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1.
Cancer Med ; 13(9): e7212, 2024 May.
Article in English | MEDLINE | ID: mdl-38686626

ABSTRACT

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors. METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence. RESULTS: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group. CONCLUSIONS: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.


Subject(s)
CTLA-4 Antigen , Head and Neck Neoplasms , Immune Checkpoint Inhibitors , Tumor Microenvironment , Animals , Mice , CTLA-4 Antigen/antagonists & inhibitors , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Cell Line, Tumor , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/pathology , Humans , Female , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Disease Models, Animal
2.
Cancer Res Commun ; 4(3): 706-722, 2024 03 08.
Article in English | MEDLINE | ID: mdl-38421310

ABSTRACT

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail. SIGNIFICANCE: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.


Subject(s)
Head and Neck Neoplasms , Humans , Animals , Mice , Down-Regulation/genetics , Cell Line, Tumor , Head and Neck Neoplasms/drug therapy , Epithelial-Mesenchymal Transition/genetics , Cadherins/genetics
3.
Molecules ; 27(12)2022 Jun 08.
Article in English | MEDLINE | ID: mdl-35744821

ABSTRACT

The work carried out by our research group over the last couple of decades in the context of quantitative crystal engineering involves the analysis of intermolecular interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding using experimental charge density methodology is reviewed. The focus is to extract electron density distribution in the intermolecular space and to obtain guidelines to evaluate the strength and directionality of such interactions towards the design of molecular crystals with desired properties. Following the early studies on halogen bonding interactions, several "sigma-hole" interaction types with similar electrostatic origins have been explored in recent times for their strength, origin, and structural consequences. These include interactions such as carbon (tetrel) bonding, pnicogen bonding, chalcogen bonding, and halogen bonding. Experimental X-ray charge density analysis has proved to be a powerful tool in unraveling the strength and electronic origin of such interactions, providing insights beyond the theoretical estimates from gas-phase molecular dimer calculations. In this mini-review, we outline some selected contributions from the X-ray charge density studies to the field of non-covalent interactions (NCIs) involving elements of the groups 14-17 of the periodic table. Quantitative insights into the nature of these interactions obtained from the experimental electron density distribution and subsequent topological analysis by the quantum theory of atoms in molecules (QTAIM) have been discussed. A few notable examples of weak interactions have been presented in terms of their experimental charge density features. These examples reveal not only the strength and beauty of X-ray charge density multipole modeling as an advanced structural chemistry tool but also its utility in providing experimental benchmarks for the theoretical studies of weak interactions in crystals.


Subject(s)
Chalcogens , Halogens , Carbon , Halogens/chemistry , Quantum Theory , Static Electricity
4.
Front Cell Dev Biol ; 10: 830208, 2022.
Article in English | MEDLINE | ID: mdl-35345849

ABSTRACT

The tumor microenvironment (TME) is a complex, dynamic battlefield for both immune cells and tumor cells. The advent of the immune checkpoint inhibitors (ICI) since 2011, such as the anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 and anti-programmed cell death receptor (PD)-(L)1 antibodies, provided powerful weapons in the arsenal of cancer treatments, demonstrating unprecedented durable responses for patients with many types of advanced cancers. However, the response rate is generally low across tumor types and a substantial number of patients develop acquired resistance. These primary or acquired resistance are attributed to various immunosuppressive elements (soluble and cellular factors) and alternative immune checkpoints in the TME. Therefore, a better understanding of the TME is absolutely essential to develop therapeutic strategies to overcome resistance. Numerous clinical studies are underway using ICIs and additional agents that are tailored to the characteristics of the tumor or the TME. Some of the combination treatments are already approved by the Food and Drug Administration (FDA), such as platinum-doublet chemotherapy, tyrosine kinase inhibitor (TKI) -targeting vascular endothelial growth factor (VEGF) combined with anti-PD-(L)1 antibodies or immuno-immuno combinations (anti-CTLA-4 and anti-PD-1). In this review, we will discuss the key immunosuppressive cells, metabolites, cytokines or chemokines, and hypoxic conditions in the TME that contribute to tumor immune escape and the prospect of relevant clinical trials by targeting these elements in combination with ICIs.

