Search

Complications of cholesteatoma result from characteristic inflammatory and resorptive processes that erode the structures of the middle and inner ear with potential to spread locally. Common intratemporal complications include hearing loss, facial nerve palsy, labyrinthine fistula, and dysgeusia. Extratemporal complications, though less common, may be life-threatening, and include cerebrospinal fluid leak and encephalocele, meningitis, epidural and intraparenchymal abscesses, subdural empyema, and otic hydrocephalus., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study of creating new molecules from clinical trial agents, an approach of Combretastatin structural modulation with the installation of NP-privileged motifs was considered, and a series of trimethoxyphenyl-2-aminoimidazole with functionalized quinolines and isoquinolines was investigated. An exciting method of quinoline C3-H iodination coupled with imidazopyridine-C3-H arylation and hydrazine-mediated fused-ring cleavage enabled synthesizing a class of compounds with two specific unsymmetric aryl substitutions. Interestingly, three compounds (6, 11, and 13) strongly inhibited HeLa cell proliferation with a half-maximal inhibitory concentration (10-46 nM). Among the compounds, compound 6 (QTMP) showed stronger antiproliferative ability than CA-4 (a clinical trial agent) in various cancer cell lines, including cervical, lung, breast, highly metastatic breast, and melanoma cells. QTMP inhibited the assembly of purified tubulin, depolymerized microtubules of A549 lung carcinoma cells, produced defective spindles, and arrested the cells in the G2/M phase. Further, QTMP binds to the colchicine site in tubulin with a dissociation constant of 5.0 ± 0.6 µM. QTMP displayed higher aqueous stability than CA-4 at 37 °C. Further, in silico analysis of QTMP indicated excellent drug-like properties, including good aqueous solubility, balanced hydrophilicity-lipophilicity, and high GI-absorption ability. The results together suggest that QTMP has anticancer potential., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper [Prof. Sankar K. Guchhait reports financial support was provided by Science and Engineering Research Board and CSIR, Government of India. Prof. Dulal Panda reports financial support was provided by JC Bose National Fellowship (JCB/2019/000016) from the Department of Science and Technology, Government of India.]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Sublingual immunotherapy (SLIT) adherence in the literature is often evaluated in closely monitored trials that may impact patient behavior; real-world SLIT adherence is relatively unknown. This systematic review intends to assess SLIT adherence in studies that reflect real-world settings., Methods: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for real-world studies examining SLIT adherence was performed. Monitored clinical trials were excluded. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up and "adherence" as persistence in accordance with prescribed SLIT dose, dosing schedule, and duration. Article quality was assessed using a modified Newcastle-Ottawa scale and then converted to AHRQ standards (good, fair, and poor)., Results: The search yielded 1596 nonduplicate abstracts, from which 32 articles (n = 63,683 patients) met criteria. Twenty-six (81%) studies reported persistence rates ranging from 7.0% to 88.7%, and 18 (56%) reported adherence rates ranging from 9.6% to 97.0%. Twenty-one (66%) studies surveyed reasons for discontinuing SLIT. All studies were Oxford level of evidence 2b and of good (n = 12) to fair (n = 20) quality., Conclusion: Reported rates of real-world SLIT persistence and adherence varied widely by study methodology (e.g., follow-up duration, objective vs. subjective assessment). Studies with longer follow-up generally reported lower rates; 3-year persistence ranged from 7% to 59.0% and 3-year adherence from 9.6% to 49.0%. Future studies of SLIT adherence would benefit from following concordant definitions of persistence/adherence and standardized reporting metrics., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Given that subcutaneous immunotherapy (SCIT) adherence in the literature is often studied in closely monitored trials, few studies report real-world SCIT adherence. The purpose of this review is to assess SCIT adherence in real-world settings., Methods: A literature search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for real-world studies examining SCIT adherence was performed. