Publications by authors named "Luis Camacho"

121 Publications

Transmucosal Boston Keratoprosthesis Type I in a Patient With Advanced Ocular Cicatricial Pemphigoid.

Cornea 2020 Dec;39(12):1563-1565

Centro de Oftalmología Barraquer, Barcelona, Spain; and.

Purpose: To describe a novel surgical technique using the Boston Keratoprosthesis (KPro) type I in a patient with advanced ocular cicatricial pemphigoid (OCP) using oral mucosa for covering the prosthesis.

Methods: We present the case of an 85-year-old man previously diagnosed with type 2 diabetes and advanced OCP nonresponsive to immunosuppressive treatment, whose best-corrected visual acuity was light perception and projection in both eyes. After examination, Boston KPro type I in the right eye was contemplated because osteo-odonto KPro and Tibial bone KPro were not feasible because of the patient's osteoporosis and edentulism. Reconstruction of the ocular surface was first performed using oral mucosa to release the symblepharon and try to deep the fornices. Three months later, the oral mucosa was lifted, and the Boston KPro type I was implanted using the patient's own cornea. Then, a modification of the standard surgical technique was carried out, replacing the use of contact lens for covering the prosthesis with an oral mucosa graft with a central trephination as an alternative option in fornix foreshortening cases.

Results: After 11 months, visual acuity was stable to 0.2 decimal. No postoperative complications have been encountered, and prosthesis was in place.

Conclusions: The surgical technique of transmucosal Boston KPro type I may be considered a surgical alternative in patients with advanced OCP who present with severe fornix foreshortening, where osteo-odonto KPro or Tibial bone KPro cannot be performed due to osteoporosis or edentulism or when the Boston KPro type II is not readily available.
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http://dx.doi.org/10.1097/ICO.0000000000002413DOI Listing
December 2020

sp. nov. (Hymenoptera, Formicidae), a new conspicuous trap-jaw ant from Ecuador.

Zookeys 2020 13;948:75-105. Epub 2020 Jul 13.

Ecological Networks, Department of Biology, Technical University of Darmstadt, Darmstadt, Germany.

One of the largest species in its genus, Hoenle, Lattke & Donoso, is described from workers and queens collected at lowland forests in the Chocó-Darién bioregion in coastal Ecuador. The workers are characterized by their uniform red coloration, their large size (16-18 mm body length), and their frontal head striation that reaches the occipital margin. DNA barcodes (COI) and high resolution 2D images of the type material are provided, as well as an updated key for the Neotropical species of . In addition, a three-dimensional digital model of the worker holotype and a paratype queen scanned with DISC3D based on photogrammetry is presented, for the first time in a species description. Findings of large and conspicuous new species are uncommon around the world and suggest that these Ecuadorian rainforests may conceal many more natural treasures that deserve conservation.
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http://dx.doi.org/10.3897/zookeys.948.48701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381719PMC
July 2020

Immunogenicity of Inactivated Varicella Zoster Vaccine in Autologous Hematopoietic Stem Cell Transplant Recipients and Patients With Solid or Hematologic Cancer.

Open Forum Infect Dis 2020 Jul 2;7(7):ofaa172. Epub 2020 Jun 2.

Merck & Co., Inc., Kenilworth, New Jersey, USA.

Background: In phase 3 trials, inactivated varicella zoster virus (VZV) vaccine (ZV) was well tolerated and efficacious against herpes zoster (HZ) in autologous hematopoietic stem cell transplant (auto-HSCT) recipients and patients with solid tumor malignancies receiving chemotherapy (STMc) but did not reduce HZ incidence in patients with hematologic malignancies (HMs). Here, we describe ZV immunogenicity from these studies.

Methods: Patients were randomized to ZV or placebo (4 doses). Immunogenicity was assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and VZV interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay in patients receiving all 4 doses without developing HZ at the time of blood sampling.

Results: Estimated geometric mean fold rise ratios (ZV/placebo) by gpELISA and IFN-y ELISPOT ~28 days post-dose 4 were 2.02 (95% confidence interval [CI], 1.53-2.67) and 5.41 (95% CI, 3.60-8.12) in auto-HSCT recipients; 1.88 (95% CI, 1.79-1.98) and 2.10 (95% CI, 1.69-2.62) in patients with STMc; and not assessed and 2.35 (95% CI, 1.81-3.05) in patients with HM.

Conclusions: ZV immunogenicity was directionally consistent with clinical efficacy in auto-HSCT recipients and patients with STMc even though HZ protection and VZV immunity were not statistically correlated. Despite a lack of clinical efficacy in patients with HM, ZV immunogenicity was observed in this population. Immunological results did not predict vaccine efficacy in these 3 populations.

Clinical Trial Registration: NCT01229267, NCT01254630.
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http://dx.doi.org/10.1093/ofid/ofaa172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336559PMC
July 2020

Point of Care Ultrasound in Pyogenic Tenosynovitis: A Case Report.

Bull Emerg Trauma 2020 Jan;8(1):41-46

Department of Emergency Medicine, The University of Arizona, Tucson, AZ, USA.