5.
Chempluschem ; 86(8): 1128-1134, 2021 Jul 26.
Article in English | MEDLINE | ID: mdl-34402211

ABSTRACT

Reactions in solids are of contemporary interest due to applications in pharmaceutical industries to environmental sustainability. Although several reactive crystals that support chemical reactions have been identified and characterized, the same cannot be said about reactive cocrystals. Earlier we correlated the facile acyl group transfer reactions in crystals with supramolecular parameters obtained from the crystal structures. The structure-reactivity correlation revealed the requirement of proper juxtaposition of electrophile (C=O) and the nucleophile (OH) with distance (∼3.2 Å) and angle (∼90°) along the chain structure. The current article describes the preparation of cocrystals that are capable of supporting intermolecular acyl group transfer reactions in a group of structurally similar molecules. The cocrystals of naphthalene 2,3-diol and its corresponding diesters showed a facile solid state acyl transfer reaction, which has been well correlated with their crystal structures.

6.
Int Forum Allergy Rhinol ; 11(10): 1452-1460, 2021 10.
Article in English | MEDLINE | ID: mdl-34259380

ABSTRACT

BACKGROUND: Recent data show uncontrolled disease in 35% of allergic rhinitis (AR) patients on medical treatment. The reasons for uncontrolled disease can arbitrarily be divided into disease-related, diagnosis-related, treatment-related, and patient-related factors. However, the relative importance of these factors in uncontrolled disease remains speculative. This explorative study aimed at determining the factors causing uncontrolled AR on four different continents worldwide, identifying the most common reasons for uncontrolled disease in AR. METHODS: Patients with uncontrolled AR (n = 430) were asked to fill out a questionnaire and underwent a clinical examination at the outpatient clinic in five university outpatient clinics (Leuven [Belgium], Beijing [China], Kinshasa [Congo], Bangalore [India], and Philadelphia [US]). Two independent physicians evaluated the reason or multiple reasons for uncontrolled disease. The study was coordinated from the University Hospital of Leuven. RESULTS: In uncontrolled AR patients, 76% of patients showed two or more reasons for uncontrolled disease according to the physicians' evaluation. Disease-related factors (64%) were considered most often the reason for uncontrolled disease, followed by treatment- (56%), patient- (54%), and diagnosis-related (47%) factors. There is limited variability in observations across different centers worldwide. CONCLUSION: We here define the multiple reasons for uncontrolled AR across different continents, with disease-related factors being most frequently associated with uncontrolled disease. A better understanding of uncontrolled disease will guide us in defining strategies to improve AR care.


Subject(s)
Rhinitis, Allergic , Allergens , China , Democratic Republic of the Congo , Humans , India , Rhinitis, Allergic/diagnosis , Rhinitis, Allergic/epidemiology , Rhinitis, Allergic/therapy , Surveys and Questionnaires
7.
J Biol Chem ; 295(50): 17169-17186, 2020 12 11.
Article in English | MEDLINE | ID: mdl-33028635

