The Turkish Neonatal Jaundice Online Registry: A national root cause analysis.
PLoS One. 2018;13(2):e0193108
Authors: Erdeve O, Okulu E, Olukman O, Ulubas D, Buyukkale G, Narter F, Tunc G, Atasay B, Gultekin ND, Arsan S, Koc E, Turkish Neonatal Jaundice Registry Collabolators
BACKGROUND: Neonatal jaundice (NNJ) is common, but few root cause analyses based on national quality registries have been performed. An online registry was established to estimate the incidence of NNJ in Turkey and to facilitate a root cause analysis of NNJ and its complications.
METHODS: A multicenter prospective study was conducted on otherwise healthy newborns born at ≥35 weeks of gestation and hospitalized for only NNJ in 50 collaborator neonatal intensive care units across Turkey over a 1-year period. Patients were analyzed for their demographic and clinical characteristics, treatment options, and complications.
RESULTS: Of the 5,620 patients enrolled, 361 (6.4%) had a bilirubin level ≥25 mg/dL on admission and 13 (0.23%) developed acute bilirubin encephalopathy. The leading cause of hospital admission was hemolytic jaundice, followed by dehydration related to a lack of proper feeding. Although all infants received phototherapy, 302 infants (5.4%) received intravenous immunoglobulin in addition to phototherapy and 132 (2.3%) required exchange transfusion. The infants who received exchange transfusion were more likely to experience hemolytic causes (60.6% vs. 28.1%) and a longer duration of phototherapy (58.5 ± 31.7 vs. 29.4 ± 18.8 h) compared to infants who were not transfused (p < 0.001). The incidence of short-term complications among discharged patients during follow-up was 8.5%; rehospitalization was the most frequent (58%), followed by jaundice for more than 2 weeks (39%), neurological abnormality (0.35%), and hearing loss (0.2%).
CONCLUSIONS: Severe NNJ and bilirubin encephalopathy are still problems in Turkey. Means of identifying at-risk newborns before discharge during routine postnatal care, such as bilirubin monitoring, blood group analysis, and lactation consultations, would reduce the frequency of short- and long-term complications of severe NNJ.
PMID: 29474382 [PubMed - in process]
Can re-cTURBT be useful in pT1HG disease as a risk indicator of recurrence and progression? A single centre experience.
Arch Ital Urol Androl. 2017 Dec 31;89(4):272-276
Authors: Giulianelli R, Gentile BC, Mirabile G, Albanesi L, Tariciotti P, Rizzo G, Buscarini M, Vermiglio M
INTRODUCTION: Understaging after initial transurethral resection is common in patients with high-risk non muscle infiltrating bladder cancer (NMIBC) and can delay accurate diagnosis and definitive treatment. The rate of upstaging from T1 to T2 disease after repeated transurethral resection ranges from 0 to 28%, although the rate of upstaging may be even higher up to 49% when muscularis propria is absent in the first specimen. A restaging classic transurethral resection of bladder tumour (re-cTURBT) is the better predictor of early stage progression. According to some reports, the rate of positivity for tumor in re-cTURBT performed within eight weeks after initial cTURBT was as high as 18-77%, and in about 40% of the patients a change in tumor stage was reported. We aimed to investigate, in high risk group, the presence of residual tumor following white light classical transurethral resection of bladder tumor (WLre-cTURBT) and the different recurrence and progression rate between patients with persistent or negative (pT0) oncological disease after WLre-cTURBT.
MATERIALS AND METHODS: A cohort of 285 patients presenting with primitive bladder cancer underwent to WLcTURBT from January 2011 to December 2015; out of them 92 (32.28%) were T1HG. In according to EAU guidelines 2011, after 4-6 weeks all HG bladder cancer patients underwent a WL recTURBT . All patients were submitted to a subsequent followup including cystoscopy every 3 months with multiple biopsies, randomly and in the previous zone of resection; urinary citology on 3 specimens and kidney/bladder ultrasound every 6 months. The average follow-up was 48 months.
RESULTS: Following WLre-cTURBT we observed a persistent disease in 18 (15.2%) patients: 14 (77.7%) with a HG-NMIBC and 4 (22.2%) with a high grade (HG) muscle invasive bladder cancer (pT2HG). After follow up of all 92 patients according to the guidelines EAU, we observed recurrence in 36/92 (39.1%) and progression in 14/92 (15.2%). Of 14 NMIBC with persistent disease, 10 patients (71.4%) showed recurrence: 4 patients (40%) were pT1HG with concomitant carcinoma in situ (CIS), 3 patients (30%) multifocal pTaHG, 2 (20%) patients CIS and one patient (10%) a muscle invasive neoplasm (pT2HG). Instead of the group of 48 patients pT0 following WL recTURBT, we observed recurrence in 26 patients (54.1%) and in two patients (4.1%) progressions, who presented after 3 months in association with CIS. The remaining 22 patients (45.9%) with initial pT1HG are still progression free. Multivariate analysis showed that the most important variable of early progression were persistent neoplasm and histopathological findings at WLre-cTURBt (p = 0.01), followed by the Summary No conflict of interest declared. INTRODUCTION Bladder cancer is a common genito-urinary malignancy, with transitional cell carcinoma comprising nearly 90% of all primary bladder tumours. At the first diagnosis 70% to 80% of urothelial tumours are confined to the epithelium, the remainder is characterized by muscle invasion. A significant number of patients with high risk non-muscle invasive bladder tumours (HG-NMIBT) treated with white light classic transurethral resection of bladder tumours (WLcTURBT) and intravesical BCG will progress to invasive disease (1-3). Progression to muscle invasion (pT2) mandates immediate radical cystectomy (4). WLcTURBT is the standard initial therapy for NMIBT, but the high percentage of recurrence after surgery is still an unresolved problem (5). High grade pT1 bladder neoplasm (pT1HG) really represents a therapeutic challenge due to the high risk of progression (about 15-30%) to muscle-invasive disease, usually within 5 years (6). However, no consensus exists regarding the treatment of patients with recurrent bladder tumours that invade the lamina propria (pT1) (7-9). Recent studies suggested that the first cTURBT may be incomplete in a significant number of cases (10). Understaging at the time of the initial transurethral resection is common for patients with high-risk NMIBC and can delay accurate diagnosis and definitive treatment. It is therefore recommended for patients with high-risk disease and in those with large or multiple tumors or when the initial transurethral resection is incomplete, to repeat WLre-cTURBT within 2-6 DOI: 10.4081/aiua.2017.4.272 result of the first cystoscopy (p = 0.002) and presence of CIS (p = 0.02).
DISCUSSION: Following WLre-cTURBt in HG-NMIBC patients we identified in 15% of cases a persistent disease with a 4.3% of MIBC. In the high risk persistent bladder neoplasms group we observed recurrent and progression rate higher than in T0 bladder tumours group (Δ = + 17.3% and = Δ + 62.5%, p < 0.05.
PMID: 29473376 [PubMed - in process]
The effects of exercise training associated with low-level laser therapy on biomarkers of adipose tissue transdifferentiation in obese women.