Pyogenic tenosynovitis is caused by hematogenous spread of infection or trauma with direct inoculation of a tendon sheath. Symptoms and clinical examination findings associated with pyogenic tenosynovitis may be confused with superficial soft tissue infections, however management plans between pyogenic tenosynovitis and superficial soft tissue infection vary significantly. In patients with pyogenic tenosynovitis, operative intervention and subsequent irrigation and debridement offer a definitive therapy. Bedside ultrasound helps clinicians inspect the involved tendon sheath and may help assisting diagnosis of pyogenic tenosynovitis. In this case report, we described three cases, where point of care ultrasound was used to assist the diagnosis of pyogenic tenosynovitis, to accelerate consultation, and to expedite operative intervention.
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http://dx.doi.org/10.29252/beat-080107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071934PMC
January 2020

Surface Roughness Gradients Reveal Topography-Specific Mechanosensitive Responses in Human Mesenchymal Stem Cells.

Small 2020 03 17;16(10):e1905422. Epub 2020 Feb 17.

College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials and Engineering, Sichuan University, 610065, Chengdu, China.

The topographic features of an implant, which mechanically regulate cell behaviors and functions, are critical for the clinical success in tissue regeneration. How cells sense and respond to the topographical cues, e.g., interfacial roughness, is yet to be fully understood and even debatable. Here, the mechanotransduction and fate determination of human mesenchymal stem cells (MSCs) on surface roughness gradients are systematically studied. The broad range of topographical scales and high-throughput imaging is achieved based on a catecholic polyglycerol coating fabricated by a one-step-tilted dip-coating approach. It is revealed that the adhesion of MSCs is biphasically regulated by interfacial roughness. The cell mechanotransduction is investigated from focal adhesion to transcriptional activity, which explains that cellular response to interfacial roughness undergoes a direct force-dependent mechanism. Moreover, the optimized roughness for promoting cell fate specification is explored.
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http://dx.doi.org/10.1002/smll.201905422DOI Listing
March 2020

Surface Roughness and Substrate Stiffness Synergize To Drive Cellular Mechanoresponse.

Nano Lett 2020 01 12;20(1):748-757. Epub 2019 Dec 12.

Institute of Chemistry and Biochemistry , Freie Universität Berlin , Takustr. 3 , 14195 Berlin , Germany.

Material surface topographic features have been shown to be crucial for tissue regeneration and surface treatment of implanted devices. Many biomaterials were investigated with respect to the response of cells on surface roughness. However, some conclusions even conflicted with each other due to the unclear interplay of surface topographic features and substrate elastic features as well as the lack of mechanistic studies. Herein, wide-scale surface roughness gradient hydrogels, integrating the surface roughness from nanoscale to microscale with controllable stiffness, were developed via soft lithography with precise surface morphology. Based on this promising platform, we systematically studied the mechanosensitive response of human mesenchymal stem cells (MSCs) to a broad range of roughnesses (200 nm to 1.2 μm for ) and different substrate stiffnesses. We observed that MSCs responded to surface roughness in a stiffness-dependent manner by reorganizing the surface hierarchical structure. Surprisingly, the cellular mechanoresponse and osteogenesis were obviously enhanced on very soft hydrogels (3.8 kPa) with high surface roughness, which was comparable to or even better than that on smooth stiff substrates. These findings extend our understanding of the interactions between cells and biomaterials, highlighting an effective noninvasive approach to regulate stem cell fate via synergetic physical cues.
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http://dx.doi.org/10.1021/acs.nanolett.9b04761DOI Listing
January 2020

Cadaver Models in Residency Training for Uncommonly Encountered Ultrasound-Guided Procedures.

J Med Educ Curric Dev 2019 Jan-Dec;6:2382120519885638. Epub 2019 Nov 19.

Department of Emergency Medicine, The University of Arizona, Tucson, AZ, USA.

Background: Arthrocentesis of the ankle and elbow and brachial plexus nerve blocks are infrequently performed procedures; however, clinicians in specialties such as emergency medicine are required to be proficient in these procedures in the event of emergent or urgent necessity.

Objectives: The objective of this study was to create, implement, and assess a fresh cadaver-based educational model to help resident physicians learn how to perform ultrasound-guided arthrocentesis of the ankle and elbow and ultrasound-guided regional nerve blocks.

Methods: This was a single-center cross-sectional study conducted at an academic medical center. After a brief didactic session, 26 emergency medicine residents with varying levels of clinical and ultrasound experience rotated through 4 fresh cadaver-based stations. The objective of each station was to understand the sonographic anatomy and to perform ultrasound-guided arthrocentesis or regional nerve block with hands-on feedback from ultrasound fellows and faculty. Participants were subsequently asked to complete a questionnaire which evaluated participants' experience level, opinions, and procedural confidence regarding the 4 stations.

Results: A total of 26 residents participated in this study. All 26 residents agreed that the cadaver model (compared with clinical anatomy) was realistic regarding ultrasound quality of the joint space, ultrasound quality of the joint effusion, ultrasound quality of nerves, tissue density, needle guidance, and artifacts. Finally, there was a statistically significant difference between mean scores for pre-simulation and post-simulation session participant procedural confidence for all 4 procedures.