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up after initiating SCIT, and "adherence" defined as persistence in accordance with prescribed SCIT dose, dosing schedule, and duration. Article quality was first assessed using a modified Newcastle-Ottawa scale and then converted to Agency for Healthcare Research and Quality standards (good, fair, and poor)., Results: The search yielded 1596 nonduplicate abstracts, from which 17 articles (n = 263,221 patients) met inclusion criteria. Fourteen (82%) studies reported persistence rates, ranging from 16.0% to 93.7%. Seven (41%) studies reported adherence rates, ranging from 15.1% to 99%. Five (29%) studies (n = 416 patients) collected original data on reasons for discontinuing SCIT, of which inconvenience was most cited. All studies were Oxford level of evidence 2b and of good (n = 10) to fair (n = 7) quality., Conclusion: Real-world SCIT persistence and adherence rates are poor, with the majority of included studies reporting rates <80%; however, they range widely, explained in part by inter-study differences in measuring and reporting adherence-related findings. Future studies on SCIT adherence may benefit from following concordant definitions of persistence and adherence in addition to standardized reporting metrics., (© 2022 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Background: Patients with acquired, idiopathic olfactory dysfunction (OD) commonly undergo magnetic resonance imaging (MRI) evaluation to rule out intracranial pathologies. This practice is highly debated given the expense of MRI relative to the probability of detecting a treatable lesion. This, combined with the increasing use of MRI in research to investigate the mechanisms underlying OD, provided the impetus for this comprehensive review., Objective: The purpose of this systematic review was to both assess the utility of MRI in diagnosis of idiopathic OD and to describe MRI findings among mixed OD etiologies to better understand its role as a research tool in this patient population., Methods: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for studies with original MRI data for patients with OD was completed. Studies exclusively investigating patients with neurocognitive deficits or those studying traumatic or congenital etiologies of OD were excluded., Results: From 1758 candidate articles, 33 studies were included. Four studies reviewed patients with idiopathic OD for structural pathologies on MRI, of which 17 of 372 (4.6%) patients had a potential central cause identified, and 3 (0.8%) had an olfactory meningioma or olfactory neuroblastoma. Fourteen studies (42.4%) reported significant correlation between olfactory bulb volume and olfactory outcomes, and 6 studies (18.8%) reported gray matter volume reduction, specifically in the orbitofrontal cortex, anterior cingulate cortex, insular cortex, parahippocampal, and piriform cortex areas, in patients with mixed OD etiologies. Functional MRI studies reported reduced brain activation and functional connectivity in olfactory network areas., Conclusion: MRI uncommonly detects intracranial pathology in patients with idiopathic OD. Among patients with mixed OD etiologies, reduced olfactory bulb and gray matter volume are the most common abnormal findings on MRI. Further research is required to better understand the role of MRI and its cost-effectiveness in patients with acquired, idiopathic OD.

A Core-Linker-Polyamine (CLP) strategy has been exploited to develop new antileishmanial agents. It involves the linker-based assembly of alkyl-polyamine side chain as a potential pharmacophore motif with a privileged heterocyclic motif, 4-arylquinoline. A series of aminoalkyl 4-arylquinoline-2-carboxamides and their analogs were synthesized and tested against L. donovani promastigotes. Among all synthesized derivatives, 10 compounds showed significant antipromastigote activities with more efficacy (IC 50 : 4.75-8 μM) than an antileishmanial oral drug Miltefosine (IC 50 : 8.9±1.55 μM). Most active aminoalkyl-quinoline-carboxamides 9 a and 9 b, displayed negligible cytotoxicity towards human monocytic (THP-1) macrophages. The compounds show antileishmanial activity by generating mitochondrial superoxide radicals. However, they did not show interference with trypanothione reductase, a redox enzyme of Leishmania. Significant change in the morphology of the L. donovani promastigote by the compounds was observed. The Structure-activity relationship analysis suggest the pharmacophoric importance of alkylpolyamine and carboxamide motifs. In silico evaluation indicated that the investigated active molecules 9 a and 9 b possess important drug-likeness, physicochemical and pharmacokinetic-relevant properties., (© 2022 Wiley-VCH GmbH.)

