Phase 3 Trial of Nemolizumab in Patients with Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic, debilitating, and severely pruritic neuroimmunologic skin disease. Nemolizumab, an interleukin-31 receptor alpha antagonist, down-regulates key pathways in the pathogenesis of prurigo nodularis. METHODS: In this phase 3, double-blind, multicenter, randomized trial, we assigned adults with moderate-to-severe prurigo nodularis to receive an initial 60-mg dose of nemolizumab followed by subcutaneous injections of 30 mg or 60 mg (depending on baseline weight) every 4 weeks for 16 weeks or matching placebo. The primary end points were an itch response (a reduction of ≥4 points on the Peak Pruritus Numerical Rating Scale [PP-NRS; scores range from 0 to 10, with higher scores indicating more severe itch]) and an Investigator's Global Assessment (IGA) response (a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4] and a reduction from baseline to week 16 of ≥2 points). There were five key secondary end points. RESULTS: A total of 274 patients underwent randomization; 183 were assigned to the nemolizumab group, and 91 to the placebo group. Treatment efficacy was shown with respect to both primary end points at week 16; a greater percentage of patients in the nemolizumab group than in the placebo group had an itch response (56.3% vs. 20.9%; strata-adjusted difference, 37.4 percentage points; 95% confidence interval [CI], 26.3 to 48.5), and a greater percentage in the nemolizumab group had an IGA response (37.7% vs. 11.0%; strata-adjusted difference, 28.5 percentage points; 95% CI, 18.8 to 38.2) (P<0.001 for both comparisons). Benefits were observed for the five key secondary end points: itch response at week 4 (41.0% vs. 7.7%), PP-NRS score of less than 2 at week 4 (19.7% vs. 2.2%) and week 16 (35.0% vs. 7.7%), and an improvement of 4 or more points on the sleep disturbance numerical rating scale (range, 0 [no sleep loss] to 10 [unable to sleep at all]) at week 4 (37.2% vs. 9.9%) and week 16 (51.9% vs. 20.9%) (P<0.001 for all comparisons). The most common individual adverse events were headache (6.6% vs. 4.4%) and atopic dermatitis (5.5% vs. 0%). CONCLUSIONS: Nemolizumab monotherapy significantly reduced the signs and symptoms of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT04501679; EudraCT number, 2019-004789-17.).

MYSM1 attenuates DNA damage signals triggered by physiologic and genotoxic DNA breaks.

BACKGROUND: Patients with deleterious variants in MYSM1 have an immune deficiency characterized by B-cell lymphopenia, hypogammaglobulinemia, and increased radiosensitivity. MYSM1 is a histone deubiquitinase with established activity in regulating gene expression. MYSM1 also localizes to sites of DNA injury but its function in cellular responses to DNA breaks has not been elucidated. OBJECTIVES: This study sought to determine the activity of MYSM1 in regulating DNA damage responses (DDRs) to DNA double-stranded breaks (DSBs) generated during immunoglobulin receptor gene (Ig) recombination and by ionizing radiation. METHODS: MYSM1-deficient pre- and non-B cells were used to determine the role of MYSM1 in DSB generation, DSB repair, and termination of DDRs. RESULTS: Genetic testing in a newborn with abnormal screen for severe combined immune deficiency, T-cell lymphopenia, and near absence of B cells identified a novel splice variant in MYSM1 that results in nearly absent protein expression. Radiosensitivity testing in patient's peripheral blood lymphocytes showed constitutive γH2AX, a marker of DNA damage, in B cells in the absence of irradiation, suggesting a role for MYSM1 in response to DSBs generated during Ig recombination. Suppression of MYSM1 in pre-B cells did not alter generation or repair of Ig DSBs. Rather, loss of MYSM1 resulted in persistent DNA damage foci and prolonged DDR signaling. Loss of MYSM1 also led to protracted DDRs in U2OS cells with irradiation induced DSBs. CONCLUSIONS: MYSM1 regulates termination of DNA damage responses but does not function in DNA break generation and repair.

Socioeconomic impacts of airborne and droplet-borne infectious diseases on industries: a systematic review.