ABSTRACT

We have observed overexpression of PACS-1, a cytosolic sorting protein in primary cervical tumors. Absence of exonic mutations and overexpression at the RNA level suggested a transcriptional and/or posttranscriptional regulation. University of California Santa Cruz genome browser analysis of PACS-1 micro RNAs (miR), revealed two 8-base target sequences at the 3' terminus for hsa-miR-34a and hsa-miR-449a. Quantitative RT-PCR and Northern blotting studies showed reduced or loss of expression of the two microRNAs in cervical cancer cell lines and primary tumors, indicating dysregulation of these two microRNAs in cervical cancer. Loss of PACS-1 with siRNA or exogenous expression of hsa-miR-34a or hsa-miR-449a in HeLa and SiHa cervical cancer cell lines resulted in DNA damage response, S-phase cell cycle arrest, and reduction in cell growth. Furthermore, the siRNA studies showed that loss of PACS-1 expression was accompanied by increased nuclear γH2AX expression, Lys382-p53 acetylation, and genomic instability. PACS-1 re-expression through LNA-hsa-anti-miR-34a or -449a or through PACS-1 cDNA transfection led to the reversal of DNA damage response and restoration of cell growth. Release of cells post 24-h serum starvation showed PACS-1 nuclear localization at G1-S phase of the cell cycle. Our results therefore indicate that the loss of hsa-miR-34a and hsa-miR-449a expression in cervical cancer leads to overexpression of PACS-1 and suppression of DNA damage response, resulting in the development of chemo-resistant tumors.


Subject(s)
DNA Damage , Drug Resistance, Neoplasm , MicroRNAs/metabolism , RNA, Neoplasm/metabolism , Uterine Cervical Neoplasms/metabolism , Vesicular Transport Proteins/metabolism , Female , G1 Phase , HeLa Cells , Humans , MicroRNAs/genetics , RNA, Neoplasm/genetics , S Phase Cell Cycle Checkpoints , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Vesicular Transport Proteins/genetics
8.
Am J Transplant ; 20(1): 159-171, 2020 01.
Article in English | MEDLINE | ID: mdl-31509331

ABSTRACT

This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [Ctrough ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target Ctrough 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Graft Rejection/drug therapy , Graft Survival/drug effects , Immunosuppressive Agents/therapeutic use , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Postoperative Complications/drug therapy , Equivalence Trials as Topic , Female , Follow-Up Studies , Graft Rejection/etiology , Graft Rejection/pathology , Humans , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Postoperative Complications/etiology , Postoperative Complications/pathology , Prognosis , Risk Factors , Tacrolimus/therapeutic use , Transplant Recipients
9.
Adv Ther ; 36(12): 3390-3408, 2019 12.
Article in English | MEDLINE | ID: mdl-31612357

ABSTRACT

INTRODUCTION: We qualitatively examined the symptoms and impact of recurrent primary focal segmental glomerulosclerosis (rpFSGS) in kidney transplant recipients, compared with two related FSGS populations, to characterize the experience of patients with rpFSGS. METHODS: A literature review identified 58 articles concerning the experience of patients with pFSGS and/or rpFSGS in three groups: pre-transplant pFSGS, post-transplant rpFSGS, or post-transplant non-recurrent pFSGS. Literature findings were used to construct a preliminary conceptual model incorporating the symptoms and impact of rpFSGS, which was refined on the basis of qualitative interviews with clinicians. Twenty-five patients (rpFSGS: n = 15; pre-transplant pFSGS: n = 5; post-transplant non-recurrent pFSGS: n = 5) were interviewed to characterize the experience of patients with rpFSGS and compare it with other FSGS populations, and findings were used to finalize the conceptual model. RESULTS: The impact of pFSGS/rpFSGS described in the literature was diverse. Treatment-related symptoms, along with anxiety and depression, were considered important features of rpFSGS in addition to the findings from the literature review, according to clinicians. Patient-reported tiredness and swelling were the most common/disturbing symptoms associated with rpFSGS, while physical activity restrictions and adverse effects on work/social life were considered the most profound impact concepts. The collective disease experience was different for patients with rpFSGS and non-recurrent pFSGS, although psychological impact, including treatment-related anxiety and depression, were common to both groups. CONCLUSIONS: Post-transplant recipients with rpFSGS display a greater symptom burden and experience a more diverse impact than those with non-recurrent pFSGS, highlighting the importance of effective patient monitoring and introducing effective treatments for the prevention and management of pFSGS recurrence. FUNDING: Astellas Pharma Global Development, Inc.