Background: Bitter and sweet taste receptors (T2Rs and T1Rs), respectively, are involved in the innate immune response of the sinonasal cavity and associated with chronic rhinosinusitis (CRS). Growing evidence suggests extraoral TRs as relevant biomarkers, but the current understanding is incomplete. This systematic review synthesizes current evidence of extraoral taste receptors in CRS., Methods: PubMed, Embase, Cochrane, Web of Science, and Scopus were reviewed in accordance with Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines and included studies of genotypic and phenotypic T2R/T1R status in CRS patients., Results: Twenty-two studies with 3845 patients were included. Seventeen studies evaluated genotype and 10 evaluated taste phenotypes. Four of 6 studies examining the haplotype distribution of the T2R, TAS2R38, demonstrated increased AVI/AVI haplotype ("nontaster") frequency in CRS. Meanwhile, 2 studies demonstrated decreased bitter sensitivity in CRS with nasal polyposis (CRSwNP), whereas 3 other studies reported decreased bitter sensitivity only in CRS without nasal polyposis (CRSsNP). Findings regarding sweet sensitivity were mixed. Three studies with cystic fibrosis patients (n = 1393) were included. Studies investigating the association between clinical outcomes and TAS2R38 alleles were limited, but the nonfunctional combination of AVI/AVI was associated with increased utilization of sinus surgery and, in CRSsNP patients, with poorer improvement of symptoms postoperatively., Conclusion: Both genotypic and phenotypic assessments of T2Rs suggest a potential association with CRS, particularly CRSsNP. However, limited evidence and mixed conclusions cloud the role of T2Rs in CRS. Future investigations should aim to increase diverse populations, broaden institutional diversity, examine T1Rs, and utilize uniform assessments., (© 2021 ARS-AAOA, LLC.)

Background: Frailty is a syndrome characterized by reduced physiologic reserve and increased vulnerability to poor health outcomes. Disruption of sensorineural function appears to serve as a novel biomarker of frailty. Using population-level data, we sought to characterize the association between otolaryngic sensory dysfunction and frailty., Methods: A cross-sectional analysis of the 2011-2012 US National Health and Nutrition Examination Survey was performed on adults ≥40 years of age (n = 2138). Participants were grouped by subjective gustatory dysfunction (sGD), olfactory dysfunction (sOD), hearing loss (sHL), and measured hearing loss (mHL) with pure tone averages (PTAs). Frailty was operationalized using a continuous 36-item frailty index (FI) scored from 0 to 1, stratified in 4 categories ("non-frail," "vulnerable," "frail," or "most frail")., Results: All sensory loss groups had significantly higher FI scores than those without sensory loss (sGD = 0.15; sOD = 0.14; sHL = 0.15; low-frequency mHL = 0.16; high-frequency mHL = 0.14 vs control = 0.11; p < 0.007 for all). "Vulnerable" individuals had increased odds of sOD (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.05-2.00), whereas "frail" individuals had increased odds of sOD (aOR, 1.85; 95% CI, 1.26-2.71) and low-frequency mHL (aOR, 4.01; 95% CI, 1.27-12.63). The "most frail" individuals had increased odds of sHL (aOR, 11.72; 95% CI, 2.88-47.66) and high-frequency mHL (aOR 5.10; 95% CI, 1.72-15.12). PTAs were linearly associated with FI (low: β = 10.15; 95% CI, 1.78-18.51; high: β = 19.85; 95% CI, 5.19-34.53)., Conclusion: Otolaryngic sensory loss is associated with increased frailty. Independent association of frailty with measures of olfaction and hearing suggests that olfactory and hearing assessments may help identify at-risk individuals with modifiable risk factors., (© 2021 ARS-AAOA, LLC.)