Conclusions: This fresh cadaver-based ultrasound-guided educational model was an engaging and well-received opportunity for residents to gain proficiency and statistically significant confidence in procedures which are uncommonly performed in clinical settings.
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http://dx.doi.org/10.1177/2382120519885638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864035PMC
November 2019

Deprotection Strategies for Thioimidates during Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides.

J Org Chem 2019 12 26;84(23):15309-15314. Epub 2019 Nov 26.

Department of Chemistry , Iowa State University , Ames , Iowa 50011 , United States.

Thioamides are important biophysical probes of peptide folding but are prone to α-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas HS. This work examines several approaches to supplant HS as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of α-C stereochemistry and conversion back to thioamide.
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http://dx.doi.org/10.1021/acs.joc.9b02317DOI Listing
December 2019

Decreasing Predator Density and Activity Explains Declining Predation of Insect Prey along Elevational Gradients.

Am Nat 2019 09 19;194(3):334-343. Epub 2019 Jul 19.

Predation, which is a fundamental force in ecosystems, has been found to decrease in intensity with elevation and latitude. The mechanisms behind this pattern, however, remain unaddressed. Using visual sampling of potential predators and live flies as baits, we assessed predation patterns along 4,000-m elevation transects on either side of the equatorial Andes. At the lower elevations, we found that around 80% of predation events on our insect baits were due to ants. The decline in predation with elevation was driven mainly by a decline in the abundance of ants, whose importance relative to other predators also declined. We show that both predator density and activity (predation rate per individual predator) decreased with elevation, thus ascribing specific mechanisms to known predation patterns. We suggest that changes in these two mechanisms may reflect changes in primary productivity and metabolic rate with temperature, factors of potential relevance across latitudinal and other macroecological gradients, particularly for ectotherm predators and prey.
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http://dx.doi.org/10.1086/704279DOI Listing
September 2019

Management of Trazodone Overdose with Severe Hypotension.

Case Rep Emerg Med 2019 4;2019:2470592. Epub 2019 Aug 4.

Department of Emergency Medicine, University of Arizona, Tucson, AZ, USA.

Trazodone is a medication that possesses antidepressant, anxiolytic, and hypnotic properties. Its mechanism of action includes blockade of serotonin type 2 receptors, weak inhibition of serotonin reuptake, blockade of histamine 1 receptors, and blockade of alpha-1-adrenergic receptors. We present a case of intentional ingestion of an estimated 2500 mg of trazodone leading to persistent hypotension, requiring aggressive fluid resuscitation, pressor support, and intensive care unit admission. Complications associated with trazodone overdoses are significant and clinicians should be aware of the associated symptoms and necessary management plans necessary for such ingestions.
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http://dx.doi.org/10.1155/2019/2470592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699354PMC
August 2019

Mechanochemical synthesis of three double perovskites: CsAgBiBr, (CHNH)TlBiBr and CsAgSbBr.

Nanoscale 2019 Sep 28;11(35):16650-16657. Epub 2019 Aug 28.

Departamento de Química Física y Termodinámica Aplicada, Instituto Universitario de Investigación en Química Fina y Nanoquímica, IUNAN, Universidad de Córdoba, Campus de Rabanales, Edificio Marie Curie, E-14071 Córdoba, Spain.

A wide majority of the organic-inorganic hybrid perovskites employed in photovoltaics contain Pb, which is a negative issue due to its high toxicity and the low stability of the Pb-based three-dimensional (3D) perovskites. The double perovskites or "elpasolites" with the formula ABB'X arise as an alternative to avoid the use of Pb, however, not many of the theoretically predicted structures have been synthesized so far due to several synthetic issues, such as, the formation of stable side products. Herein, we report the synthesis of three double perovskites, CsAgBiBr, MATlBiBr and CsAgSbBr, through a highly efficient and reproducible mechanochemical approach: the high energy ball milling. This synthetic approach does not require the use of organic solvents, so it is a greener method compared to those reported for other double perovskites. The CsAgBiBr and MATlBiBr double perovskites were synthesized with high purity as proved by X-ray diffraction (XRD) and X-ray fluorescence (XRF) measurements. However, the CsAgSbBr double perovskite was obtained in mixture with CsSbBr, a side product of the reaction. Several attempts to prepare the CsAgSbBr double perovskite by using other synthetic methods have been unsuccessful due to the low formation enthalpy of the CsSbBr side product and only the hydrothermal method afforded CsAgSbBr in mixture with other compounds. We believe that the low temperature required in the ball milling synthesis is the key factor that allows the formation of the antimony double perovskite. CsAgSbBr is a brown powder with a bandgap energy of 1.93 eV as shown with diffuse reflectance measurements. The three powders exhibit a very high stability with no changes at all in the crystal structure after several months of storage at room temperature and ambient humidity.
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http://dx.doi.org/10.1039/c9nr06092hDOI Listing
September 2019

A Bottom-Up Approach To Preserve Thioamide Residue Stereochemistry during Fmoc Solid-Phase Peptide Synthesis.

