Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment.

The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and ß-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Aß aggregation inhibition in a self- and AChE-induced Aß aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Aß-induced cognitive deficits in the Aß-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the Aꞵ-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Aß and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.

Structure-Guided Design, Synthesis, and Biological Evaluation of Peripheral Anionic Site Selective and Brain Permeable Novel Oxadiazole-Piperazine Conjugates against Alzheimer's Disease with Antioxidant Potential.

Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC50 = 0.103 ± 0.0172 µM, hBChE, IC50 ≥ 10 µM, and hBACE-1, IC50 = 1.342 ± 0.078 µM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory (p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD, there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD.

Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy.

Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), ß secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aß aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC50 value = 0.486 ± 0.047 µM), BACE-1 inhibition (IC50 value = 0.542 ± 0.099 µM) along with good anti-Aß aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC50 value = 2.000 ± 0.360 µM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aß-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.

Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer's Disease Therapy.

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human ß-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 µM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Aß aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Aß-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aß, BACE-1, APP/Aß, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.

Cr- and Ga-Modified ZSM-5 Catalyst for the Production of Renewable BTX from Bioethanol.

Light aromatics (benzene, toluene, and xylene, collectively known as BTX) are essential commodity chemicals in the petrochemical industry. The present study examines the aromatization of bioethanol with Cr- and Ga-modified ZSM-5. Both Cr and Ga were incorporated by the ion-exchange method. Cr-modified ZSM-5 outperforms the Ga-modified ZSM-5 and H-ZSM-5 catalysts. Cr-H-ZSM-5 almost doubled the carbon yield of aromatics compared to H-ZSM-5 at an optimum reaction temperature of 450 °C. Cr-H-ZSM-5 produced aromatics with a yield of ~40 %. The effect of dilution in feed on BTX production is also studied. Cr-H-ZSM-5 was found to be more active than H-ZSM-5. Complete ethanol conversion was obtained with both pure and dilute bioethanol. The Bronsted-Lewis acid (BLA) pair formed after metal incorporation is responsible for dehydrogenation followed by aromatization, leading to increased aromatic production.

Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease.

Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Aß-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 µM concentration which was comparable to donepezil and also demonstrated anti-Aß aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 µM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Aß-phenotypic drosophila AD model and amelioration of behavioral deficits in the Aß-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.

Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer's Disease Therapy.

Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), ß-secretase-1 (hBACE-1), and amyloid ß (Aß) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Aß aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 µM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 µM concentrations. In both the scopolamine- and Aß-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Aß, amyloid precursor protein (APP)/Aß, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Aß levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics.

Development and Evaluation of Some Molecular Hybrids of N-(1-Benzylpiperidin-4-yl)-2-((5-phenyl-1,3,4-oxadiazol-2-yl)thio) as Multifunctional Agents to Combat Alzheimer's Disease.

A series of some novel compounds (SD-1-17) were designed following a molecular hybridization approach, synthesized, and biologically tested for hAChE, hBChE, hBACE-1, and Aß aggregation inhibition potential to improve cognition and memory functions associated with Alzheimer's disease. Compounds SD-4 and SD-6 have shown multifunctional inhibitory profiles against hAChE, hBChE, and hBACE-1 enzymes in vitro. Compounds SD-4 and SD-6 have also shown anti-Aß aggregation potential in self- and acetylcholinesterase (AChE)-induced thioflavin T assay. Both compounds have shown a significant propidium iodide (PI) displacement from the cholinesterase-peripheral active site (ChE-PAS) region with excellent blood-brain barrier (BBB) permeability and devoid of neurotoxic liabilities. Compound SD-6 ameliorates cognition and memory functions in scopolamine- and Aß-induced behavioral rat models of Alzheimer's disease (AD). Ex vivo biochemical estimation revealed a significant decrease in malonaldehyde (MDA) and AChE levels, while a substantial increase of superoxide dismutase (SOD), catalase, glutathione (GSH), and ACh levels is seen in the hippocampal brain homogenates. The histopathological examination of brain slices also revealed no sign of neuronal or any tissue damage in the SD-6-treated experimental animals. The in silico molecular docking results of compounds SD-4 and SD-6 showed their binding with hChE-catalytic anionic site (CAS), PAS, and the catalytic dyad residues of the hBACE-1 enzymes. A 100 ns molecular dynamic simulation study of both compounds with ChE and hBACE-1 enzymes also confirmed the ligand-protein complex's stability, while quikprop analysis suggested drug-like properties of the compounds.