Lasers Med Sci. 2018 Feb 23;:
Authors: da Silveira Campos RM, Dâmaso AR, Masquio DCL, Duarte FO, Sene-Fiorese M, Aquino AE, Savioli FA, Quintiliano PCL, Kravchychyn ACP, Guimarães LI, Tock L, Oyama LM, Boldarine VT, Bagnato VS, Parizotto NA
Investigations suggest the benefits of low-level laser therapy (LLLT) to improve noninvasive body contouring treatments, inflammation, insulin resistance and to reduce body fat. However, the mechanism for such potential effects in association with exercise training (ET) and possible implications in browning adiposity processes remains unclear. Forty-nine obese women were involved, aged between 20 and 40 years with a body mass index (BMI) of 30-40 kg/m2. The volunteers were divided into Phototherapy (808 nm) and SHAM groups. Interventions consisted of exercise training and phototherapy applications post exercise for 4 months, with three sessions/week. Body composition, lipid profile, insulin resistance, atrial natriuretic peptide (ANP), WNT5 signaling, interleukin-6 (IL-6), and fibroblast growth factor-21 (FGF-21) were measured. Improvements in body mass, BMI, body fat mass, lean mass, visceral fat, waist circumference, insulin, HOMA-IR, total cholesterol, LDL-cholesterol, triglycerides, and ANP in both groups were demonstrated. Only the Phototherapy group showed a reduction in interleukin-6 and an increase in WNT5 signaling. In addition, it was possible to observe a higher magnitude change for the fat mass, insulin, HOMA-IR, and FGF-21 variables in the Phototherapy group. In the present investigation, it was demonstrated that exercise training associated with LLLT promotes an improvement in body composition and inflammatory processes as previously demonstrated. The Phototherapy group especially presented positive modifications of WNT5 signaling, FGF-21, and ANP, possible biomarkers associated with browning adiposity processes. This suggests that this kind of intervention promotes results applicable in clinical practice to control obesity and related comorbidities.
PMID: 29473115 [PubMed - as supplied by publisher]
A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation.
Front Immunol. 2018;9:161
Authors: Bachmann M, Pfeilschifter J, Mühl H
Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)]-induced acute liver injury (ALI) not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL)-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc) to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.
PMID: 29472923 [PubMed]
Regenerative endodontic therapy for managing immature non-vital teeth: a national survey of UK paediatric dental specialists and trainees.
Br Dent J. 2018 Feb 23;224(4):247-254
Authors: Nazzal H, Tong H, Nixon P, Duggal M
Background Several guidelines have been published advocating the use of regenerative endodontic therapy (RET) in managing non-vital immature permanent teeth. It is unclear, however, how many UK paediatric dental specialists routinely use this technique and their opinion of its outcomes, and barriers to its use.Aim To assess the knowledge, experience and the opinion of UK based paediatric dental specialists/trainees (UKPDS/T) and practitioners working in the capacity of paediatric dental specialists on the use of RET.Design A cross-sectional study using a 22-item questionnaire was developed using the Bristol Online Survey tool and circulated electronically to members of the British Society of Paediatric Dentistry between August and November 2016.Results Ninety-eight UKPDS/T completed the survey. A quarter of respondents (N = 24, 24.5%) reported using RET. Reasons cited for not using RET included lack of: training (N = 48, 45%), materials (N = 28, 26%), evidence (N = 17, 16%) and suitable cases (N = 6, 6%). Different protocols in terms of disinfection, medicaments, scaffolds, and obturation material were identified.Conclusions This survey highlights a low uptake of RET by current UKPDS and trainees with several barriers identified. Deviations from the current RET guidelines were identified. Recommendations addressing the use of RET in light of the findings of this survey were made.
PMID: 29472688 [PubMed - in process]
Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury.
Sci Rep. 2018 Feb 22;8(1):3481
Authors: Sanderson TH, Wider JM, Lee I, Reynolds CA, Liu J, Lepore B, Tousignant R, Bukowski MJ, Johnston H, Fite A, Raghunayakula S, Kamholz J, Grossman LI, Przyklenk K, Hüttemann M
The interaction of light with biological tissue has been successfully utilized for multiple therapeutic purposes. Previous studies have suggested that near infrared light (NIR) enhances the activity of mitochondria by increasing cytochrome c oxidase (COX) activity, which we confirmed for 810 nm NIR. In contrast, scanning the NIR spectrum between 700 nm and 1000 nm revealed two NIR wavelengths (750 nm and 950 nm) that reduced the activity of isolated COX. COX-inhibitory wavelengths reduced mitochondrial respiration, reduced the mitochondrial membrane potential (ΔΨm), attenuated mitochondrial superoxide production, and attenuated neuronal death following oxygen glucose deprivation, whereas NIR that activates COX provided no benefit. We evaluated COX-inhibitory NIR as a potential therapy for cerebral reperfusion injury using a rat model of global brain ischemia. Untreated animals demonstrated an 86% loss of neurons in the CA1 hippocampus post-reperfusion whereas inhibitory NIR groups were robustly protected, with neuronal loss ranging from 11% to 35%. Moreover, neurologic function, assessed by radial arm maze performance, was preserved at control levels in rats treated with a combination of both COX-inhibitory NIR wavelengths. Taken together, our data suggest that COX-inhibitory NIR may be a viable non-pharmacologic and noninvasive therapy for the treatment of cerebral reperfusion injury.
PMID: 29472564 [PubMed - in process]
Fork Protection and Therapy Resistance in Hereditary Breast Cancer.
Cold Spring Harb Symp Quant Biol. 2018 Feb 22;:
Authors: Cantor SB, Calvo JA
The BRCA-Fanconi anemia (FA) pathway preserves the genome and suppresses cancer and is a main determinant of chemotherapeutic efficacy. The hereditary breast cancer genes BRCA1 and BRCA2 function in DNA double-strand break repair mediating distinct steps of homologous recombination (HR). More recently, independent of DNA repair, functions in the replication stress response have come to light, providing insight as to how the BRCA-FA pathway also balances genome preservation with proliferation. The BRCA-FA proteins associate with the replisome and contribute to the efficiency and recovery of replication following perturbations that slow or arrest DNA replication. Although the full repertoire of functions in the replication stress response remains to be elucidated, the function of BRCA1 and BRCA2 in protecting stalled replication forks contributes along with HR to the sensitivity of BRCA-associated tumors to chemotherapy. Moreover, chemoresistance evolves from restoration of either HR and/or fork protection. Although mechanisms underlying the restoration of HR have been characterized, it remains less clear how restoration of fork protection is achieved. Here, we outline mechanisms of "rewired" fork protection and chemotherapy resistance in BRCA cancer. We propose that mechanisms are linked to permissive replication that limits fork remodeling and therefore opportunities for fork degradation. Combating this chemoresistance mechanism will require drugs that inactivate replication bypass mechanisms.
PMID: 29472318 [PubMed - as supplied by publisher]
Luminal A Breast Cancer and Molecular Assays: A Review.