Org Lett 2019 09 12;21(17):7015-7018. Epub 2019 Aug 12.

Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States.

Thioamides are useful biophysical probes for the study of peptide structure and folding. The α-C stereochemistry of thioamide amino acids, however, is easily epimerized during solid-phase peptide synthesis (SPPS), which limits the sequence space that is available to thioamide incorporation. This work demonstrates that the α-C stereochemistry of thioamides can be reversibly protected in a manner that is compatible with the standard methodology of SPPS to enable the facile implementation of thioamide probes.
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http://dx.doi.org/10.1021/acs.orglett.9b02598DOI Listing
September 2019

Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial.

Lancet Infect Dis 2019 09 6;19(9):1001-1012. Epub 2019 Aug 6.

Merck & Co, Inc, Kenilworth, NJ, USA.

Background: Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies.

Methods: This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered (NCT01254630 and EudraCT 2010-023156-89).

Findings: Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI -1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI -17·8 to 41·3).

Interpretation: The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies.

Funding: Merck & Co, Inc.
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http://dx.doi.org/10.1016/S1473-3099(19)30310-XDOI Listing
September 2019

Surgical Management of Lateral Ankle Instability in Athletes.

J Athl Train 2019 Jun;54(6):639-649

Department of Orthopaedic Surgery, University of Arizona, Tucson.

Ankle sprains are common injuries involving the lateral ankle ligaments and affect athletes of all levels. Most patients heal uneventfully, but those with symptoms persisting past 3 months should be evaluated for chronic ankle instability and its associated conditions as well as for the presence of varus malalignment. Chronic ankle instability is initially treated nonoperatively, with surgical management reserved for those who have failed to improve after 3 to 6 months of bracing and functional rehabilitation. Anatomic repair using a modification of the Broström procedure is the preferred technique for initial surgery. Anatomic reconstruction with tendon graft should be considered when repair is not possible, as it maintains physiological joint kinematics. Nonanatomic reconstructions are seldom indicated. Arthroscopic repair or reconstruction of the lateral ankle ligaments is a promising new technique with results similar to those of open surgery.
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http://dx.doi.org/10.4085/1062-6050-348-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602388PMC
June 2019

Optimization of Amino Acid Sequence of Fmoc-Dipeptides for Interaction with Lipid Membranes.

J Phys Chem B 2019 05 22;123(17):3721-3730. Epub 2019 Apr 22.

Departamento de Química Física y T. Aplicada, Instituto Universitario de Investigación en Química Fina y Nanoquímica IUIQFN, Facultad de Ciencias , Universidad de Córdoba (UCO) , Campus de Rabanales, Ed. Marie Curie , E-14071 Córdoba , Spain.

Fmoc-dipeptides appear as highly relevant building blocks in smart hydrogels and nanovehicles for biological applications. The interactions of the Fmoc-dipeptides with the cell membrane determine the efficiency of the nanomaterials based on the Fmoc-dipeptides' internalization of nanovehicles for drug delivery. Here, we aim to understand the interplay of the interactions between the Fmoc-dipeptides and a phospholipid surface as a function of the amino acid sequence. The DMPA (1,2-dimyristoyl- sn-glycero-3-phosphate) phospholipid in Langmuir monolayers was used as a model cell surface. A set of seven derivatives of Fmoc-dipeptides with a broad range of hydrophobicity were included. Mixed monolayers composed of DMPA/Fmoc-dipeptides in an equimolar ratio were built and characterized in situ at the air/water interface. Surface pressure-molecular area isotherms (π- A), Brewster angle microscopy (BAM), and UV-vis reflection spectroscopy (Δ R) were combined to provide a holistic picture of the interactions of the Fmoc-dipeptide with the phospholipid molecules. An increase in the hydrophobicity led to enhanced interaction of the Fmoc-dipeptide and DMPA molecules. The compression of the mixed monolayer could displace a significant fraction of the Fmoc-dipeptide from the monolayer. High hydrophobicity promoted self-assembly of the Fmoc-dipeptides over interaction with the phospholipid surface. The interplay of these two phenomena was analyzed as a function of the amino acid sequence of the Fmoc-dipeptides. The toxicity effect of Fmoc-FF could be observed and detailed at the molecular level. This study suggests that the adjustment of the hydrophobicity of the Fmoc-dipeptides within a defined range might optimize their efficiency for interaction with the lipid membranes. A semiquantitative guide for the chemical design of Fmoc-dipeptides for biological applications is proposed herein.
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http://dx.doi.org/10.1021/acs.jpcb.9b01132DOI Listing
May 2019

Mimicking the bioelectrocatalytic function of recombinant CotA laccase through electrostatically self-assembled bioconjugates.

Nanoscale 2019 Jan;11(4):1549-1554

Departamento de Química Física y Termodinamica Aplicada, Instituto Universitario de Investigación en Química Fina y Nanoquímica IUIQFN, Facultad de Ciencias, Universidad de Córdoba, Campus de Rabanales, Ed. Marie Curie, E-14071 Córdoba, Spain.