Design, Fabrication, and Testing of a Fully 3D-Printed Pressure Sensor Using a Hybrid Printing Approach.

Pressure sensing is not a new concept and can be applied by using different transduction mechanisms and manufacturing techniques, including printed electronics approaches. However, very limited efforts have been taken to realise pressure sensors fully using additive manufacturing techniques, especially for personalised guide prosthetics in biomedical applications. In this work, we present a novel, fully printed piezoresistive pressure sensor, which was realised by using Aerosol Jet® Printing (AJP) and Screen Printing. AJ®P was specifically chosen to print silver interconnects on a selective laser sintered (SLS) polyamide board as a customised substrate, while piezoresistive electrodes were manually screen-printed on the top of the interconnects as the sensing layer. The sensor was electromechanically tested, and its response was registered upon the application of given signals, in terms of sensitivity, hysteresis, reproducibility, and time drift. When applying a ramping pressure, the sensor showed two different sensitive regions: (i) a highly sensitive region in the range of 0 to 0.12 MPa with an average sensitivity of 106 Ω/MPa and a low sensitive zone within 0.12 to 1.25 MPa with an average sensitivity of 7.6 Ω/MPa with some indeterminate overlapping regions. Hysteresis was negligible and an electrical resistance deviation of about 14% was observed in time drift experiments. Such performances will satisfy the demands of our application in the biomedical field as a smart prosthetics guide.

Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies.

A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 µM and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 ± 0.27 µM, 6.44 ± 0.29 µM and 9.54 ± 0.15 µM against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 ± 0.67 µM, 3.15 ± 0.23 µM and 3.36 ± 0.29 µM against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules.

The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological illness that causes dementia mainly in the elderly. The challenging obstacles related to AD has freaked global healthcare system to encourage scientists in developing novel therapeutic startegies to overcome with the fatal disease. The current treatment therapy of AD provides only symptomatic relief and to some extent disease-modifying effects. The current approach for AD treatment involves designing of cholinergic inhibitors, Aß disaggregation inducing agents, tau inhibitors and several antioxidants. Hence, extensive research on AD therapy urgently requires a deep understanding of its pathophysiology and exploration of various chemical scaffolds to design and develop a potential drug candidate for the treatment. Various issues linked between disease and therapy need to be considered such as BBB penetration capability, clinical failure and multifaceted pathophisiology requires a proper attention to develop a lead candidate. This review article covers all probable mechanisms including one of the recent areas for investigation i.e., lipid dyshomeostasis, pathogenic involvement of P. gingivalis and neurovascular dysfunction, recently reported molecules and drugs under clinical investigations and approved by FDA for AD treatment. Our summarized information on AD will attract the researchers to understand and explore current status and structural modifications of the recently reported heterocyclic derivatives in drug development for AD therapy.

Screen Printed Antennas on Fiber-Based Substrates for Sustainable HF RFID Assisted E-Fulfilment Smart Packaging.

Intelligent packaging is an emerging technology, aiming to improve the standard communication function of packaging. Radio frequency identification (RFID) assisted smart packaging is of high interest, but the uptake is limited as the market needs cost-efficient and sustainable applications. The integration of screen printed antennas and RFID chips as smart labels in reusable cardboard packaging could offer a solution. Although paper is an interesting and recyclable material, printing on this substrate is challenging as the ink conductivity is highly influenced by the paper properties. In this study, the best paper/functional silver ink combinations were first selected out of 76 paper substrates based on the paper surface roughness, air permeance, sheet resistance and SEM characterization. Next, a flexible high frequency RFID chip (13.56 MHz) was connected on top of screen printed antennas with a conductive adhesive. Functional RFID labels were integrated in cardboard packaging and its potential application as reusable smart box for third party logistics was tested. In parallel, a web-based software application mimicking its functional abilities in the logistic cycle was developed. This multidisciplinary approach to developing an easy-scalable screen printed antenna and RFID-assisted smart packaging application is a good example for future implementation of hybrid electronics in sustainable smart packaging.

Unravelling Cotton Nonexpressor of Pathogenesis-Related 1(NPR1)-Like Genes Family: Evolutionary Analysis and Putative Role in Fiber Development and Defense Pathway.