Oncologist. 2018 Feb 22;:
Authors: Gao JJ, Swain SM
PURPOSE: Chemotherapy has been the historical mainstay of treatment for patients with breast cancer, with immunohistochemical markers and tumor characteristics driving treatment decisions. The discovery of different intrinsic subtypes of breast cancer has advanced the understanding of breast cancer, with gene-based assays shedding further light on tumor behavior and response to treatment.
DESIGN: This review focuses on the landscape of the luminal A subtype, its definition based on immunohistochemistry (IHC) and gene assays, the prognostic and predictive value of these assays, guideline recommendations, and treatment implications.
RESULTS: Clinical studies of the prognostic value of gene-based and IHC-based assays in patients with luminal A-subtype breast cancers suggest a better prognosis for these patients compared with those with breast cancers of other subtypes.
CONCLUSION: In today's era of precision medicine, the best treatment regimen for patients with luminal A-subtype tumors is still undetermined, but available data raise the question whether chemotherapy can be omitted and endocrine therapy alone is sufficient for this patient population.
IMPLICATIONS FOR PRACTICE: Immunohistochemical markers have traditionally guided treatment decisions in breast cancer. However, advances in gene-expression profiling and availability of gene-based assays have launched these newer tests into everyday clinical practice. Luminal A-subtype tumors are a unique subset that may have favorable tumor biology. Properly defining this tumor subtype is important and may identify a subset of patients for whom endocrine therapy alone is sufficient.
PMID: 29472313 [PubMed - as supplied by publisher]
Plasmodium falciparum diagnostic tools in HIV-positive under-5-year-olds in two ART clinics in Ghana: are there missed infections?
Malar J. 2018 Feb 23;17(1):92
Authors: Owusu EDA, Djonor SK, Brown CA, Grobusch MP, Mens PF
BACKGROUND: Plasmodium falciparum, the most dominant species in sub-Saharan Africa, causes the most severe clinical malaria manifestations. In resource-limited Ghana, where malaria and HIV geographically overlap, histidine-rich protein 2 (HRP2)-based rapid diagnostic test (RDT) is a faster, easier and cheaper alternative to clinical gold standard light microscopy. However, mutations in parasite hrp2 gene may result in missed infections, which have severe implications for malaria control.
METHODS: The performance of a common HRP2-based RDT and expert light microscopy in HIV-positive and HIV-negative children under 5 years old was compared with PCR as laboratory gold standard. Finger-prick capillary blood was tested with First Response® Malaria Ag P. falciparum (HRP2). Giemsa-stained thick and thin blood films were examined with ≥ 200 high power fields and parasites counted per 200 white blood cells. Nested PCR species identification of P. falciparum was performed and resolved on agarose gel. False negatives from RDT were further tested for deleted pfhrp2/3 and flanking genes, using PCR. The study was performed in two anti-retroviral therapy clinics in Accra and Atibie.
RESULTS: Out of 401 participants enrolled, 150 were HIV positive and 251 HIV negative. Malaria was more prevalent in children without HIV. Microscopy had a higher sensitivity [100% (99-100)] than RDT [83% (53.5-100)]. Parasites with pfhrp2/3 deletions contributed to missed infections from RDT false negatives.
CONCLUSION: Circulation of malaria parasites with pfrhp2/3 deletions in this population played a role in missed infections with RDT. This ought to be addressed if further strides in malaria control are to be made.
PMID: 29471833 [PubMed - in process]
Probing Light Chain Mutation Effects on Thrombin via Molecular Dynamics Simulations and Machine Learning.
J Biomol Struct Dyn. 2018 Feb 22;:1-55
Authors: Xiao J, Melvin RL, Salsbury FR
Thrombin is a key component for chemotherapeutic and antithrombotic therapy development. As the physiologic and pathologic roles of the light chain still remain vague, here, we continue previous efforts to understand the impacts of the disease-associated single deletion of LYS9 in the light chain. By combining supervised and unsupervised machine learning methodologies and more traditional structural analyses on data from 10 μs molecular dynamics simulations, we show that the conformational ensemble of the ΔK9 mutant is significantly perturbed. Our analyses consistently indicate that LYS9 deletion destabilizes both the catalytic cleft and regulatory functional regions and result in some conformational changes that occur in tens to hundreds of nanosecond scaled motions. We also reveal that the two forms of thrombin each prefer a distinct binding mode of a Na+ ion. We expand our understanding of previous experimental observations and shed light on the mechanisms of the LYS9 deletion associated bleeding disorder by providing consistent but more quantitative and detailed structural analyses than early studies in literature. With a novel application of supervised learning, i.e. the decision tree learning on the hydrogen bonding features in the wild-type and ΔK9 mutant forms of thrombin, we predict that seven pairs of critical hydrogen bonding interactions are significant for establishing distinct behaviors of wild-type thrombin and its ΔK9 mutant form. Our calculations indicate the LYS9 in the light chain has both localized and long-range allosteric effects on thrombin, supporting the opinion that light chain has an important role as an allosteric effector.
PMID: 29471734 [PubMed - as supplied by publisher]
Aeromonas Salmonicida as a Causative Agent for Postoperative Endophthalmitis.
Middle East Afr J Ophthalmol. 2017 Oct-Dec;24(4):213-215
Authors: Varshney A, Das M, Chaudhary P, Kumari R, Yadav K
We report a case of a 55-year-old female who presented with pain, redness, and profound visual loss in her right eye 2 weeks after cataract surgery. An ophthalmic examination showed light perception vision, corneal edema with severe anterior chamber reaction and hypopyon, exudative membranes on the anterior lens surface, and dense vitreous exudates. Under the impression of acute postoperative exogenous endophthalmitis, immediate pars plana vitrectomy with culture of vitreous aspirate and intravitreal antibiotic injections were performed. Bacterial growth was observed on culture plates and broths which were identified as Aeromonas salmonicida by VITEK 2 compact system. So far, no report has been published regarding endophthalmitis due to A. salmonicida. Here, we present the first report of A. salmonicida isolated from the ocular specimen.
PMID: 29422757 [PubMed - indexed for MEDLINE]
Gd³⁺ Tethered Gold Nanorods for Combined Magnetic Resonance Imaging and Photo-Thermal Therapy.