Unprecedented 3D nanobiosystems composed of recombinant CotA laccases and citrate-stabilised gold nanoparticles have been successfully achieved by an electrostatic self-assembly strategy. The bioelectrochemical reduction of O2 driven by CotA laccase at the spore coat was mimicked. Consequently key insights into its bioelectrocatalytic function were unravelled.
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http://dx.doi.org/10.1039/c8nr06001kDOI Listing
January 2019

Folding of cytosine-based nucleolipid monolayer by guanine recognition at the air-water interface.

J Colloid Interface Sci 2019 Mar 16;537:694-703. Epub 2018 Nov 16.

Institute of Fine Chemistry and Nanochemistry, Department of Physical Chemistry and Applied Thermodynamics, University of Córdoba, Campus Universitario de Rabanales, Edificio Marie Curie, Córdoba E-14014, Spain.

Monolayers of a cytosine-based nucleolipid (1,2-dipalmitoyl-sn-glycero-3-(cytidine diphosphate) (ammonium salt), CDP-DG) at basic subphase have been prepared at the air-water interface both in absence and presence of guanine. The formation of the complementary base pairing is demonstrated by combining surface experimental techniques, i.e., surface pressure (π)-area (A), Brewster angle microscopy (BAM), infrared spectroscopy (PM-IRRAS) and computer simulations. A folding of the cytosine-based nucleolipid molecules forming monolayer at the air-water interface occurs during the guanine recognition as absorbate host and is kept during several compression-expansion processes under set experimental conditions. The specificity between nitrogenous bases has been also registered. Finally, mixed monolayers of CDP-DG and a phospholipid (1,2-dimyristoyl-sn-glycero-3-phosphate (sodium salt), DMPA) has been studied and a molecular segregation of the DMPA molecules has been inferred by the additivity rule.
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http://dx.doi.org/10.1016/j.jcis.2018.11.036DOI Listing
March 2019

Unravelling the 2D self-assembly of Fmoc-dipeptides at fluid interfaces.

Soft Matter 2018 Nov;14(46):9343-9350

Departamento de Química Física y T. Aplicada, Instituto Universitario de Investigación en Química Fina y Nanoquímica IUIQFN, Facultad de Ciencias, Universidad de Córdoba, Campus de Rabanales, Ed. Marie Curie, E-14071 Córdoba, Spain.

Dipeptides self-assemble into supramolecular structures showing plenty of applications in the nanotechnology and biomedical fields. A set of Fmoc-dipeptides with different aminoacid sequences has been synthesized and their self-assembly at fluid interfaces has been assessed. The relevant molecular parameters for achieving an efficient 2D self-assembly process have been established. The self-assembled nanostructures of Fmoc-dipeptides displayed significant chirality and retained the chemical functionality of the aminoacids. The impact of the sequence on the final supramolecular structure has been evaluated in detail using in situ characterization techniques at air/water interfaces. This study provides a general route for the 2D self-assembly of Fmoc-dipeptides.
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http://dx.doi.org/10.1039/c8sm01508bDOI Listing
November 2018

Fluorinated CdSe/ZnS quantum dots: Interactions with cell membrane.

Colloids Surf B Biointerfaces 2019 Jan 21;173:148-154. Epub 2018 Sep 21.

Institute of Fine Chemistry and Nanochemistry, Department of Physical Chemistry and Applied Thermodynamics, University of Córdoba, Campus Universitario de Rabanales, Edificio Marie Curie, Córdoba, E-14014, Spain. Electronic address:

Fluorescent inorganic quantum dots are highly promising for biomedical applications as sensing and imaging agents. However, the low internalization of the quantum dots, as well as for most of the nanoparticles, by living cells is a critical issue which should be solved for success in translational research. In order to increase the internalization rate of inorganic CdSe/ZnS quantum dots, they were functionalized with a fluorinated organic ligand. The fluorinated quantum dots displayed an enhanced surface activity, leading to a significant cell uptake as demonstrated by in vitro experiments with HeLa cells. We combined the experimental and computational results of Langmuir monolayers of the DPPC phospholipid as a model cell membrane with in vitro experiments for analyzing the mechanism of internalization of the fluorinated CdSe/ZnS quantum dots. Surface pressure-molecular area isotherms suggested that the physical state of the DPPC molecules was greatly affected by the quantum dots. UV-vis reflection spectroscopy and Brewster Angle Microscopy as in situ experimental techniques further confirmed the significant surface concentration of quantum dots. The disruption of the ordering of the DPPC molecules was assessed. Computer simulations offered detailed insights in the interaction between the quantum dots and the phospholipid, pointing to a significant modification of the physical state of the hydrophobic region of the phospholipid molecules. This phenomenon appeared as the most relevant step in the internalization mechanism of the fluorinated quantum dots by cells. Thus, this work sheds light on the role of fluorine on the surface of inorganic nanoparticles for enhancing their cellular uptake.
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http://dx.doi.org/10.1016/j.colsurfb.2018.09.050DOI Listing
January 2019

First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors.