2-Arylquinazolines with a range of alkyl polyamines as side chain/ring functional motifs at the 4th-position were considered for antileishmanial study with the rationale that related heterocyclic scaffolds and polyamine functionalities are present in drugs, clinical trial agents, natural products and anti-parasitic/leishmanial agents. Synthesis involves construction of the 2-arylquinazolin-4-one ring and deoxyamination via deoxychlorination followed by S N Ar-based amination or a methodology of S N Ar-deoxyamination driven by BOP-mediated hydroxyl-activation. Various alkyl-polyamines important for activities were incorporated. A total of 26 compounds were prepared and screened against Leishmania donovani ( Ld ) promastigote cells using the MTT assay. Most of the investigated series of compounds showed characteristic leishmanicidal properties. Several compounds showed pronounced leishmanicidal activities (IC 50 : 5-6.5 μM) with higher efficiency than the antileishmanial drug miltefosine (IC 50 : 10.5 μM), and relatively less cytotoxicity to macrophage host cells (SI: 9.27-13.5) compared to miltefosine (SI: 3.42). Important pharmacophoric skeletons were identified., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objectives: The underlying mechanism of the association between olfactory impairment and dementia may be explained by neurodegenerative changes detected on magnetic resonance imaging (MRI). The purpose of this systematic review is to describe neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment (MCI) or dementia., Study Design: Systematic review., Methods: A literature search encompassing PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Google Scholar for studies with MRI and olfactory testing among participants diagnosed with MCI or dementia was performed. Sample size, study design, cognitive impairment type, olfactory testing, and MRI findings were abstracted. Two investigators independently reviewed all articles., Results: The search yielded 556 nonduplicate abstracts, from which 86 articles were reviewed and 24 were included. Seventeen (71%) of 24 studies reported hippocampal volume findings, with 14 studies reporting a relationship between hippocampal volume and olfactory performance. Two (50%) of four prospective studies reported the potential utility of baseline hippocampal volume as a marker of dementia conversion from MCI. Five (21%) of 24 studies reporting olfactory functional MRI (fMRI) findings highlighted the utility of olfactory fMRI to identify individuals in the early stages of cognitive decline., Conclusion: Current evidence suggests hippocampal volume correlates with olfactory performance in individuals with cognitive impairment, and that olfactory fMRI may improve early detection of AD. However, the predictive utility of these imaging markers is limited in prospective studies. MRI may be a useful modality for selecting patients at high risk of future cognitive decline for enrollment in early treatment trials. Laryngoscope, 132:177-187, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: As endoscopic endonasal skull base surgery (EESBS) for sellar pathology has become routine, there is increasing awareness of quality-of-life (QOL) outcomes related to this approach. Similarly, there is a growing interest in postoperative chemosensory function, with notable emphasis on olfaction and the corresponding psychosocial implications of olfactory dysfunction. Meanwhile, there has been minimal direct investigation into gustatory outcomes, and the association between these 2 chemosensory functions remains poorly understood., Objective: To investigate patient-reported chemosensory function and rhinologic-specific QOL following EESBS for routine sellar pathologies., Methods: Comprehensive clinical characteristics and sinonasal QOL assessments, measured using Anterior Skull Base Nasal Inventory-12 (ASK Nasal-12), were collected from 46 patients undergoing EESBS for sellar pathology., Results: Forty-six patients were included: 65.2% female, average age 52.8 yr (range: 27-89). The most common pathology was nonfunctioning pituitary adenoma (n = 28). Preoperative ASK Nasal-12 scores (mean = 0.81) demonstrated postoperative worsening at 2 wk (mean = 2.52, P < .0001) and 1 mo (mean = 1.33, P = .0031), with no difference at 3 mo postoperatively (mean = 0.89, P = .92). Meanwhile, there was significant worsening of preoperative subjective smell (mean = 0.62) and taste function (mean = 0.42) at 2 wk (mean = 3.48, P < .0001; mean = 2.69, P < .0001) and 1 mo (mean = 2.40, P < .0001; mean = 2.03, P < .0001) postoperatively, which persisted at approximately 3 mo postoperatively (mean = 1.26, P = .04; mean = 1.15, P = .0059)., Conclusion: Patients undergoing EESBS for sellar pathologies experience anticipated, temporary disruptions in sinonasal QOL but may have longer lasting perturbations in subjective olfaction and gustation. Given the increasing use of the endoscopic endonasal corridor, further investigation in postoperative chemosensory function is essential., (© Congress of Neurological Surgeons 2021.)