Subject(s)
Glomerulosclerosis, Focal Segmental/etiology , Glomerulosclerosis, Focal Segmental/physiopathology , Kidney Transplantation/adverse effects , Female , Glomerulosclerosis, Focal Segmental/psychology , Humans , Male , Mental Health , Middle Aged , Recurrence , Treatment Outcome
10.
J Mol Graph Model ; 92: 280-295, 2019 11.
Article in English | MEDLINE | ID: mdl-31425905

ABSTRACT

Piperine is a pungent alkaloid, largely present in the skin of pepper. It is the most active component of pepper and being used as a medicine in many Asian countries. The effect of piperine on memory impairment and neurodegeneration in Alzheimer's disease model has been investigated. In the present study, we aim to investigate the effect of piperine molecule in different environments (crystal and active site of proteins) from crystallography, molecular docking, QM/MM based charge density analysis and molecular dynamic simulation. The crystal structure of piperine has been used to determine the topological electron density of intermolecular interactions. The O-atoms of piperine is forming C-H⋅⋅⋅O interactions with the neighboring molecules in the crystal, these interactions also confirmed from the Hirshfeld surface. Further, to understand the nature of interactions and the conformational flexibility of piperine in the active site of recombinant human acetylcholinesterase (rhAChE), molecular docking analysis has been performed. The selected docked complex suggests favorable hydrogen bonding and hydrophobic interactions with rhAChE enzyme; notably, the O3 atom of piperine molecule forms strong hydrogen bonding interaction with Glu202 at 1.8 Å. To determine the charge density distribution and the electrostatic properties of piperine molecule in the active site of rhAChE, the piperine-rhAChE complex was minimized at QM/MM energy level; in which, the binding pocket with piperine was considered as QM region. The charge density analysis of piperine and the interacting amino acid groups have been carried out. The topological analysis of O3⋯H-O/Glu202 hydrogen bonding interaction exhibits strong interactions and the electron density ρcp(r): 0.242 eÅ-3 and the Laplacian ∇2ρcp(r): 3.176 eÅ-5 respectively. These results were compared with the corresponding molecule present in the crystal and gas phase environments of piperine. The comparison of active site structure with the corresponding crystal phase and gas phase structures reveal that piperine exhibits large conformational modification in the active site. The molecular dynamics simulation and binding free energy calculations were performed, this gives the stability, binding affinity of the molecule in the active site of rhAChE. The O3⋯H-O/Glu202 interaction shows the high stability (89.2%), this was confirmed from the stability of hydrogen bond analysis. The binding free energy was used to measure the rate of inhibition of enzyme in the presence of ligand molecule. The comparative study allows to understand the nature of piperine molecule in the gas and crystal phases, and amino acids environment.


Subject(s)
Alkaloids/chemistry , Benzodioxoles/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Piperidines/chemistry , Polyunsaturated Alkamides/chemistry , Acetylcholinesterase/chemistry , Algorithms , Catalytic Domain , Crystallography , Humans , Hydrogen Bonding , Molecular Conformation , Molecular Structure , Protein Binding
11.
Acc Chem Res ; 52(2): 437-446, 2019 02 19.
Article in English | MEDLINE | ID: mdl-30698945