BACKGROUND: Recent pandemics have had far-reaching effects on the world's largest economies and amplified the need to estimate the full extent and range of socioeconomic impacts of infectious diseases outbreaks on multi-sectoral industries. This systematic review aims to evaluate the socioeconomic impacts of airborne and droplet-borne infectious diseases outbreaks on industries. METHODS: A structured, systematic review was performed according to the PRISMA guidelines. Databases of PubMed, Scopus, Web of Science, IDEAS/REPEC, OSHLINE, HSELINE, and NIOSHTIC-2 were reviewed. Study quality appraisal was performed using the Table of Evidence Levels from Cincinnati Children's Hospital Medical Center, Joanna Briggs Institute tools, Mixed Methods Appraisal Tool, and Center of Evidence Based Management case study critical appraisal checklist. Quantitative analysis was not attempted due to the heterogeneity of included studies. A qualitative synthesis of primary studies examining socioeconomic impact of airborne and droplet-borne infectious diseases outbreaks in any industry was performed and a framework based on empirical findings was conceptualized. RESULTS: A total of 55 studies conducted from 1984 to 2021 were included, reporting on 46,813,038 participants working in multiple industries across the globe. The quality of articles were good. On the whole, direct socioeconomic impacts of Coronavirus Disease 2019, influenza, influenza A (H1N1), Severe Acute Respiratory Syndrome, tuberculosis and norovirus outbreaks include increased morbidity, mortality, and health costs. This had then led to indirect impacts including social impacts such as employment crises and reduced workforce size as well as economic impacts such as demand shock, supply chain disruptions, increased supply and production cost, service and business disruptions, and financial and Gross Domestic Product loss, attributable to productivity losses from illnesses as well as national policy responses to contain the diseases. CONCLUSIONS: Evidence suggests that airborne and droplet-borne infectious diseases have inflicted severe socioeconomic costs on regional and global industries. Further research is needed to better understand their long-term socioeconomic impacts to support improved industry preparedness and response capacity for outbreaks. Public and private stakeholders at local, national, and international levels must join forces to ensure informed systems and sector-specific cost-sharing strategies for optimal global health and economic security.

Efficiency enhancement of ultrathin CIGS solar cells by optimal bandgap grading. Part III: piecewise-homogeneous grading.

In Parts I [Appl. Opt.58, 6067 (2019)APOPAI0003-693510.1364/AO.58.006067] and II [Appl. Opt.61, 10049 (2022)APOPAI0003-693510.1364/AO.474920], we used a coupled optoelectronic model to optimize a thin-film CIGS solar cell with a graded-bandgap photon-absorbing layer, periodically corrugated backreflector, and multilayered antireflection coatings. Bandgap grading of the CIGS photon-absorbing layer was continuous and either linear or nonlinear, in the thickness direction. Periodic corrugation and multilayered antireflection coatings were found to engender slight improvements in the efficiency. In contrast, bandgap grading of the CIGS photon-absorbing layer leads to significant enhancement of efficiency, especially when the grading is continuous and nonlinear. However, practical implementation of continuous nonlinear grading is challenging compared to piecewise-homogeneous grading. Hence, for this study, we investigated piecewise-homogeneous approximations of the optimal linear and nonlinear grading profiles, and found that an equivalent efficiency is achieved using piecewise-homogeneous grading. An efficiency of 30.15% is predicted with a three-layered piecewise-homogeneous CIGS photon-absorbing layer. The results will help experimentalists to implement optimal designs for highly efficient CIGS thin-film solar cells.

Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.

BACKGROUND: Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis. METHODS: We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18. RESULTS: A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms. CONCLUSIONS: Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.).

Non-POU Domain-Containing Octomer-Binding (NONO) protein expression and stability promotes the tumorigenicity and activation of Akt/MAPK/ß-catenin pathways in human breast cancer cells.