Objectives: Sublingual immunotherapy (SLIT) has emerged as an effective treatment alternative to subcutaneous immunotherapy (SCIT) given its improved safety profile and more convenient dosing. However, SLIT still relies on daily dosing for many years to optimize effectiveness. This study sought to investigate factors that influence patient completion of SLIT., Methods: We performed an institutional retrospective review of patients who received SLIT (2008-2020). Completion was defined as completing at least 36 months of SLIT. Patient demographics and characteristics, including the number of allergens treated, history of asthma and sinus surgery, number of clinic visits, and total time undergoing SLIT, were documented. Multivariate models were used to analyze predictors of SLIT completion. Subgroup analysis was performed among pediatric patients and patients who discontinued SLIT., Results: Of the 404 total patients, 249 (61.6%) discontinued, 47 (11.6%) completed, and 108 (26.7%) were currently undergoing SLIT. The mean duration of therapy was 11.2 months for those who discontinued and 49.4 months for patients who completed SLIT. The odds of SLIT completion were twice as high with each additional clinic visit (P < .001), and twice as high when the dosage was increased during therapy (P = .06). Pediatric patients younger than age 12 with a history of asthma were over five times more likely to complete therapy (P = .045). Patients with more clinic visits (P < .001) and higher associated costs (P = .003) were less likely to be lost to follow-up., Conclusion: Increasing the frequency of clinic visits, improving therapy availability, and mitigating concerns about clinical efficacy may increase patient completion of SLIT., Level of Evidence: 4 Laryngoscope, 131:E2111-E2115, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Background: Post-viral olfactory dysfunction (PVOD) is one of the most common causes of olfactory loss. Despite its prevalence, optimal treatment strategies remain unclear. This article provides a comprehensive review of PVOD treatment options and provides evidence-based recommendations for their use., Methods: A systematic review of the Medline, Embase, Cochrane, Web of Science, Scopus, and Google Scholar databases was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies with defined olfactory outcomes of patients treated for PVOD following medical, surgical, acupuncture, or olfactory training interventions were included. The Clinical Practice Guideline Development Manual and Conference on Guideline Standardization (COGS) instrument recommendations were followed in accordance with a previously described, rigorous, iterative process to create an evidence-based review with recommendations., Results: From 552 initial candidate articles, 36 studies with data for 2183 patients with PVOD were ultimately included. The most common method to assess olfactory outcomes was Sniffin' Sticks. Broad treatment categories included: olfactory training, systemic steroids, topical therapies, a variety of heterogeneous non-steroidal oral medications, and acupuncture., Conclusion: Based on the available evidence, olfactory training is a recommendation for the treatment of PVOD. The use of short-term systemic and/or topical steroids is an option in select patients after careful consideration of potential risks of oral steroids. Though some pharmacological investigations offer promising preliminary results for systemic and topical medications alike, a paucity of high-quality studies limits the ability to make meaningful evidence-based recommendations for the use of these therapies for the treatment of PVOD., (© 2020 ARS-AAOA, LLC.)