The nonexpressor of pathogenesis-related 1 (NPR1) family plays diverse roles in gene regulation in the defense and development signaling pathways in plants. Less evidence is available regarding the significance of the NPR1-like gene family in cotton (Gossypium species). Therefore, to address the importance of the cotton NPR1-like gene family in the defense pathway, four Gossypium species were studied: two tetraploid species, G.hirsutum and G. barbadense, and their two potential ancestral diploids, G. raimondii and G. arboreum. In this study, 12 NPR1-like family genes in G. hirsutum were recognized, including six genes in the A-subgenome and six genes in the D-subgenome. Based on the phylogenetic analysis, gene and protein structural features, cotton NPR-like proteins were grouped into three different clades. Our analysis suggests the significance of cis-regulatory elements in the upstream region of cotton NPR1-like genes in hormonal signaling, biotic stress conditions, and developmental processes. The quantitative expression analysis for different developmental tissues and fiber stages (0 to 25 days post-anthesis), as well as salicylic acid induction, confirmed the distinct function of different cotton NPR genes in defense and fiber development. Altogether, this study presents specifications of conservation in the cotton NPR1-like gene family and their functional divergence for development of fiber and defense properties.

T4 cervical esophageal cancer cured with modern chemoradiotherapy: A case report.

BACKGROUND: T4 esophageal cancer portends a poor prognosis, particularly when it is complicated by a tracheoesophageal fistula (TEF) either resulting from disease or occurring as a complication of treatment. Patients with TEF that occurs during treatment are commonly treated with palliative intent because fistula-associated treatment complications such as aspiration pneumonia and mediastinitis are associated with high morbidity and mortality. To date, there is no clear evidence on the optimal treatment of T4 esophageal cancer, particularly when a TEF formation occurs. CASE SUMMARY: A 67-year-old gentleman who presented with dysphagia and weight loss. Endoscopy and imaging revealed a T4N1M0 cervical esophageal squamous cell carcinoma. He received image-guided intensity-modulated radiation therapy, with concurrent weekly carboplatin (area under curve 2 mg/mL per minute) and paclitaxel (50 mg/m2 of body surface area). One week after treatment initiation (16.2 Gy thus far), he developed cough on swallowing. A TEF was detected on image-guided radiation therapy using cone-beam computed tomography during the treatment course, for which a tracheal stent was inserted. After discussing the risks and morbidity of continuing treatment, he resumed chemoradiotherapy with an additional radiation dose of 45 Gy in 25 fractions. Three months after completion of chemoradiotherapy, he developed an esophageal stricture that required esophageal stenting and dilatation. The patient remains cancer-free at two year on follow-up. Complete response of esophageal cancer was evident on post-treatment endoscopy and computed tomography imaging, with successful closure of TEF. CONCLUSION: This case highlights that successful curative treatment for esophageal cancer complicated by a TEF is possible using novel chemotherapeutic regimens and modern radiation technologies.

The Interleukin (IL) 17R/IL-22R Signaling Axis Is Dispensable for Vulvovaginal Candidiasis Regardless of Estrogen Status.

Candida albicans, a ubiquitous commensal fungus that colonizes human mucosal tissues and skin, can become pathogenic, clinically manifesting most commonly as oropharyngeal candidiasis and vulvovaginal candidiasis (VVC). Studies in mice and humans convincingly show that T-helper 17 (Th17)/interleukin 17 (IL-17)-driven immunity is essential to control oral and dermal candidiasis. However, the role of the IL-17 pathway during VVC remains controversial, with conflicting reports from human data and mouse models. Like others, we observed induction of a strong IL-17-related gene signature in the vagina during estrogen-dependent murine VVC. As estrogen increases susceptibility to vaginal colonization and resulting immunopathology, we asked whether estrogen use in the standard VVC model masks a role for the Th17/IL-17 axis. We demonstrate that mice lacking IL-17RA, Act1, or interleukin 22 showed no evidence for altered VVC susceptibility or immunopathology, regardless of estrogen administration. Hence, these data support the emerging consensus that Th17/IL-17 axis signaling is dispensable for the immunopathogenesis of VVC.

Long-term tolerance of a fractured self-expanding metal stent in a patient with adenoid cystic carcinoma.

Self-expanding metals stent are used for recanalization of malignant CAO. Fracture of such a stent has been described. This prompts its removal. However removal of a metal stent is difficult and can be hazardous. Due to this US FDA advisory was released against their insertion in benign diseases where long life expectancy can expose the patients to the complications of prolonged indwelling time of these stents. We describe a case of adenoid cystic carcinoma who required SEMS placement for tracheal obstruction. However, stent fracture developed soon after its insertion causing patient to cough out stent pieces multiple times. In view of the challenge associated with removal of metal stent fixed to the tracheal walls at its proximal and distal ends, the stent was left in-situ. Patient has tolerated the fractured stent for 1-year and remains on follow-up without any complication or adverse event. This illustrates the long-term tolerance and safety of a fractured stent and helps to allay anxiety associated with this complication.