Breast cancer is one of the most common cancers with a high mortality rate, underscoring the need to identify new therapeutic targets. Here we report that non-POU domain-containing octamer-binding (NONO) protein is overexpressed in breast cancer and validated the interaction of the WW domain of PIN1 with c-terminal threonine-proline (thr-pro) motifs of NONO. The interaction of NONO with PIN1 increases the stability of NONO by inhibiting its proteasomal degradation, and this identifies PIN1 as a positive regulator of NONO in promoting breast tumor development. Functionally, silencing of NONO inhibits the growth, survival, migration, invasion, epithelial to mesenchymal transition (EMT), and stemness of breast cancer cells in vitro. A human metastatic breast cancer cell xenograft was established in transparent zebrafish (Danio rerio) embryos to study the metastatic inability of NONO-silenced breast cancer cells in vivo. Mechanistically, NONO depletion promotes the expression of the PDL1 cell-surface protein in breast cancer cells. The identification of novel interactions of NONO with c-Jun and ß-catenin proteins and activation of the Akt/MAPK/ß-catenin signaling suggests that NONO is a novel regulator of Akt/MAPK/ß-catenin signaling pathways. Taken together, our results indicated an essential role of NONO in the tumorigenicity of breast cancer and could be a potential target for anti-cancerous drugs. Video Abstract.

Identification and validation of microtubule depolymerizing agent, CYT997, as a potential drug candidate for hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a typically fatal malignancy with limited treatment options and poor survival rates, despite recent FDA approvals of newer treatment options. We aim to address this unmet need by using a proprietary computational drug discovery platform that identifies drug candidates with the potential to advance rapidly and successfully through preclinical studies. METHODS: We generated an in silico model of HCC biology to identify the top 10 small molecules with predicted efficacy. The most promising candidate, CYT997, was tested for its in vitro effects on cell viability and cell death, colony formation, cell cycle changes, and cell migration/invasion in HCC cells. We used an HCC patient-derived xenograft (PDX) mouse model to assess its in vivo efficacy. RESULTS: CYT997 was significantly more cytotoxic against HCC cells than against primary human hepatocytes, and sensitized HCC cells to sorafenib. It arrested cell cycle at the G2/M phase with associated up-regulations of p21, p-MEK1/2, p-ERK, and down-regulation of cyclin B1. Cell apoptosis and senescence-like morphology were also observed. CYT997 inhibited HCC cell migration and invasion, and down-regulated the expressions of acetylated tubulins, ß-tubulin, glypican-3 (GPC3), ß-catenin, and c-Myc. In vivo, CYT997 (20 mg/kg, three times weekly by oral gavage) significantly inhibited PDX growth, while being non-toxic to mice. Immunohistochemistry confirmed the down-regulation of GPC3, c-Myc, and Ki-67, supporting its anti-proliferative effect. CONCLUSION: CYT997 is a potentially efficacious and non-toxic drug candidate for HCC therapy. Its ability to down-regulate GPC3, ß-catenin, and c-Myc highlights a novel mechanism of action.

Optoelectronic optimization of graded-bandgap thin-film AlGaAs solar cells. Part II: optimal antireflection front-surface texturing.

In Part I [Appl. Opt.59, 1018 (2020)APOPAI0003-693510.1364/AO.381246], we used a coupled optoelectronic model to optimize a thin-film AlGaAs solar cell with a graded-bandgap photon-absorbing layer and a periodically corrugated Ag backreflector combined with localized ohmic Pd-Ge-Au backcontacts, because both strategies help to improve the performance of AlGaAs solar cells. However, the results in Part I were affected by a normalization error, which came to light when we replaced the hybridizable discontinuous Galerkin scheme for electrical computation by the faster finite-difference scheme. Therefore, we re-optimized the solar cells containing an n-AlGaAs photon-absorbing layer with either a (i) homogeneous, (ii) linearly graded, or (iii) nonlinearly graded bandgap. Another way to improve the power conversion efficiency is by using a surface antireflection texturing on the wavelength scale, so we also optimized four different types of 1D periodic surface texturing: (i) rectangular, (ii) convex hemi-elliptical, (iii) triangular, and (iv) concave hemi-elliptical. Our new results show that the optimal nonlinear bandgap grading enhances the efficiency by as much as 3.31% when the n-AlGaAs layer is 400 nm thick and 1.14% when that layer is 2000 nm thick. A hundredfold concentration of sunlight can enhance the efficiency by a factor of 11.6%. Periodic texturing of the front surface on the scale of 0.5-2 free-space wavelengths provides a small relative enhancement in efficiency over the AlGaAs solar cells with a planar front surface; however, the enhancement is lower when the n-AlGaAs layer is thicker.

Hydrogen-deuterium exchange reveals a dynamic DNA-binding map of replication protein A.