Objectives: Large vestibular aqueduct syndrome (LVAS) is a congenital inner ear malformation that commonly results in progressive sensorineural hearing loss (SNHL) and cochlear implantation (CI). Though LVAS accounts for approximately 15% of pediatric SNHL, little is known regarding the rate and severity of SNHL in these patients. We sought to characterize the timing of SNHL progression to CI in patients with LVAS., Methods: We performed a retrospective chart review at our institution from 2000 to 2018 using ICD-10 "large vestibular aqueduct syndrome," and through identifying patients with CI who had LVAS. Demographic, surgical, and audiometric data were collected. Theoretical CI candidacy was approximated using a pure tone average (PTA) HL threshold of 70 dB., Results: Of 103 patients, 96 had bilateral LVAS, and 7 had unilateral LVAS. Forty-one patients had bilateral implants, 52 had unilateral implants, and 10 were not implanted. The mean age at first implant was 8.62 years old [95%CI = 6.75,10.49], the mean age at second implant was 12.24 years old [95%CI = 8.33,16.15], and the mean time between implants was 4.37 years [95%CI = 3.02,5.73]. LVAS patients reached HL threshold of 70 dB at a mean age of 5.16 years old (SD = 3.04) for the "worse ear" and 9.08 years old (SD = 4.96) for the "better ear.", Conclusions: LVAS patients are a heterogenous population of patients, in which some may undergo progression of HL and some may not. Further, there may be a discrepancy in the timing between patients' theoretical CI candidacy and when they undergo CI. In order to optimize timing of CI, individual monitoring and close observation of LVAS patients is recommended., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Silent sinus syndrome (SSS) is a condition characterized by ophthalmologic features, such as spontaneous enophthalmos and hypoglobus with ipsilateral maxillary sinus atelectasis and an otherwise asymptomatic presentation. SSS has been documented secondary to a number of external causes, including trauma or surgery, but has less commonly been described in the setting of a potential mass in the deep masticator space., Case Presentation: A 56-year-old woman with a history of chronic headaches with normal prior sinonasal imaging presented with increasing right-sided facial pain and headaches that radiated to her occiput, subjective visual changes, sharp ear pain, and long-standing subjective diminished sense of smell. Physical examination was normal, while nasal endoscopy demonstrated lateral bowing of the medial maxillary wall on the right. Magnetic resonance imaging demonstrated a homogenous 2 × 2 × 2.4 cm T1- and T2-weighted, hyperintense mass lesion in the deep masticator space splaying the right medial and lateral pterygoid muscles concerning for a possible lipomatous lesion. Computed tomography revealed an atelectatic and opacified maxillary sinus with inward bowing of the posterior maxillary wall and increased orbital volume on that side. Endoscopic maxillary antrostomy was performed with biopsy of the retromaxillary space lesion and with near immediate resolution of the patient's symptoms. Histologic examination of the mass demonstrated mature adipose tissue with few aggregates of benign small vessels., Discussion: This is an unusual presentation of SSS, with an accompanying enlargement of the retromaxillary fat pad. We herein review our clinical experience with SSS and provide a literature review of the presentation, management, and perioperative considerations for SSS., (© The Author(s) 2020.)