J Biomed Nanotechnol. 2017 Apr;13(4):417-26
Authors: Pitchaimani A, Duong T, Nguyen T, Maurmann L, Key J, Bossmann SH, Aryal S
Near infrared (NIR) mediated photothermal therapy and magnetic resonance imaging (MRI) are promising treatment and imaging modalities in the field of cancer theranostics. Gold nanorods are the first choice of materials for NIR-mediated photothermal therapy due to their strong localized surface plasmon resonance (LSPR) at NIR region. Similarly, gadolinium based MRI contrast agents have an ability to increase the ionic and molecular relaxivity, thereby enhancing the solvent proton relaxation rate resulting in contrast enhancement. Herein, the effort has been made to engineer a dual front theranostic agent with combined photothermal and magnetic resonance imaging capacity using gadolinium tethered gold nanorods (Gd3+-AuNR). NIR-responsive gold nanorods were surface fabricated by means of Au-thiol interaction using a thiolated macrocyclic chelator that chelates Gd3+ ions, and further stabilized by thiolated polyethylene glycol (PEG-SH). The magnetic properties of the Gd3+-AuNR displayed an enhanced r 1 relaxivity of 12.1 mM–1s–1, with higher biological stability, and contrast enhancement in both solution state and in cell pellets. In-vitro (cell-free) and ex-vivo (on pig skin) analysis of the Gd3+-AuNR shows enhanced photothermal properties as equivalent to that of the raw AuNR. Furthermore, Gd3+-AuNR showed competent cellular entry and intracellular distribution as revealed by hyperspectral microscopy. In addition, Gd3+-AuNR also exhibits significant thermal ablation of B16–F10 cells in the presence of NIR. Thus, Gd3+-AuNR features a significant theranostic potential with combined photothermal and imaging modality, suggesting a great potential in anticancer therapy.
PMID: 29384618 [PubMed - indexed for MEDLINE]
Sulforaphene Enhances The Efficacy of Photodynamic Therapy In Anaplastic Thyroid Cancer Through Ras/RAF/MEK/ERK Pathway Suppression.
J Photochem Photobiol B. 2018 Feb;179:46-53
Authors: Chatterjee S, Rhee Y, Chung PS, Ge RF, Ahn JC
Sulforaphene (SFE), a natural isothiocyanate from cruciferous vegetables has shown a potential anticancer effect against cervical and lung cancer. Palliative treatments like photodynamic therapy (PDT) are being implemented for a long time however, the results are still not promising in case of aggressive cancers like anaplastic thyroid cancer. The objective of this work is to establish an alternative method with the combination of photofrin-PDT and sulforaphene, a natural isothiocyanate from cruciferous vegetables, against human anaplastic thyroid cancer to enhance the efficacy of PDT. In this study, cell viability of FRO cells due to combination treatment was analyzed by MTT assay, Cell cycle arrest, MMP depolarization and ROS generation, analyzed by flow cytometry. Western blot analysis of various proliferative proteins was performed to assess the activity of combination treatment against FRO cells. From the results, sulforaphene alone showed no cytotoxicity against normal cells, however, combination of sulforaphene and photofrin mediated PDT showed a noticeable decrease in cell proliferation against FRO cells. Combination treatment synergistically caused cell cycle arrest via ROS generation and MMP depolarization. The expressions of Ras, MEK, ERK, B-Raf proteins significantly modulated due to combination treatment. PDT and SFE can induce apoptosis in anaplastic thyroid cancer cells individually but while treated in combination, it enhanced the apoptotic and anti-proliferative effect, much higher than the individual doses. In summary, our work designates sulforaphene as a unique natural enhancer of efficacy with PDT against anaplastic thyroid cancer.
PMID: 29331658 [PubMed - indexed for MEDLINE]
In Vivo Early Corneal Biomechanical Changes After Corneal Cross-linking in Patients With Progressive Keratoconus.
J Refract Surg. 2017 Dec 01;33(12):840-846
Authors: Vinciguerra R, Romano V, Arbabi EM, Brunner M, Willoughby CE, Batterbury M, Kaye SB
PURPOSE: To report early corneal biomechanical changes after corneal cross-linking (CXL) in patients with keratoconus.
METHODS: Thirty-four eyes of 34 patients undergoing CXL for progressive keratoconus were included in this prospective clinical study. Dynamic corneal response (DCR) parameters obtained with the Corvis ST (OCULUS Optikgeräte GmbH; Wetzlar, Germany) were assessed at baseline (day of CXL) and after 1 month of follow-up; conversely, corneal tomography with the Pentacam (OCULUS Optikgeräte GmbH) was assessed at baseline and at 1, 3, and 6 months after CXL.
RESULTS: At the last follow-up visit (123.7 ± 69.6 days), all morphological parameters including steepest point (Kmax) and thinnest corneal thickness (ThCT) indicated stabilization of keratoconus (P > .05). Comparative analyses showed a rise of corneal stiffness demonstrated by a significant increase of Stiffness Parameter A1 (SP-A1) and Highest Concavity (SP-HC) and a significant decrease of Inverse Concave Radius (1/R) and Deformation Amplitude Ratio (DA Ratio) (P < .05). There was a significant correlation between the preoperative keratoconus characteristics (Kmax, Belin/Ambrósio final D value [BAD-D], and ThCT) and the DCR parameters (P < .05). Kmax and BAD-D showed a significant positive correlation with DA Ratio, Deflection Amplitude (DefA), and 1/R and a significant negative correlation with SPA1 and SP-HC. ThCT showed a significant positive correlation with SP-A1 and SP-HC and a significant negative correlation with DA Ratio, DefA, and 1/R.
CONCLUSIONS: This study suggests that the new DCR parameters of the Corvis ST are able to detect early changes in biomechanics following CXL and those that are measurable before corneal shape modifications take place. Based on these results, the authors suggest the use of these metrics to assess the early efficacy of cross-linking. [J Refract Surg. 2017;33(12):840-846.].
PMID: 29227513 [PubMed - indexed for MEDLINE]
Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors.
Int J Nanomedicine. 2017;12:8129-8142
Authors: Dapkute D, Steponkiene S, Bulotiene D, Saulite L, Riekstina U, Rotomskis R
Purpose: Cell-mediated delivery of nanoparticles is emerging as a new method of cancer diagnostics and treatment. Due to their inherent regenerative properties, adult mesenchymal stem cells (MSCs) are naturally attracted to wounds and sites of inflammation, as well as tumors. Such characteristics enable MSCs to be used in cellular hitchhiking of nanoparticles. In this study, MSCs extracted from the skin connective tissue were investigated as transporters of semiconductor nanocrystals quantum dots (QDs).
Materials and methods: Cytotoxicity of carboxylated CdSe/ZnS QDs was assessed by lactate dehydrogenase cell viability assay. Quantitative uptake of QDs was determined by flow cytometry; their intracellular localization was evaluated by confocal microscopy. In vitro tumor-tropic migration of skin-derived MSCs was verified by Transwell migration assay. For in vivo migration studies of QD-loaded MSCs, human breast tumor-bearing immunodeficient mice were used.
Results: QDs were found to be nontoxic to MSCs in concentrations no more than 16 nM. The uptake studies showed a rapid QD endocytosis followed by saturating effects after 6 h of incubation and intracellular localization in the perinuclear region. In vitro migration of MSCs toward MDA-MB-231 breast cancer cells and their conditioned medium was up to nine times greater than the migration toward noncancerous breast epithelial cells MCF-10A. In vivo, systemically administered QD-labeled MSCs were mainly located in the tumor and metastatic tissues, evading most healthy organs with the exception being blood clearance organs (spleen, kidneys, liver).
Conclusion: Skin-derived MSCs demonstrate applicability in cell-mediated delivery of nanoparticles. The findings presented in this study promise further development of a cell therapy and nanotechnology-based tool for early cancer diagnostics and therapy.
PMID: 29158674 [PubMed - indexed for MEDLINE]
New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study.