Replication protein A (RPA) binds to single-stranded DNA (ssDNA) and interacts with over three dozen enzymes and serves as a recruitment hub to coordinate most DNA metabolic processes. RPA binds ssDNA utilizing multiple oligosaccharide/oligonucleotide binding domains and based on their individual DNA binding affinities are classified as high versus low-affinity DNA-binding domains (DBDs). However, recent evidence suggests that the DNA-binding dynamics of DBDs better define their roles. Utilizing hydrogen-deuterium exchange mass spectrometry (HDX-MS), we assessed the ssDNA-driven dynamics of the individual domains of human RPA. As expected, ssDNA binding shows HDX changes in DBDs A, B, C, D and E. However, DBD-A and DBD-B are dynamic and do not show robust DNA-dependent protection. DBD-C displays the most extensive changes in HDX, suggesting a major role in stabilizing RPA on ssDNA. Slower allosteric changes transpire in the protein-protein interaction domains and linker regions, and thus do not directly interact with ssDNA. Within a dynamics-based model for RPA, we propose that DBD-A and -B act as the dynamic half and DBD-C, -D and -E function as the less-dynamic half. Thus, segments of ssDNA buried under the dynamic half are likely more readily accessible to RPA-interacting proteins.

Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.

Differential Analysis of Mycelial Proteins and Metabolites From Rigidoporus Microporus During In Vitro Interaction With Hevea Brasiliensis.

Rigidoporus microporus is the fungus accountable for the white root rot disease that is detrimental to the rubber tree, Hevea brasiliensis. The pathogenicity mechanism of R. microporus and the identity of the fungal proteins and metabolites involved during the infection process remain unclear. In this study, the protein and metabolite profiles of two R. microporus isolates, Segamat (SEG) and Ayer Molek (AM), were investigated during an in vitro interaction with H. brasiliensis. The isolates were used to inoculate H. brasiliensis clone RRIM 2025, and mycelia adhering to the roots of the plant were collected for analysis. Transmission electron microscope (TEM) images acquired confirms the hyphae attachment and colonization of the mycelia on the root of the H. brasiliensis clones after 4 days of inoculation. The protein samples were subjected to 2-DE analysis and analyzed using MALDI-ToF MS/MS, while the metabolites were extracted using methanol and analyzed using LC/MS-QTOF. Based on the differential analyses, upregulation of proteins that are essential for fungal evolution such as malate dehydrogenase, fructose 1,6-biphosphate aldolase, and glyceraldehyde-3-phosphate dehydrogenase hints an indirect role in fungal pathogenicity, while metabolomic analysis suggests an increase in acidic compounds which may lead to increased cell wall degrading enzyme activity. Bioinformatics analyses revealed that the carbohydrate and amino acid metabolisms were prominently affected in response to the fungal pathogenicity. In addition to that, other pathways that were significantly affected include "Protein Ubiquitination Pathway," Unfolded Protein Response," "HIFα Signaling," and "Sirtuin Signaling Pathway." The identification of responsive proteins and metabolites from this study promotes a better understanding of mechanisms underlying R. microporus pathogenesis and provides a list of potential biological markers for early recognition of the white root rot disease.

Efficiency enhancement of ultrathin CIGS solar cells by optimal bandgap grading. Part II: finite-difference algorithm and double-layer antireflection coatings.