Purpose: In a recent study, it was found that, although intrinsic midbrain signal abnormality (IMSA) on MRI is associated with Parinaud's syndrome (PS) in patients with pineal gland masses (PM), it had no predictive value with respect to resolution of PS. We sought to compare the PM and non-pineal etiologies (NPE) of PS by reviewing imaging features of PS and whether or not they are predictive of resolution of symptoms., Methods: We reviewed electronic medical records from 1980 to 2017 and identified 71 patients with PS from any etiology who had MR imaging: 26 with PM and 45 with NPE. We subdivided the 45 NPE patients into those with intrinsic midbrain lesions (IMBL) (n = 23) and those with extrinsic midbrain lesions (EMBL) (n = 22). PS resolution and hydrocephalus data were collected. Imaging studies were reviewed for the presence of IMSA and hydrocephalus., Results: PS patients with EMBL were less likely to have IMSA than those with PM or IMBL (p ≤0.001). PS resolution occurred more commonly with PM than IMBL and NPE (p = 0.03, p = 0.01). For all NPE patients, resolution of PS occurred with equal frequency in patients with and without IMSA (p = 1.00). Hydrocephalus occurred more frequently in patients with PM and EMBL than IMBL (p = 0.01, p = 0.03)., Conclusions: IMSA is present more often in patients with PS from PM or IMBL than in patients with EMBL. EMBL, including PM, have an increased likelihood for PS resolution. There is no predictive value of IMSA with respect to resolution of PS in NPE as well as PM., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Maintenance of a transparent corneal stroma is imperative for proper vision. The corneal stroma is composed of primarily collagen fibrils, small leucine-rich proteoglycans (SLRPs), as well as sparsely distributed cells called keratocytes. The lattice arrangement and spacing of the collagen fibrils that allows for transparency may be disrupted due to genetic mutations and injuries. The purpose of this study is to examine the therapeutic efficacy of human umbilical cord mesenchymal stem/stromal cells (UMSCs) in treating congenital and acquired corneal opacity associated with the loss of collagen V., Methods: Experimental mice, i.e., wild-type, Col5a1 f/f and Kera-Cre/Col5a1 f/f ( Col5a1 ∆st/∆st , collagen V null in the corneal stroma) mice in a C57BL/6J genetic background, were subjected to a lamellar keratectomy, and treated with or without UMSC (10 4 cells/cornea) transplantation via an intrastromal injection or a fibrin plug. In vivo Heidelberg retinal tomograph (HRT II) confocal microscopy, second harmonic generated (SHG) confocal microscopy, histology, and immunofluorescence microscopy were used to assess the corneal transparency of the regenerated corneas., Results: Col5a1 ∆st/∆st mice display a cloudy cornea phenotype that is ameliorated following intrastromal transplantation of UMSCs. Loss of collagen V in Col5a1 ∆st/∆st corneas augments the formation of cornea scarring following the keratectomy. UMSC transplantation with a fibrin plug improves the healing of injured corneas and regeneration of transparent corneas, as determined with in vivo HRT II confocal microscopy. Second harmonic confocal microscopy revealed the improved collagen fibril lamellar architecture in the UMSC-transplanted cornea in comparison to the control keratectomized corneas., Conclusions: UMSC transplantation was successful in recovering some corneal transparency in injured corneas of wild-type, Col5a1 f/f and Col5a1 ∆st/∆st mice. The production of collagen V by transplanted UMSCs may account for the regeneration of corneal transparency, as exemplified by better collagen fiber organization, as revealed with SHG signals.

Purpose: The association between MRI findings in patients with pineal lesions and the presence or absence of Parinaud's syndrome (PS) remains poorly described. We sought to better understand what MRI characteristics of a pineal lesion make PS more likely. Can these features predict prognosis for clinical resolution? Based on the anatomical relationship of the pineal gland and midbrain, we hypothesized that the degree of midbrain injury by a pineal mass as assessed by abutment, displacement, or intrinsic midbrain signal abnormality (IMSA) may predict PS., Methods: We reviewed our institution's databases to find patients with MRI evidence of an intrinsic lesion of the pineal gland. Seventy-seven patients with intrinsic pineal gland lesions, 26 with PS and 51 without PS (NPS), were identified. Data regarding clinical history were collected, and an experienced neuroradiologist reviewed all MRI studies and recorded mass size, midbrain abutment, displacement by the pineal lesion, and presence or absence of IMSA., Results: IMSA occurred with increased frequency in pineal lesions with PS (85%) when compared with NPS (39.2%) (p = 0.0001). Midbrain abutment, compression, and displacement occurred with similar frequencies in both groups, with no statistically significant difference. Hydrocephalus was present in 80.8% of patients with PS and 84% without PS (p = 0.75)., Conclusion: IMSA in a patient with an intrinsic pineal gland mass is associated with PS. Other findings such as hydrocephalus and midbrain displacement are common in patients with pineal masses both with and without PS and do not have any predictive value.