ABSTRACT

It is far more difficult to recognize and predict the chemical reactions that a molecule of an organic compound can undergo in crystalline (solid) state as compared to the solution state (the "organic functional group" approach), since the published data on solid-state structure-reactivity investigations and correlations are scant. The discovery of the first intermolecular acyl-transfer reaction in molecular crystals of racemic 2,4-di- O-benzoyl- myo-inositol-1,3,5-orthoformate (DiBz) during our attempts to develop methods for the synthesis of phosphoinositols, motivated us to find other molecular crystals capable of supporting similar reactions. Small changes to the molecular structure of DiBz yielded analogues with different crystal structures which showed varying degrees of acyl transfer reactivity as compared to the crystals of DiBz. A systematic investigation of the structures, polymorphism, cocrystallization behavior, and the corresponding reactivity of these crystals allowed us to correlate the acyl transfer reactivity with their structures and inherent noncovalent interactions and provided crucial insights into the mechanism of these reactions. Polymorphs or cocrystals of these compounds exhibited dissimilar reactivities due to differences in the molecular conformation and/or arrangements in their crystals. The knowledge of phase transitions between polymorphs enabled us to control and tune the reactivity in the solid state. We could identify three conditions essential for intermolecular acyl transfer: (i) favorable relative geometry of the electrophile (ester C═O) and the nucleophile (OH), (ii) noncovalent interactions (C-H···π) between the reacting molecules which help in maintaining the facility and specificity of the reaction, and (iii) the presence of channels in the lattice which enable propagation of the reaction in the crystal. Based on this supramolecular structure-reactivity correlation, we identified other molecular crystals (composed of molecules of widely different molecular structure from that of DiBz) from a survey of the Cambridge Structural Database (CSD) and predicted their acyl transfer reactivity. The increased availability of user-friendly modern X-ray diffractometers and related software has enabled efficient collection, analysis and interpretation of single crystal X-ray diffraction data, essential for such studies. The rapidly expanding CSD facilitates the identification of crystals with similar structures and reactivity patterns. In a wider perspective, facile reactions in molecular crystals fascinate chemists because these reactions usually exhibit unique product selectivity and have the potential to be developed as sustainable green reactions. We are optimistic that similar approaches for the study of other group transfer reactions in molecular crystals would augment and widen the scope of chemical reactions in molecular crystals in particular and the solid state in general. The ability to predict the reactivity of molecules in their crystals could find applications in organic synthesis, material science and industry. Realization of the involvement of inositol derivatives in cellular processes led to the discovery of cellular signal transduction mechanisms. The ability of inositol derivatives to support facile acyl-transfer reactions in the crystalline state might well have opened a new avenue for research in the area of organic solid-state reactions.

12.
Am J Kidney Dis ; 73(1): 112-118, 2019 01.
Article in English | MEDLINE | ID: mdl-29705074

ABSTRACT

Hahnemann University Hospital has performed 120 kidney transplantations in human immunodeficiency virus (HIV)-positive individuals during the last 16 years. Our patient population represents ∼10% of the entire US population of HIV-positive kidney recipients. In our earlier years of HIV transplantation, we noted increased rejection rates, often leading to graft failure. We have established a multidisciplinary team and over the years have made substantial protocol modifications based on lessons learned. These modifications affected our approach to candidate evaluation, donor selection, perioperative immunosuppression, and posttransplantation monitoring and resulted in excellent posttransplantation outcomes, including 100% patient and graft survival at 1 year and patient and graft survival at 3 years of 100% and 96%, respectively. We present key clinical data, including a granular patient-level analysis of the associations of antiretroviral therapy regimens with long-term survival, cellular and antibody-mediated rejection rates, and the causes of allograft failures. In summary, we provide details on the evolution of our approach to HIV transplantation during the last 16 years, including strategies that may improve outcomes among HIV-positive kidney transplantation candidates throughout the United States.


Subject(s)
HIV Seropositivity/complications , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/surgery , Kidney Transplantation , Aged , Female , Hospitals, University , Humans , Male , Retrospective Studies , Time Factors
13.
Ann Otol Rhinol Laryngol ; 127(12): 962-968, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30296832

ABSTRACT

OBJECTIVES:: Cell therapies using mesenchymal stromal cells (MSCs) have been proposed as a promising new tool for the treatment of vocal fold scarring. However, the mechanisms by which MSCs promote healing as well as their duration of survival within the host vocal fold have yet to be defined. The aim of this work was to assess the persistence of embedded MSCs within a tissue-engineered vocal fold mucosal replacement in a rabbit model of vocal fold injury. METHODS:: Male rabbit adipose-derived MSCs were embedded within a 3-dimensional fibrin gel, forming the cell-based outer vocal fold replacement. Four female rabbits underwent unilateral resection of vocal fold epithelium and lamina propria and reconstruction with cell-based outer vocal fold replacement implantation. Polymerase chain reaction and fluorescent in situ hybridization for the sex-determining region of the Y chromosome (SRY-II) in the sex-mismatched donor-recipient pairs sought persistent cells after 4 weeks. RESULTS:: A subset of implanted male cells was detected in the implant site at 4 weeks. Many SRY-II-negative cells were also detected at the implant site, presumably representing native female cells that migrated to the area. No SRY-II signal was detected in contralateral control vocal folds. CONCLUSIONS:: The emergent tissue after implantation of a tissue-engineered outer vocal fold replacement is derived both from initially embedded adipose-derived stromal cells and infiltrating native cells. Our results suggest this tissue-engineering approach can provide a well-integrated tissue graft with prolonged cell activity for repair of severe vocal fold scars.