In Part I [Appl. Opt.58, 6067 (2019)APOPAI003-693510.1364/AO.58.006067], we used a coupled optoelectronic model to optimize a thin-film C u I n 1-ξ G a ξ S e 2 (CIGS) solar cell with a graded-bandgap photon-absorbing layer and a periodically corrugated backreflector. The increase in efficiency due to the periodic corrugation was found to be tiny and that, too, only for very thin CIGS layers. Also, it was predicted that linear bandgap-grading enhances the efficiency of the CIGS solar cells. However, a significant improvement in solar cell efficiency was found using a nonlinearly (sinusoidally) graded-bandgap CIGS photon-absorbing layer. The optoelectronic model comprised two submodels: optical and electrical. The electrical submodel applied the hybridizable discontinuous Galerkin (HDG) scheme directly to equations for the drift and diffusion of charge carriers. As our HDG scheme sometimes fails due to negative carrier densities arising during the solution process, we devised a new, to the best of our knowledge, computational scheme using the finite-difference method, which also reduces the overall computational cost of optimization. An unfortunate normalization error in the electrical submodel in Part I came to light. This normalization error did not change the overall conclusions reported in Part I; however, some specifics did change. The new algorithm for the electrical submodel is reported here along with updated numerical results. We re-optimized the solar cells containing a CIGS photon-absorbing layer with either (i) a homogeneous bandgap, (ii) a linearly graded bandgap, or (iii) a nonlinearly graded bandgap. Considering the meager increase in efficiency with the periodic corrugation and additional complexity in the fabrication process, we opted for a flat backreflector. The new algorithm is significantly faster than the previous algorithm. Our new results confirm efficiency enhancement of 84% (resp. 63%) when the thickness of the CIGS layer is 600 nm (resp. 2200 nm), similarly to Part I. A hundredfold concentration of sunlight can increase the efficiency by an additional 27%. Finally, the currently used 110-nm-thick layer of M g F 2 performs almost as well as optimal single- and double-layer antireflection coatings.

A prospective multi-center study comparing the complication profile of modest systemic hypothermia versus normothermia for acute cervical spinal cord injury.

STUDY DESIGN: Prospective multi-center trial. OBJECTIVES: To characterize the complication profile associated with modest systemic hypothermia after acute cervical SCI in a prospective multi-center study. SETTING: Five trauma centers in the United States. METHODS: We analyzed data from a prospective, multi-center trial on the use of modest systemic hypothermia for acute cervical SCI. Patients with acute cervical SCI were assigned to receive modest systemic hypothermia (33 C) or standard of care medical treatment. Patients in the hypothermia group were cooled to 33 C and maintained at the target temperature for 48 h. Complication profile and the rate of complications within the first 6 weeks after injury were compared between the two groups. Multiple regression analysis was performed to determine risk factors for complications after injury. RESULTS: Fifty patients (hypothermia: 27, control: 23) were analyzed for this study. Median age was significantly lower in the hypothermia arm (39 vs 59 years, p = 0.02). Respiratory complications were the most common (hypothermia: 55.6% vs control: 52.2%, p = 0.81). The rate of deep vein thrombosis was not significantly different between the two groups (hypothermia: 14.8% vs control 17.4%, p = 0.71). The rate of complications was not statistically different between the two groups. CONCLUSION: In this prospective multi-center controlled trial, preliminary data show that modest systemic hypothermia was not associated with increased risk of complications within the first 6 weeks after acute cervical SCI. TRIAL INFORMATION: The study is registered on clinicaltrials.gov NCT02991690. University of Miami IRB (Central IRB) approval No.: 20160758. Emory University IRB #IRB00093786.

Hypothermia for Patients Requiring Evacuation of Subdural Hematoma: A Multicenter Randomized Clinical Trial.

BACKGROUND: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome. METHODS: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels. RESULTS: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups. CONCLUSIONS: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups.

Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

Natural Polymer-Based Graphene Oxide Bio-nanocomposite Hydrogel Beads: Superstructures with Advanced Potentials for Drug Delivery.

The current study sought to create graphene oxide-based superstructures for gastrointestinal drug delivery. Graphene oxide has a large surface area that can be used to load anti-cancer drugs via non-covalent methods such as surface adsorption and hydrogen bonding. To enhance the bio-applicability of graphene oxide, nano-hybrids were synthesized by encapsulating the graphene oxide into calcium alginate hydrogel beads through the dripping-extrusion technique. These newly developed bio-nanocomposite hybrid hydrogel beads were evaluated in structural analysis, swelling study, drug release parameters, haemolytic assay, and antibacterial activity. Doxorubicin served as a model drug. The drug entrapment efficiency was determined by UV-spectroscopy analysis and was found to be high at ⁓89% in graphene oxide hybrid hydrogel beads. These fabricated hydrogel beads ensure the drug release from a hybrid polymeric matrix in a more controlled and sustained pattern avoiding the problems associated with a non-hybrid polymeric system. The drug release study of 12 h shows about 83% release at pH 6.8. In vitro drug release kinetics proved that drug release was a Fickian mechanism. The cytotoxic effect of graphene oxide hybrid alginate beads was also determined by evaluating the morphology of bacterial cells and red blood cells after incubation. Additionally, it was determined that the sequential encapsulation of graphene oxide in alginate hydrogel beads hides its uneven edges and lessens the graphene oxide's negative impacts. Also, the antibacterial study and biocompatibility of fabricated hydrogel beads made them potential candidates for gastrointestinal delivery.

