet TCC, which distinguishes AdhFChD (Fast Chateau Douglas) from AdhF (Fast). The molecular similarity of Adh thermostable alleles suggests that they had a common origin, and it is argued that the mutation probably occurred in China where high frequencies of AdhFChD are found.

Genetic differentiation in populations of Drosophila melanogaster from the Peoples' Republic of China: comparison with patterns on other continents.

Geographic variation at eight allozyme loci in eight natural populations of Drosophila melanogaster from the People's Republic of China (P.R.C.) was collated with data from Japanese populations and compared with previous reports for other continents. G6pdF, Est-6(1.00) and AdhS were significantly correlated with latitude. Whilst the variation in Est6(1.00) was opposite to that previously reported, AdhS showed latitudinal clines consistent with data from the northern and southern hemispheres. A thermostable variant, AdhFChD, was found at high frequency in the southern P.R.C. populations and it is suggested that the mutation occurred in this region and was then dispersed to other continents.

Restriction endonucleases variation in the region of the alcohol dehydrogenase gene: a comparison of null and normal alleles from natural populations of Drosophila melanogaster.

The restriction endonuclease variation in the 12 kb region surrounding twelve Adh null alleles extracted from three Tasmanian populations has been compared with normal alleles from the same populations. Each of the null alleles had the same haplotype as revealed by digestions with eight hexanucleotide restriction enzymes. This haplotype also occurred in 4 of the 46 chromosomes bearing normal alleles which were tested; these four chromosomes with the null allele haplotype carried the AdhS allele. The data suggest that the Adh null alleles from geographically separate populations share a common ancestry and are derived from the same mutation in an AdhS allele.