Invest New Drugs 2018 10 29;36(5):860-868. Epub 2018 Jan 29.

Center for Oncology and Blood Disorders, Houston, TX, USA.

Background C-Met, which is frequently activated in multiple cancers, has been implicated in tumor formation, progression, metastasis, angiogenesis, and resistance to multiple therapies. MK-8033 is a small-molecule inhibitor of c-Met that binds preferentially to the activated conformation, and has demonstrated anti-tumor activity in preclinical models. This first-in-human trial was performed to establish the safety and maximum tolerated dose (MTD), as well as preliminary pharmacokinetics (PK) and clinical activity. Methods Forty-seven patients were enrolled in three parts. The primary objective of Parts A and B was safety, whereas Part C evaluated the effect of proton-pump inhibitors on MK-8033 absorption. Dose escalation used an accelerated continual reassessment method, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity (except alopecia or inadequately treated nausea/vomiting/diarrhea), grade 4 hematologic toxicity (except grade 3 neutropenic fever and thrombocytopenia), or toxicity where treatment is held >3 weeks. Results Forty-six patients were treated across nine dose levels, and the MTD was 750 mg twice daily. DLTs were fatigue, nausea, vomiting, transaminitis, and hypokalemia. Most frequent toxicities were fatigue (28.3%), nausea (21.7%), and alopecia (19.6%), predominately grade ≤ 2. One patient with endometriod adenocarcinoma achieved a partial response and eight had stable disease. Median progression-free survival (PFS) was 57 days. Strikingly, the PFS for the one responder was 846 days. PK results showed that proton-pump inhibitors have no effect on MK-8033 absorption. Conclusion MK-8033 was well tolerated with no significant toxicity issues, albeit with limited clinical activity. Unfortunately, the company decided to discontinue further clinical development of MK-8033.
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http://dx.doi.org/10.1007/s10637-018-0567-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507839PMC
October 2018

Intravascular hemolysis induced by phospholipases A from the venom of the Eastern coral snake, Micrurus fulvius: Functional profiles of hemolytic and non-hemolytic isoforms.

Toxicol Lett 2018 Apr 29;286:39-47. Epub 2017 Nov 29.

Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica San José 11501, Costa Rica. Electronic address:

A unique feature of the venom of Micrurus fulvius (Eastern coral snake) is its ability to induce severe intravascular hemolysis in particular species, such as dogs or mice. This effect was previously shown to be induced by distinct phospholipase A (PLA) isoforms which cause direct hemolysis in vitro, an uncommon finding for such enzymes. The functional profiles of PLA-17, a direct hemolytic enzyme, and PLA-12, a co-existing venom isoform lacking such effect, were compared. The enzymes differed not only in their ability to cause intravascular hemolysis: PLA-17 additionally displayed lethal, myotoxic, and anticoagulant actions, whereas PLA-12 lacked these effects. PLA-12 was much more active in hydrolyzing a monodisperse synthetic substrate than PLA-17, but the catalytic activity of latter was notably higher on a micellar substrate, or towards pure phospholipid artificial monolayers under controlled lateral pressures. Interestingly, PLA-17 could hydrolyze substrate at a pressure of 20 mN m, in contrast to PLA-12 or the non-toxic pancreatic PLA. This suggests important differences in the monolayer penetrating power, which could be related to differences in toxicity. Comparative examination of primary structures and predicted three-dimensional folding of PLA-12 and PLA-17, revealed that differences concentrate in their N-terminal and central regions, leading to variations of the surface properties at the membrane interacting interface. PLA-17 presents a less basic interfacial surface than PLA-12, but more bulky aromatic residues, which could be associated to its higher membrane-penetrating strength. Altogether, these structural and functional comparative observations suggest that the ability of PLAs to penetrate substrate interfaces could be a major determinant of toxicity, perhaps more important than protein surface charge.
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http://dx.doi.org/10.1016/j.toxlet.2017.11.037DOI Listing
April 2018

Organization and structure of mixed Langmuir films composed of polydiacetylene and hemicyanine.

J Colloid Interface Sci 2017 Dec 22;508:583-590. Epub 2017 Aug 22.

Institute of Fine Chemistry and Nanochemistry, Department of Physical Chemistry and Applied Thermodynamics, University of Córdoba, Campus Universitario de Rabanales, Edificio Marie Curie, Córdoba E-14014, Spain. Electronic address:

Mixed Langmuir monolayers of 10,12-Pentacosadiynoic acid (DA) monomer and an amphiphilic Hemicyanine dye derivative have been formed at the air/water interface. Two derivatives of docosylpyridinium have been used, with either one included in the monolayer in 1:1molar ratio. The DA monomers within the mixed monolayers have been polymerized in situ at the air/water interface. The crystalline structure of the monolayer and the kinetics of polymerization have been probed by grazing incidence X-ray diffraction (GIXD). The polymerization of DA proceeds with no phase segregation, exclusively leading to the red polydiacetylene form. The kinetics of polymerization at the air/water interface has been monitored in situ by GIXD. The experimental results have been combined with Molecular Mechanics computer simulations, revealing that DA molecules are sequentially arranged with molecules of Hemicyanine dye in alternating rows. The hydrophobic chains of the dye molecules act as spacers between the DA monomers. Surprisingly, such molecular arrangement does not hinder the in situ photopolymerization of DA. The mechanism of polymerization of DA within the mixed Langmuir monolayers has been convincingly described in molecular detail. This approach for interfacial polymerization of DA holds great potential for optically active devices and nanostructures comprising self-assembled thin films based in polydiacetylene.
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http://dx.doi.org/10.1016/j.jcis.2017.08.069DOI Listing
December 2017