1,3,4-oxadiazole conjugates of capsaicin as potent NorA efflux pump inhibitors of Staphylococcus aureus.

NorA efflux pump pertaining to the major facilitator superfamily (MFS) is known to play a key role in antibiotic and biocide resistance in Staphylococcus aureus (S. aureus). It accounts for the extrusion of antibiotics like fluoroquinolones (e.g. ciprofloxacin). Several compounds including synthetic and natural products have been identified as potential NorA efflux pump inhibitors (EPIs) and found to restore the antibacterial activity of antibiotics. However, none of the reported EPIs have reached to clinical approval probably due to their high toxicity profiles. Considering the NorA efflux pump inhibitory potential of capsaicin, a series of capsaicin-based 1,3,4 oxadiazole conjugates were prepared and evaluated for ciprofloxacin activity potentiating effect. Among the new capsaicinoids tested, 17i displayed a minimum effective concentration (MEC) of 12.5 µg/mL against NorA overexpressing S. aureus strain (SA1199B), whereas capsaicin showed MEC of 50 µg/mL. The kill kinetics curve for the combination showed that ciprofloxacin at a sub-inhibitory concentration (0.25 × MIC) was equipotent in effect, to its MIC. 17i has significantly decreased the ethidium bromide efflux confirming NorA inhibition as the mode of action. Mutation prevention concentration of the ciprofloxacin was reduced in combination with 17i.In silico studies revealed the binding efficiency and binding affinity of 17i with NorA. This compound may serve as a template for the further drug discovery.

Enhanced efficiency of graded-bandgap thin-film solar cells due to concentrated sunlight.

A systematic study was performed with a coupled optoelectronic model to examine the effect of the concentration of sunlight on the efficiencies of CIGS, CZTSSe and AlGaAs thin-film solar cells with a graded-bandgap absorber layer. Efficiencies of 34.6% for CIGS thin-film solar cells and 29.9% for CZTSSe thin-film solar cells are predicted with a concentration of 100 suns, the respective one-sun efficiencies being 27.7% and 21.7%. An efficiency of 36.7% is predicted for AlGaAs thin-film solar cells with a concentration of 60 suns, in comparison to 34.5% one-sun efficiency. Sunlight concentration does not affect the per-sun electron-hole-pair (EHP) generation rate but reduces the per-sun EHP recombination rate either near the front and back faces or in the graded-bandgap regions of the absorber layer, depending upon the semiconductor used for that layer, and this is the primary reason for the improvement in efficiency. Other effects include the enhancement of open-circuit voltage, which can be positively correlated to the higher short-circuit current density. Sunlight concentration can therefore play a significant role in enhancing the efficiency of thin-film solar cells.

Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus.

BACKGROUND: Nemolizumab targets the IL-31 receptor α subunit involved in atopic dermatitis (AD) pathogenesis. OBJECTIVE: We sought to evaluate a new dosing strategy of nemolizumab in patients with AD. METHODS: We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90 mg) subcutaneous injections every 4 weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n = 226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator's Global Assessment (IGA) were assessed. Standard safety assessments were performed. RESULTS: Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30 mg) reduced EASI scores versus placebo at week 24 (-68.8% vs -52.1%, P = .016); significant differences were observed by week 8 (P ≤ .01). With significant improvement (P = .028) as early as week 4, IGA 0/1 rates were higher for 30 mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P = .008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P = .06). PP-NRS scores were improved for 30 mg of nemolizumab versus placebo at week 16 (-68.6% vs -34.3%, P < .0001) and week 24 (-67.3% vs -35.8%, P < .0001), with a difference by week 1 (P < .001). NRS response rates (≥4-point decrease) were greater for 30 mg of nemolizumab versus placebo at week 16 (P ≤ .001) and week 24 (P ≤ .01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection. CONCLUSIONS: Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30 mg. Nemolizumab had an acceptable safety profile.