Subject(s)
Cicatrix/therapy , Mesenchymal Stem Cells/physiology , Tissue Engineering/methods , Tissue Transplantation/methods , Vocal Cord Dysfunction/therapy , Vocal Cords , Animals , Cicatrix/pathology , Cicatrix/physiopathology , Rabbits , Regeneration/physiology , Treatment Outcome , Vocal Cord Dysfunction/etiology , Vocal Cord Dysfunction/physiopathology , Vocal Cords/pathology , Vocal Cords/physiology , Vocal Cords/transplantation
14.
Carbohydr Res ; 463: 32-36, 2018 Jun 30.
Article in English | MEDLINE | ID: mdl-29751207

ABSTRACT

scyllo-Inositol derived 1,2-trans-diequatorial halohydrins can be efficiently converted to the corresponding epoxides in the presence of lithium hydride. The structure of one of the epoxides was determined by single crystal X-ray diffraction analysis. This provides a potential route for the preparation of ring modified inositol derivatives. DFT calculations suggest that this epoxide formation could be proceeding through the intermediacy of the cyclohexane ring-inverted axial-rich conformer (1,2-trans-diaxial halohydrin). This is supported by the results of DFT calculations on the formation of inositol orthoformate, where the product is locked in the axial-rich conformation, while the starting inositol has the equatorial-rich conformation.


Subject(s)
Epoxy Compounds/chemical synthesis , Inositol/chemistry , Lithium/chemistry , Epoxy Compounds/chemistry , Indicators and Reagents , Models, Molecular , Molecular Structure , Stereoisomerism , X-Ray Diffraction
15.
Biopharm Drug Dispos ; 39(5): 245-255, 2018 May.
Article in English | MEDLINE | ID: mdl-29679478

ABSTRACT

This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose-escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area-under-the-concentration-time curve over 336 hours (AUC336 ) and the maximum serum concentration (Cmax ), and dose proportionality of AUC336 and Cmax were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab Cmax and AUC336 were more than dose proportional in the range 0.1-3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine-release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.


Subject(s)
Antibodies, Monoclonal , Immunosuppressive Agents , Psoriasis/drug therapy , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/blood , Double-Blind Method , Female , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/immunology , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Psoriasis/blood , Psoriasis/metabolism
16.
J Org Chem ; 83(7): 3952-3959, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29537268

ABSTRACT

Intermolecular acyl transfer reactivity in several molecular crystals was studied, and the outcome of the reactivity was analyzed in the light of structural information obtained from the crystals of the reactants. Minor changes in the molecular structure resulted in significant variations in the noncovalent interactions and packing of molecules in the crystal lattice, which drastically affected the facility of the intermolecular acyl transfer reactivity in these crystals. Analysis of the reactivity vs crystal structure data revealed dependence of the reactivity on electrophile···nucleophile interactions and C-H···π interactions between the reacting molecules. The presence of these noncovalent interactions augmented the acyl transfer reactivity, while their absence hindered the reactivity of the molecules in the crystal. The validity of these correlations allows the prediction of intermolecular acyl transfer reactivity in crystals and co-crystals of unknown reactivity. This crystal structure-reactivity correlation parallels the molecular structure-reactivity correlation in solution-state reactions, widely accepted as organic functional group transformations, and sets the stage for the development of a similar approach for reactions in the solid state.