Lasers Med Sci. 2017 Dec;32(9):2013-2021
Authors: Weissheimer C, Curra M, Gregianin LJ, Daudt LE, Wagner VP, Martins MAT, Martins MD
Oral mucositis (OM) is an adverse side effect among hematopoietic stem cell transplantation (HSCT) recipients. The objective of this retrospective study was to evaluate the preventive effect of photobiomodulation (PBM) applied three times per week versus seven times per week in patients undergoing HSCT. The risk factors related to the incidence and severity of OM were also assessed. This was a retrospective study that evaluated 99 HSCT recipients who received different PBM protocols. Group I received three sessions per week, and group II received daily treatment. PBM was applied using a continuous-wave diode laser (InGaAlP; MM Optics, São Carlos, SP, Brazil) at a wavelength of 660 nm (visible-red) and a total radiant energy of 0.24 J per point. The baseline disease, type of transplant, type of conditioning, prophylaxis against graft-versus-host disease, OM grade, absolute leukocyte and platelet counts, and levels of liver and renal function markers were collected from medical records. The patients' age ranged from 13 to 71 years (mean/SD, 40.54 ± 16.45). No significant difference was observed between groups I and II regarding sex, age, ethnic, diagnosis, donor type, and conditioning treatment. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA). Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01-Fischer's exact test), total body irradiation (TBI-12Gy) (p = 0.01-chi-square test), busulfan + cyclophosphamide (p < 0.01-chi-square test), or methotrexate-containing regimens (p < 0.01-Fischer's exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01-Mann-Whitney test) and impaired renal function (p = 0.02-Mann-Whitney test) were also considered risk factors for OM. Based on this retrospective data, PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. A prospective study might be necessary to confirm these findings.
PMID: 28840382 [PubMed - indexed for MEDLINE]
How do red and infrared low-level lasers affect folliculogenesis cycle in rat's ovary tissue in comparison with clomiphene under in vivo condition.
Lasers Med Sci. 2017 Dec;32(9):1971-1979
Authors: Naseri P, Alihemmati A, Rasta SH
Folliculogenesis is a cycle that produces the majority of oocyte. Any disruption to this cycle leads to ovulation diseases, like polycystic ovarian syndrome (PCOS). Treatments include drugs and surgery; lasers have also been used complementarily. Meanwhile, still there is no definite treatment for PCOS. This study investigated the photo-bio stimulation effect of near-infrared and red low-level laser on producing follicles and compared the result with result of using common drug, clomiphene. Therefore, the aim of this study was to propose the use of lasers autonomously treatment. So, there was one question: how do lasers affect folliculogenesis cycle in rat's ovary tissue? In this study, 28 rats were assigned to four groups as follows: control (CT), clomiphene drug (D), red laser (RL), and near-infrared laser (NIRL). Afterwards, 14 rats of RL and NIRL groups received laser on the first 2 days of estrous cycle, each 6 days, for 48 days. During treatment period, each rat received energy density of 5 J/cm2. Seven rats in D group received clomiphene. After the experiment, lasers' effects at two wavelengths of 630 and 810 nm groups have been investigated and compared with clomiphene and CT groups. Producing different follicles to complement folliculogenesis cycle increased in NIRL and RL groups, but this increase was significant only in the NIRL group. This indicates that NIRL increases ovarian activity to produce oocyte that certainly can be used in future studies for finding a cure to ovarian negligence to produce more oocyte and treat diseases caused by it like PCOS.
PMID: 28801854 [PubMed - indexed for MEDLINE]
Leishmanicidal effect of antiparasitic photodynamic therapy-ApPDT on infected macrophages.
Lasers Med Sci. 2017 Dec;32(9):1959-1964
Authors: de Oliveira S, da Ordem Trahamane EJ, Monteiro J, Santos GP, Crugeira P, Sampaio F, Oliveira C, Neto MB, Pinheiro A
The aim of this study is to evaluate the effects of ApPDT (antiparasitic photodynamic therapy) on the interaction of Leishmania braziliensis with J774 macrophages, used as a photosensitizer, methylene blue associated with red laser. The tests are in triplicate and the samples divided into four groups: control, photosensitizer, laser, and ApPDT. The photosensitizer used was the methylene blue at concentration of 12.5 μg/mL. The parameters of the laser were λ = 660 nm, 40 mW, and 8.4 J/cm2. Samples are analyzed by optical microscopy through the identification and counting of infected and uninfected macrophages, parasite load, infectivity, and infection index. Statistical analysis used ANOVA test with Tukey post-test, being considered statistically significant p < 0.05. The analysis of the interaction tests shows that the infection rate in the ApPDT group in relation to the control group presents a statistically significant reduction (p < 0.0001) of 71% at both 24 and 48 h (p < 0.0001) of 62%. ApPDT reduces the number of macrophages infected by Leishmania braziliensis, as well as the number of intracellular parasites, being a possible alternative therapy in the treatment of cutaneous leishmaniosis.
PMID: 28752261 [PubMed - indexed for MEDLINE]
Evaluation of the effects of photobiomodulation on vertebras in two rat models of experimental osteoporosis.
Lasers Med Sci. 2017 Sep;32(7):1545-1560
Authors: Fredoni M, Ghatrehsamani M, Abdollahifar MA, Bayat S, Bayat M
The aim of this study was to evaluate the effects of photobiomodulation (PBM) on cancellous bone in rat models of ovariectomized induced osteoporosis (OVX-D) and glucocorticoid-induced osteoporosis (GIOP). The experiment comprised of nine groups. A group of healthy rats was used for baseline evaluations. The OVX-D rats were further divided into groups as follows: control rats with osteoporosis, OVX-D rats that received alendronate (1 mg/kg 60 days), OVX-D rats treated with pulsed wave laser (890 nm, 80 Hz, 900 s, 0.0061 W/cm2, 5.5 J/cm2, three times a week, 60 days), and OVX-D rats treated with alendronate + pulsed laser. Dexamethasone was administered to the remaining rats that were split into four groups: control, alendronate-treated rats, laser-treated rats, and GIOP rats treated with alendronate + laser. T12, L1, L2, and L3 vertebrae were subjected to laser. Results of the current study demonstrated that OVX-D and GIOP significantly decreased some stereological parameters, and type 1 collagen gene expression compared to the healthy group. There was a significant increase in osteoclast number in both OVX-D and glucocorticoid administration compared to the healthy group. However, the detrimental effect of the OVX-D procedure on bone was more serious than glucocorticoid administration. Results showed that laser alone had a detrimental effect on trabecular bone volume, and cortical bone volume in groups GIOP and OVX-D compared to those in the healthy group. Alendronate significantly improved total vertebral bone volume, trabecular bone volume, and cortical bone volume, in GIOP and OVX-D groups compared to the laser-treated groups. Furthermore, the alendronate + laser in OVX-D rats and GIOP rats produced significantly increased osteoblast number and type 1 collagen gene expression and caused a significant decrease in osteoclast number compared to the controls.