Dermatophyte Immune Memory Is Only Skin-Deep.

A new report in this issue of Journal of Investigative Dermatology reveals a role for IL-17 and IFN-gamma, signature cytokines of T-helper 17 and T-helper 1 cells, in immunity to Trichophyton benhamiae (Heinen et al., 2018). While there have been many recent advances in understanding host defenses against common fungi, this work illuminates not only adaptive immunity, but also innate immune responses to dermatophytosis.

Combined Blockade of TNF-α and IL-17A Alleviates Progression of Collagen-Induced Arthritis without Causing Serious Infections in Mice.

The cytokines TNF-α and IL-17A are elevated in a variety of autoimmune diseases, including rheumatoid arthritis. Both cytokines are targets of several biologic drugs used in the clinic, but unfortunately many patients are refractory to these therapies. IL-17A and TNF-α are known to mediate signaling synergistically to drive expression of inflammatory genes. Hence, combined blockade of TNF-α and IL-17A represents an attractive treatment strategy in autoimmune settings where monotherapy is not fully effective. However, a major concern with this approach is the potential predisposition to opportunistic infections that might outweigh any clinical benefits. Accordingly, we examined the impact of individual versus combined neutralization of TNF-α and IL-17A in a mouse model of rheumatoid arthritis (collagen-induced arthritis) and the concomitant susceptibility to infections that are likely to manifest as side effects of blocking these cytokines (oral candidiasis or tuberculosis). Our findings indicate that combined neutralization of TNF-α and IL-17A was considerably more effective than monotherapy in improving collagen-induced arthritis disease even when administered at a minimally efficacious dose. Encouragingly, however, dual cytokine blockade did not cooperatively impair antimicrobial host defenses, as mice given combined IL-17A and TNF-α neutralization displayed infectious profiles and humoral responses comparable to mice given high doses of individual anti-TNF-α or anti-IL-17A mAbs. These data support the idea that combined neutralization of TNF-α and IL-17A for refractory autoimmunity is likely to be associated with acceptable and manageable risks of opportunistic infections associated with these cytokines.

Outcome differences between recanalized malignant central airway obstruction from endoluminal disease versus extrinsic compression.

We compared the outcome of Nd:YAG laser therapy with stent placement for malignant central airway obstruction (CAO) at our center over a 10-year period. This is a retrospective review of patients undergoing Nd:YAG laser therapy or self-expanding metal stent (SEMS) placement for malignant CAO between November 2007 and October 2017. Seventy-two patients were recanalized for malignant CAO. The median (range) age was 63 (23-86) years, with 49 (68%) males. Patients underwent either laser therapy alone (N = 36), stent placement alone (N = 30), or both (N = 6). The wavelength of Nd:YAG laser used was 1064 nm, and median (range) laser energy used was 25 (15-35) W, in 377 (115-1107) pulses. Fifty-one (71%) patients died with median survival of 7.2 months. In subgroup analysis, 21 (58.3%) vs. 25 (83.3%), p = 0.03 patients died in the "laser resection" vs. "stent placement" group with longer median survival of 12.4 months in the former vs. 4.5 months, p = 0.0004 in the later. Esophageal cancer and left main bronchus involvement were significantly more common (10 (33.3%) vs. 0, p = 0.0001, and 16 (53.3%) vs. 8 (22.2%), p = 0.01), in the stent placement vs. laser resection group, respectively. Trachea or main bronchi involvement and respiratory failure on presentation requiring mechanical ventilation correlated with poorer survival. The immediate restoration of luminal patency, complication rate, and 30-day mortality was similar among the two groups. The median (range) energy used for laser therapy was 25 (15-35) W. Median of 377 pulses was used for the duration of 287.5 s. The results were compared using a Wilcoxon two-sample test, and Fischer exact test with p values considered indicative of a significant difference if less than 0.05. In patients requiring recanalization of malignant CAO, the extrinsic compression from esophageal cancer, trachea or main bronchi involvement, respiratory failure on presentation requiring mechanical ventilation, and stent placement correlated with poorer survival. Interventional pulmonology training program should emphasize on dedicated training in laser therapy as it is associated with improved survival.