Combretastatin (CA-4) and its analogues are undergoing several clinical trials for treating different types of tumors. In this work, the antiproliferative activity of a series of 2-aminoimidazole-carbonyl analogs of clinically relevant combretastatins A-4 (CA-4) and A-1 was evaluated using a cell-based assay. Among the compounds tested, C-13 and C-21 displayed strong antiproliferative activities against HeLa cells. C-13 inhibited the proliferation of lung carcinoma (A549) cells more potently than combretastatin A-4. C-13 also retarded the migration of A549 cells. Interestingly, C-13 displayed much stronger antiproliferative effects against breast carcinoma and skin melanoma cells compared to noncancerous breast epithelial and skin fibroblast cells. C-13 strongly disassembled cellular microtubules, perturbed the localization of EB1 protein, inhibited mitosis in cultured cells, and bound to tubulin at the colchicine site and inhibited the polymerization of reconstituted microtubules in vitro. C-13 treatment increased the level of reactive oxygen species and induced apoptosis via poly(ADP-ribose) polymerase-cleavage in HeLa cells. The results revealed the importance of the 2-aminoimidazole-carbonyl motif as a double bond replacement in combretastatin and indicated a pharmacodynamically interesting pattern of H-bond acceptors/donors and requisite syn-templated aryls., Competing Interests: The authors declare no competing financial interest.

A new approach for the synthesis of tetrasubstituted/functionalized NH-pyrroles from gem-diactivated acrylonitriles and TMSCN has been developed. The strategy utilizes the generation of vic-dinitrile via Michael addition and cyanide-mediated nitrile-to-nitrile cyclocondensation, which proceed in tandem guided by manifold roles of "CN". An extended application to the production of fused pyrrole has also been realized.

Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional N -heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin-(trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3-(trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 ( C-23 ) was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, C-23 displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. C-23 depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. C-23 inhibited the assembly of tubulin in vitro . C-23 bound to tubulin at the colchicine binding site and altered the secondary structures of tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazole as a cis-restricted double bond-alternative bridging motif, and carboxymethyl-substituted phenyl as ring B for activities and interaction with tubulin. The results indicated that the combretastatin-(trifluoromethyl)pyrazole hybrid class of analogues has the potential for further development as anticancer agents., Competing Interests: The authors declare no competing financial interest.

Diffuse intrinsic pontine glioma (DIPG) is a poor-prognosis pediatric brain tumor. No effective curative therapy is currently available and no therapeutic advances have been made in several decades. BMI-1 is a member of the multimeric protein complex Polycomb repressor complex 1. It is highly expressed in a number of diseases and malignancies and has been implicated in self-renewal of normal and cancer cells, and in DNA damage signaling. The role of BMI-1 in DIPG is largely unknown. Here, we show that BMI-1 is highly expressed in tumor tissue samples of DIPG patients and in patient-derived cancer stem-like cells. BMI-1 downregulation leads to the inhibition of DIPG patient-derived neurosphere cell proliferation, cell cycle signaling, self-renewal, telomerase expression and activity, and suppresses DIPG cell migration. Moreover, targeted inhibition of BMI-1 sensitizes DIPG cells to radiomimetic drug-induced DNA damage. Together, our data validate BMI-1 as a potential therapeutic target to treat children with DIPG., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest.

A step-economical access to polysubstituted aminoimidazoles has been accomplished via alkene vicinal C-N bonds formation of 2-bromo-2-alkenones with guanidine avoiding its NH-protection/derivatization prerequisite for electronic modulation. The approach has excellent substrate scope, is amenable to diverse guanidine-containing substrates, and introduces distinctive substitutions/functionalities into aminoimidazole core. It is also applicable to preparation of fused-imidazoles. The reaction involves a tandem pathway of aza-Michael addition, S N 2, and a unique redox-neutral process, as evident by spectroscopic study and control experiments.