PMID: 28725994 [PubMed - indexed for MEDLINE]
Fractional Er:YAG laser assisting topical betamethasone solution in combination with NB-UVB for resistant non-segmental vitiligo.
Lasers Med Sci. 2017 Sep;32(7):1571-1577
Authors: Yan R, Yuan J, Chen H, Li YH, Wu Y, Gao XH, Chen HD
Resistant non-segmental vitiligo is difficult to be treated. Ablative erbium-YAG (Er:YAG) laser has been used in the treatment of vitiligo, but the ablation of entire epidermis frustrated the compliance of patients. The purpose of this study is to investigate the effects of fractional Er:YAG laser followed by topical betamethasone and narrow band ultraviolet B (NB-UVB) therapy in the treatment of resistant non-segmental vitiligo. The vitiligo lesions of each enrolled patient were divided into four treatment parts, which were all irradiated with NB-UVB. Three parts were, respectively, treated with low, medium, or high energy of Er:YAG laser, followed by topical betamethasone solution application. A control part was spared with laser treatment and topical betamethasone. The treatment period lasted 6 months. The efficacy was assessed by two blinded dermatologists. Treatment protocol with high energy of 1800 mJ/P of fractional Er:YAG laser followed by topical betamethasone solution and in combination with NB-UVB made 60% patients achieve marked to excellent improvement in white patches. The protocol with medium energy of 1200 mJ/P of laser assisted approximate 36% patients achieve such improvement. The two protocols, respectively, showed better efficacies than NB-UVB only protocol. However, fractional Er:YAG laser at low energy of 600 mJ/P did not provide such contributions to the treatment of vitiligo. The fractional Er:YAG laser in combination with topical betamethasone solution and NB-UVB was suitable for resistant non-segmental vitiligo. The energy of laser was preferred to be set at relatively high level.
PMID: 28710660 [PubMed - indexed for MEDLINE]
Effect of low-level laser-treated mesenchymal stem cells on myocardial infarction.
Lasers Med Sci. 2017 Sep;32(7):1637-1646
Authors: El Gammal ZH, Zaher AM, El-Badri N
Cardiovascular disease is the leading cause of death worldwide. Although cardiac transplantation is considered the most effective therapy for end-stage cardiac diseases, it is limited by the availability of matching donors and the complications of the immune suppressive regimen used to prevent graft rejection. Application of stem cell therapy in experimental animal models was shown to reverse cardiac remodeling, attenuate cardiac fibrosis, improve heart functions, and stimulate angiogenesis. The efficacy of stem cell therapy can be amplified by low-level laser radiation. It is well established that the bio-stimulatory effect of low-level laser is influenced by the following parameters: wavelength, power density, duration, energy density, delivery time, and the type of irradiated target. In this review, we evaluate the available experimental data on treatment of myocardial infarction using low-level laser. Eligible papers were characterized as in vivo experimental studies that evaluated the use of low-level laser therapy on stem cells in order to attenuate myocardial infarction. The following descriptors were used separately and in combination: laser therapy, low-level laser, low-power laser, stem cell, and myocardial infarction. The assessed low-level laser parameters were wavelength (635-804 nm), power density (6-50 mW/cm2), duration (20-150 s), energy density (0.96-1 J/cm2), delivery time (20 min-3 weeks after myocardial infarction), and the type of irradiated target (bone marrow or in vitro-cultured bone marrow mesenchymal stem cells). The analysis focused on the cardioprotective effect of this form of therapy, the attenuation of scar tissue, and the enhancement of angiogenesis as primary targets. Other effects such as cell survival, cell differentiation, and homing are also included. Among the evaluated protocols using different parameters, the best outcome for treating myocardial infarction was achieved by treating the bone marrow by one dose of low-level laser with 804 nm wavelength and 1 J/cm2 energy density within 4 h of the infarction. This approach increased stem cell survival, proliferation, and homing. It has also decreased the infarct size and cell apoptosis, leading to enhanced heart functions. These effects were stable for 6 weeks. However, more studies are still required to assess the effects of low-level laser on the genetic makeup of the cell, the nuclei, and the mitochondria of mesenchymal stromal cells (MSCs).
PMID: 28681086 [PubMed - indexed for MEDLINE]
Laser irradiation promotes the proliferation of mouse pre-osteoblast cell line MC3T3-E1 through hedgehog signaling pathway.
Lasers Med Sci. 2017 Sep;32(7):1489-1496
Authors: Li Q, Chen Y, Dong S, Liu S, Zhang X, Si X, Zhou Y
Low-level laser could promote osteoblast proliferation, and it has been applied in clinical practice to promote wound healing and tissue regeneration. However, the mechanism related to laser irradiation remains unclear. This study aimed to investigate the effects of low-level laser irradiation on the cell proliferation and the expressions of hedgehog signaling molecules Indian hedgehog (Ihh), Ptch, and Gli in vitro. In our present study, the MTT method was used to evaluate the effect on cell proliferation of laser irradiation on MC3T3-E1 cells. And cell cycle was examined by flow cytometry. Gene and protein expressions of hedgehog signaling molecules, including Ihh, Ptch, Smoothened (Smo), and Gli, were examined by qRT-PCR and western blot analysis. The results showed that laser irradiation at dosage of 3.75 J/cm2 enhances the proliferation of MC3T3-E1 cells compared with control groups (p = 0.00). Moreover, laser irradiation (3.75 J/cm2) increased the cell amount at S phase (p = 0.00). In addition, the expressions of Ihh, Ptch, Smo, and Gli were significantly increased compared to the control during laser irradiation (3.75 J/cm2)-induced MC3T3-E1 osteoblast proliferation. After adding the hedgehog signaling inhibitor CY (cyclopamine), cell proliferation and Ihh, Ptch, Smo, and Gli expressions were inhibited (p = 0.00), and the cell amount at S phase was reduced compared with combination groups (p = 0.00). These results indicated that laser irradiation promotes proliferation of MC3T3-E1 cells through hedgehog signaling pathway. Our findings provide insights into the mechanistic link between laser irradiation-induced osteogenesis and hedgehog signaling pathway.
PMID: 28667508 [PubMed - indexed for MEDLINE]
Biomechanical Changes After LASIK Flap Creation Combined With Rapid Cross-Linking Measured With Brillouin Microscopy.
J Refract Surg. 2017 Jun 01;33(6):408-414
Authors: Randleman JB, Su JP, Scarcelli G
PURPOSE: To evaluate the biomechanical changes occurring after LASIK flap creation and rapid corneal cross-linking (CXL) measured with Brillouin light microscopy.
METHODS: Porcine eyes (n = 11) were evaluated by Brillouin light microscopy sequentially in the following order: virgin state, after LASIK flap creation, and after rapid CXL. Each eye served as its own control. Depth profile of the Brillouin frequency shift was computed to reveal the depth-dependent changes in corneal stiffness.