17.
Carbohydr Res ; 461: 38-44, 2018 May 22.
Article in English | MEDLINE | ID: mdl-29574293

ABSTRACT

A method for the preparation of benzene derivatives from myo-inositol, an abundantly available phyto chemical is described. 1,3-Bridged acetals of inososes undergo step-wise elimination leading to the formation of polyoxygenated benzene derivatives. This aromatization reaction proceeds through the intermediacy of a ß-alkoxyenone, which could be isolated. This sequence of reactions starting from myo-inositol, provides a novel route for the preparation of polyoxygenated benzene derivatives including polyoxygenated biphenyl. This scheme of synthesis demonstrates the potential of myo-inositol as a sustainable non-petrochemical resource for aromatic compounds.


Subject(s)
Benzene/chemistry , Inositol/chemistry , Biomass
18.
Chemistry ; 24(16): 4133-4139, 2018 Mar 15.
Article in English | MEDLINE | ID: mdl-29315895

ABSTRACT

The pincer-like double ester naphthalene-2,3-diyl-bis(4-fluorobenzoate) (2) is pentamorphic. Upon heating crystals of form I to below their melting point (441-443 K), they undergo a phase transition accompanied by a thermosalient effect, that is, rare and visually striking motility whereby the crystals jump or disintegrate. The phase transition and the thermosalient effect are reversible. Analysis of the crystal structure revealed that form I is a class II thermosalient solid. Crystals of form III also underwent a reversible phase transition in the temperature range of 160 to 170 K; however, they were not thermosalient. Comparison of the structures and the mechanical responses of the two polymorphs revealed that the thermosalient effect of form I was due to reversible closing and opening of the arms of the diester molecules in a tweezer-like action.

19.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 73(Pt 4): 626-633, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28762972

ABSTRACT

Experimental and theoretical charge density analyses on isomers of mercaptobenzoic acid have been carried out to quantify the hydrogen bonding of the hitherto less explored thiols, to assess the strength of the interactions using the topological features of the electron density. The electron density study offers interesting insights into the nature of the S-H...S interaction. The interaction energy is comparable with that of a weak hydrogen bond. The strength and directionality of the S-H...S hydrogen bond is demonstrated to be mainly due to the conformation locking potential of the intramolecular S...O chalcogen bond in 2-mercaptobenzoic acid and is stronger than in 3-mercaptobenzoic acid, which lacks the intramolecular S...O bond. The para-substituted mercaptobenzoic acid depicts a type I S...S interaction.

20.
Faraday Discuss ; 203: 201-212, 2017 10 13.
Article in English | MEDLINE | ID: mdl-28766629

ABSTRACT

The isomeric compounds, 4-bromo-2-chloro benzoic acid (4Br) and 2-bromo-4-chlorobenzoic acid (2Br), crystallize in entirely different space groups, P21/n and P1[combining macron] respectively. Both structures are stabilized by a strong O-HO hydrogen bonds generating a carboxylic acid dimer along with an unusual triangular halogen bonded motif in the former and a well-defined halogen bond in the latter. Charge density analysis establishes the nature of halogen bonds by bringing out significant changes in the packing features of the two structures as well as the quantification of the interaction energies involved in the formation of the motifs. Cocrystallization efforts lead to the formation of solid solutions of varied stoichiometric ratios among the two entirely different crystalline forms, a feature which is observed for the first time, and depends on the nature of the halogen bonds. Despite the significant variations in the charge density distribution in intermolecular space, the triangular motif, with two type II BrCl and ClBr and one type I BrBr contact in the structure of 4Br dictates the packing preferences in the solid solution as established by accurate single crystal diffraction studies supported by cognate powder diffraction analysis (PXRD) and differential scanning calorimetric (DSC) studies. A systematic study of the solid solution by varying the stoichiometric ratios establishes the hierarchy in halogen bonded motifs and consequently its directional influence to form the resultant supramolecular assembly.

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