A Randomized, Open-Label, Safety and Exploratory Efficacy Study of Kanglaite Injection (KLTi) plus Gemcitabine versus Gemcitabine in Patients with Advanced Pancreatic Cancer.

J Cancer 2017 3;8(10):1872-1883. Epub 2017 Jul 3.

KangLaiTe USA, Redwood City, CA.

This study was designed to assess the safety and preliminary efficacy of KLTi plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer. In a randomized, open-label study, patients with locally advanced or metastatic pancreatic cancer were randomized 2:1 to receive KLTi plus gemcitabine or gemcitabine monotherapy. Three sequential cohorts were tested at 30 g/day, 50 g/day, and 30 g/day. Gemcitabine was administered at 1000 mg/m on days 1, 8 and 15 of each 28 day cycle. KLTi was administered on days 1-5, 8-12, and 15-19 of each 28 day cycle. Patients received study treatment until disease progression. The primary endpoint was progression-free survival in the ITT population. Safety evaluation was based on patients who received any study treatment. ClinicalTrials.gov identifier NCT00733850. Eighty-five patients were randomized including 41 (28:13) in Cohort 1, 18 (12:6) in Cohort 2, and 26 (17:9) in Cohort 3. Due to a different dose and/or shift in patient populations in Cohort 2 and 3, efficacy data for the 30 gm dose are presented in this manuscript for Cohort 1 alone, and for the combination of Cohort 1+3. The 30 gm KLTi + gemcitabine group had a statistically significant improvement in progression-free survival (PFS) as assessed by blinded independent radiology review in the ITT population, with a median of 112 days, versus 58 days in the gemcitabine group (HR 0.50; 95% CI: 0.27, 0.92), p = 0.0240. The incidence rates of TEAEs, CTCAE Grade 3 or higher TEAEs, and SAEs were similar between the two arms. There were no deaths related to KLTi + gemcitabine treatment. Kanglaite Injection (30 g/day) plus a standard regimen of gemcitabine demonstrated encouraging clinical evidence of anti-neoplastic activity and a well-tolerated safety profile.
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http://dx.doi.org/10.7150/jca.15407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556651PMC
July 2017

Current Status of Biosimilars in Oncology.

Authors:
Luis H Camacho

Drugs 2017 Jun;77(9):985-997

Center for Oncology and Blood Disorders, 6560 Fannin St. Suite 1224, Houston, TX, 77030, USA.

Four medicinal cancer biological blockbusters will end their patent lifespan by 2020. It is estimated that the total market for cancer biologicals will reach approximately US$68 billion at that time. Approximately 20 biosimilars have entered the European market since the launch of the original approval guidelines in 2005, and four biosimilars have been approved in the USA since 2015. Data from European countries with the highest market entrance of biosimilars suggest that the incorporation of biosimilars into healthcare systems worldwide may result in a 30-45% cost savings. Initial levels of apprehension expressed by healthcare providers regarding the safety and efficacy of integrating biosimilars into the treatment of cancer patients have gradually decreased through active educational programs. The trust generated by regulatory agencies and drug manufacturers will ultimately make the adoption of biosimilars by healthcare providers and patients a smooth process. Future efforts to improve on the global acceptance and safety of biosimilars must include standardization of naming, regulatory requirements, and pharmacovigilance programs worldwide. High expectations are being placed on the cost savings, safety, and efficacy of these products. The entry costs for biosimilars and the pricing reaction of their originator products will determine the true savings by troubled health systems in dire need of cost cuts. This article discusses basic principles of biosimilars in hematology and oncology, the current status of their clinical development, and trends of acceptance by healthcare providers, and provides insight into potential future challenges.
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http://dx.doi.org/10.1007/s40265-017-0743-zDOI Listing
June 2017

Synthesis and Validation of Functional Nanogels as pH-Sensors in the Hair Follicle.

Macromol Biosci 2017 10 10;17(10). Epub 2017 Apr 10.

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin, 14195, Germany.