RESULTS: There was a statistically significant reduction of Brillouin shift (reduced corneal stiffness) after LASIK flap creation compared to virgin corneas across total corneal thickness (-0.035 GHz, P = .0195) and within the anterior stromal region (-0.104 GHz, P = .0039). Changes in the central (-0.029 GHz, P = .0391) and posterior (-0.005 GHz, P = .99) stromal regions were not significant. There was a small increase in Brillouin shift after rapid cross-linking that was not statistically or clinically significant across total corneal thickness (0.006 GHz, P = .4688 for any specific stromal region; 0.002 to 0.009 GHz, P > .46 for all).
CONCLUSIONS: LASIK flap creation significantly reduced Brillouin shift in the anterior third of the stroma in porcine eyes. Rapid corneal cross-linking had no significant effect on Brillouin shift after LASIK flap creation in porcine eyes. With further validation, non-contact, non-perturbative Brillouin microscopy could become a useful monitoring tool to evaluate the biomechanical impact of corneal refractive procedures and corneal cross-linking protocols. [J Refract Surg. 2017;33(6):408-414.].
PMID: 28586502 [PubMed - indexed for MEDLINE]
Fluorous-tag assisted synthesis of bile acid-bisphosphonate conjugates via orthogonal click reactions: an access to potential anti-resorption bone drugs.
Org Biomol Chem. 2017 Jun 07;15(22):4907-4920
Authors: Massarenti C, Bortolini O, Fantin G, Cristofaro D, Ragno D, Perrone D, Marchesi E, Toniolo G, Massi A
The synthesis of a small collection of novel bile acid-bisphosphonate (BA-BP) conjugates as potential drug candidates is reported. The disclosed methodology relied on the installation of azide and thiol functionalities at the head and tail positions, respectively, of the BA scaffold and its subsequent decoration by orthogonal click reactions (copper-catalyzed azide-alkyne cycloaddition, thiol-ene or thiol-yne coupling) to introduce BP units and a fluorophore. Because of the troublesome isolation of the target conjugates by standard procedures, the methodology culminated with the functionalization of the BA scaffold with a light fluorous tag to rapidly and efficiently purify intermediates and final products by fluorous solid-phase extraction.
PMID: 28548149 [PubMed - indexed for MEDLINE]
Photothermal and photodynamic activity of polymeric nanoparticles based on α-tocopheryl succinate-RAFT block copolymers conjugated to IR-780.
Acta Biomater. 2017 Jul 15;57:70-84
Authors: Palao-Suay R, Martín-Saavedra FM, Rosa Aguilar M, Escudero-Duch C, Martín-Saldaña S, Parra-Ruiz FJ, Rohner NA, Thomas SN, Vilaboa N, San Román J
The aim of this work was the generation of a multifunctional nanopolymeric system that incorporates IR-780 dye, a near-infrared (NIR) imaging probe that exhibits photothermal and photodynamic properties; and a derivate of α-tocopheryl succinate (α-TOS), a mitochondria-targeted anticancer compound. IR-780 was conjugated to the hydrophilic segment of copolymer PEG-b-polyMTOS, based on poly(ethylene glycol) (PEG) and a methacrylic derivative of α-tocopheryl succinate (MTOS), to generate IR-NP, self-assembled nanoparticles (NPs) in aqueous media which exhibit a hydrophilic shell and a hydrophobic core. During assembly, the hydrophobic core of IR-NP could encapsulate additional IR-780 to generate derived subspecies carrying different amount of probe (IR-NP-eIR). Evaluation of photo-inducible properties of IR-NP and IR-NP-eIR were thoroughly assessed in vitro. Developed nanotheranostic particles showed distinct fluorescence and photothermal behavior after excitation by a laser light emitting at 808nm. Treatment of MDA-MB-453 cells with IR-NP or IR-NP-eIR resulted in an efficient internalization of the IR-780 dye, while subsequent NIR-laser irradiation led to a severe decrease in cell viability. Photocytoxicity conducted by IR-NP, which could not be attributed to the generation of lethal hyperthermia, responded to an increase in the levels of intracellular reactive oxygen species (ROS). Therefore, the fluorescence imaging and inducible phototoxicity capabilities of NPs derived from IR-780-PEG-b-polyMTOS copolymer confer high value to these nanotheranostics tools in clinical cancer research.
STATEMENT OF SIGNIFICANCE: Multifunctional polymeric nanoparticles (NPs) that combine imaging and therapeutic properties are highly valuable in cancer treatment. In this paper we describe the development of NPs that are fluorescent in the near-infrared (NIR). This is important for their visualization in living tissues that present low absorption and low autofluorescence in this wavelength region (between 700 and 1000nm). Moreover, NPs present photothermal and photodynamic properties when NIR irradiated: the NPs produce an efficient increment of temperature and increase the intracellular reactive oxygen species (ROS) when laser irradiated at 808nm. These tuneable photoinduced properties make the NPs highly cytotoxic after NIR irradiation and provide a new tool for highly precise cancer treatment.
PMID: 28511874 [PubMed - indexed for MEDLINE]
Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study.
Drug Des Devel Ther. 2017;11:1383-1391
Authors: El-Nabarawi N, El-Wakd M, Salem M
OBJECTIVE: The aim of this study was to evaluate the effect of atorvastatin on the bone formation and resorption markers in ovariectomized rats (experimental study), and to study its effect on the bone mineral density (BMD) in postmenopausal osteoporotic women (clinical study).
MATERIALS AND METHODS: The study involved experimental and clinical aspects. In the experimental aspect, 42 female Wistar rats were divided into five groups: Group I (n=6; sham-operated), Group II (n=6; 1 mL of carboxymethyl cellulose [CMC] was administered orally), Group III (n=6; 20 mg/kg orally of atorvastatin was administered), Group IV (n=12; untreated ovariectomized [OVX] rats and served as a model of osteoporosis [OP]) and Group V (n=12; 20 mg/kg orally of atorvastatin was administered to ovariectomized rats). After 4 weeks, serum acid phosphatase, alkaline phosphatase, osteocalcin, total calcium and inorganic phosphorus were assessed. Then, 3 µm thickness lumbar and femur sections were examined using a light microscope to assess cortical thickness, trabecular area, numbers of osteoblasts and osteoclasts. In the clinical aspect, 85 post-menopausal osteoporotic females with recently detected hyperlipidemia participated in the study. Atorvastatin 40 mg/day, calcium carbonate 500 mg/day and vitamin D 800 international units were given to all patients for a period of 18 months. BMD was measured at the start and at the end of the study by dual-energy X-ray absorptiometry (DEXA).
RESULTS: In the experiment aspect, the biomarkers of bone remodeling were notably elevated in the OVX group. Administration of atorvastatin produced a significant decrease in the level of these bone metabolic markers. Atorvastatin significantly ameliorates osteoporotic changes induced by ovariectomy. In the clinical aspect, after 18 months the DEXA showed improvement in the T-score for the three measured zones; however, these changes were statistically significant only in the femoral neck area.
CONCLUSION: Atorvastatin was able to decrease the rate of bone metabolism and increase osteogenic activity. It has dual mode of action; both anabolic and antiresorptive effect on bone. This lipophilic statin member may act as a double weapon drug.