In the present study, a pH responsive dendritic polyglycerol nanogel (dPG-NG) is developed to measure the pH values inside the hair follicle (HF) using an ex vivo porcine ear model. The macromolecular precursors are labeled with a pH sensitive indodicarbocyanine dye (pH-IDCC) and a control dye (indocarbocyanine dye: ICC) and crosslinked via a mild and surfactant-free Thiol-Michael reaction using an inverse nanoprecipitation method. With this method, it is possible to prepare tailor-made particles in the range of 100 nm to 1 µm with a narrow polydispersity. The dPG-NGs are characterized using dynamic light scattering, nanoparticle tracking analysis, and atomic force microscopy. Systematic analysis of confocal microscope images of histological sections of the skin enables accurate determination of the pH gradient inside the HF. The results show that these novel pH-nanosensors deeply penetrate the skin via the follicular pathway and the pH of the pig hair follicles increase from 6.5 at the surface of the skin to 7.4 in deeper areas of the HF. The pH-nanosensor shows no toxicity potentials.
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http://dx.doi.org/10.1002/mabi.201600505DOI Listing
October 2017

Tailoring a compact and stable Langmuir bi-dimensional PbX-based layered perovskite film at the air-water interface and on solid support.

J Colloid Interface Sci 2017 Jul 14;498:194-201. Epub 2017 Mar 14.

Institute of Fine Chemistry and Nanochemistry, Department of Physical Chemistry and Applied Thermodynamics, University of Córdoba, Campus Universitario de Rabanales, Edificio Marie Curie, Córdoba E-14014, Spain.

The present work studies the stability of Langmuir organic-inorganic superlattice materials thin films consisting of layered perovskite-based films with controlled 2D framework as well as to design experimental conditions for increasing the efficiency of the organic-inorganic perovskite motif by mechanical stimulus. Therefore, a whole covering of the air/water interface by a compact and stable lead-based layered perovskite structure is pursued. A 2D layered perovskite-type hybrid structure of the form [(CH(CH)NH)(PbX)], X=Cl, and Br, in which, two-dimensional sheets stabilized by a inner bilayer of organic monoammonium cation matrix, is mechanically tailored by successive compression-expansion cycles. The formation of 2D molecular patterns has been characterized by ΔR, BAM, XRD and XPS.
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http://dx.doi.org/10.1016/j.jcis.2017.03.054DOI Listing
July 2017

Mechanosensitive Gold Colloidal Membranes Mediated by Supramolecular Interfacial Self-Assembly.

J Am Chem Soc 2017 01 17;139(3):1120-1128. Epub 2017 Jan 17.

Departamento de Química Física I, Universidad Complutense de Madrid , Avda. Complutense s/n, 28040 Madrid, Spain.

The ability to respond toward mechanical stimuli is a fundamental property of biological organisms at both the macroscopic and cellular levels, yet it has been considerably less observed in artificial supramolecular and colloidal homologues. An archetypal example in this regard is cellular mechanosensation, a process by which mechanical forces applied on the cell membrane are converted into biochemical or electrical signals through nanometer-scale changes in molecular conformations. In this article, we report an artificial gold nanoparticle (Au NP)-discrete π-conjugated molecule hybrid system that mimics the mechanical behavior of biological membranes and is able to self-assemble into colloidal gold nanoclusters or membranes in a controlled and reversible fashion by changing the concentration or the mechanical force (pressure) applied. This has been achieved by rational design of a small π-conjugated thiolated molecule that controls, to a great extent, the hierarchy levels involved in Au NP clustering by enabling reversible, cooperative non-covalent (π-π, solvophobic, and hydrogen bonding) interactions. In addition, the Au NP membranes have the ability to entrap and release aromatic guest molecules reversibly (K = 5.0 × 10 M) for several cycles when subjected to compression-expansion experiments, in close analogy to the behavior of cellular mechanosensitive channels. Not only does our hybrid system represent the first example of a reversible colloidal membrane, but it also can be controlled by a dynamic mechanical stimulus using a new supramolecular surface-pressure-controlled strategy. This approach holds great potential for the development of multiple colloidal assemblies within different research fields.
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http://dx.doi.org/10.1021/jacs.6b09485DOI Listing
January 2017

Benign-by-Design Solventless Mechanochemical Synthesis of Three-, Two-, and One-Dimensional Hybrid Perovskites.

Angew Chem Int Ed Engl 2016 11 28;55(48):14972-14977. Epub 2016 Oct 28.

Institute of Fine Chemistry and Nanochemistry, Department of Physical Chemistry and Applied Thermodynamics, University of Cordoba, Campus Universitario de Rabanales, Edificio Marie Curie, 14014, Córdoba, Spain.

Organic-inorganic hybrid perovskites have attracted significant attention owing to their extraordinary optoelectronic properties with applications in the fields of solar energy, lighting, photodetectors, and lasers. The rational design of these hybrid materials is a key factor in the optimization of their performance in perovskite-based devices. Herein, a mechanochemical approach is proposed as a highly efficient, simple, and reproducible method for the preparation of four types of hybrid perovskites, which were obtained in large amounts as polycrystalline powders with high purity and excellent optoelectronics properties. Two archetypal three-dimensional (3D) perovskites (MAPbI and FAPbI ) were synthesized, together with a bidimensional (2D) perovskite (Gua PbI ) and a "double-chain" one-dimensional (1D) perovskite (GuaPbI ), whose structure was elucidated by X-ray diffraction.
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http://dx.doi.org/10.1002/anie.201607397DOI Listing
November 2016