PMID: 28496308 [PubMed - indexed for MEDLINE]
Photosensitive multifunctional poly(vinyl alcohol) micelles for enhanced antitumor effect.
Mater Sci Eng C Mater Biol Appl. 2017 Jul 01;76:918-924
Authors: Yu Q, Xie A, Huang F, Li S, Xiao Y, Shen Y
Polyvinyl alcohol (PVA) micelles were firstly synthesized by using hemin molecules as novel crosslinked bridges (PVA-H crosslinked micelles). On one hand, the crosslinked micelles can allow high stability against extensive dilution (1800-fold) to reduce side-effects; On the other hand, the bridges not only can destruct by means of laser irradiation (405nm, 200mw), but also can induce the production of singlet oxygen (1O2) and the release of 5-fluorouracil (5FU) (i.e. 46% release in 360min). But above all, that 5FU-loaded PVA-H crosslinked micelles irradiating by laser is more efficient than PVA-H crosslinked micelles and free 5FU in killing tumor cells, suggest the effective synergistic antitumor effect about chemotherapy and photodynamic therapy (PDT).
PMID: 28482607 [PubMed - indexed for MEDLINE]
Concise Review: MSC Adhesion Cascade-Insights into Homing and Transendothelial Migration.
Stem Cells. 2017 Jun;35(6):1446-1460
Authors: Nitzsche F, Müller C, Lukomska B, Jolkkonen J, Deten A, Boltze J
Mesenchymal stem cells (MSCs) are promising candidates for adult cell therapies in regenerative medicine. To fully exert their potential, efficient homing and migration toward lesion sites play an important role. Local transplantation deposits MSC in spatial proximity to the lesion, but often requires invasive procedures. Systemic administration routes are favored, but require the targeted extravasation of the circulating MSC at the site of injury. Transplanted MSC can indeed leave the blood flow and transmigrate through the endothelial barrier, and reach the lesion site. However, the underlying processes are not completely dissolved yet. Recent in vitro and in vivo research identified some key molecules scattered light on the extravasation mechanism. This review provides a detailed overview over the current knowledge of MSC transendothelial migration. We use the leukocyte extravasation process as a role model to build a comprehensive concept of MSC egress mechanisms from the blood stream and identified relevant similarities as well as important differences between the extravasation mechanisms. Stem Cells 2017;35:1446-1460.
PMID: 28316123 [PubMed - indexed for MEDLINE]
Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.
J Pediatr Gastroenterol Nutr. 2017 May;64(5):818-835
Authors: Amil-Dias J, Kolacek S, Turner D, Pærregaard A, Rintala R, Afzal NA, Karolewska-Bochenek K, Bronsky J, Chong S, Fell J, Hojsak I, Hugot JP, Koletzko S, Kumar D, Lazowska-Przeorek I, Lillehei C, Lionetti P, Martin-de-Carpi J, Pakarinen M, Ruemmele FM, Shaoul R, Spray C, Staiano A, Sugarman I, Wilson DC, Winter H, Kolho KL, IBD Working Group of ESPGHAN (IBD Porto Group)
The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.
PMID: 28267075 [PubMed - indexed for MEDLINE]
The microbiome and systemic lupus erythematosus.
Immunol Res. 2017 Apr;65(2):432-437
Authors: Katz-Agranov N, Zandman-Goddard G
The microbiota, which is comprised of the collective of all microbes inhabiting the gut and its effect on the human host in which it resides, has become a growing field of interest. Various parameters of health and disease have been found to be associated with the variation in the human gut microbiome. In recent years, many studies have demonstrated an important role of gut microbes in the development of various illnesses including autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Although the mechanism of the disease involves both genetic and environmental factors, lupus has been found to be affected by the composition of the microbes lining the intestines. Several recent studies have suggested that alterations of the gut microbial composition may be correlated with SLE disease manifestations, while the exact roles of either symbiotic or pathogenic microbes in this disease have yet to be explored. Elucidation of the roles of gut microbes in SLE will shed light on how this autoimmune disorder develops and provide opportunities for improved biomarkers of the disease and the potential to probe new therapies. This new knowledge, along with that enabling alteration in composition of the gut microbiome, via diet modification, antibiotic, and probiotics, may bring forward a new era in the future of lupus treatment.
PMID: 28233089 [PubMed - indexed for MEDLINE]
Myriocin treatment affects lipid metabolism in skeletal muscles of rats with streptozotocin-induced type 1 diabetes.
Adv Med Sci. 2017 Mar;62(1):65-73
Authors: Kurek K, Garbowska M, Ziembicka DM, Łukaszuk B, Rogowski J, Chabowski A, Górski J, Żendzian-Piotrowska M
PURPOSE: The aim of this work was to assess the effect(s) of de novo ceramide synthesis inhibition on lipid metabolism in skeletal muscle tissue of type 1 diabetic rats. The latter seems to be of vital importance, since previous works have shown its positive influence on lipid metabolism and glucose homeostasis in the case of its counterpart - type 2 diabetes.
MATERIALS/METHODS: The animals were randomly assigned to one of the following groups: C - control, M - myriocin (ceramide de novo synthesis inhibitor), D - diabetes (induced by streptozotocin injections); D+M - diabetes+myriocin. We have evaluated intracellular concentration of key sphingolipid species, via chromatography (GC and HPLC), and the activity of their most important enzymes, using radiometric approach. The aforementioned assessments were evaluated in respect to the three different types of muscle tissue representing different spectra of muscle metabolism (soleus - oxidative, red gastrocnemious - oxidative-glycolytic, white gastrocnemious - glycolytic).
RESULTS: Interestingly, our therapeutic intervention not only lowered the level of ceramide, its precursors (sphinganine) and derivatives (sphingosine and sphingosine-1-phosphate), but also reduced other lipid species (triacylglycerols, diacylglycerols and free fatty acids) content, thus improving glucose homeostasis in type 1 diabetic animals.
CONCLUSIONS: In the light of the results ensuing from this study, it seems conceivable that the reduction of intramuscular ceramide production and accumulation could bestow an insulin-sensitizing effect. If so, then SPT inhibition could find potential future applications as a therapeutic intervention aimed to mitigate the effects of insulin resistance.
PMID: 28189121 [PubMed - indexed for MEDLINE]
Children with dorsal midbrain syndrome as a result of pineal tumors.
J AAPOS. 2017 Feb;21(1):34-38
Authors: Hoehn ME, Calderwood J, O'Donnell T, Armstrong GT, Gajjar A
BACKGROUND: Dorsal midbrain syndrome (also known as Parinaud syndrome and pretectal syndrome) is a well-known complication of tumors of the pineal region. However, there are few reports regarding outcomes, especially in children. The purpose of this study was to report the ophthalmic outcomes in a group of children with pineal tumors treated at a single institution.
METHODS: The medical records of pediatric patients diagnosed with pineal region tumors and evaluated at our ophthalmology clinic were studied retrospectively. Descriptive statistics were used to assess rate of dorsal midbrain syndrome, defined as one or more of the following: limitation of upgaze, pupillary light-near dissociation, and convergence retraction nystagmus. Treatment outcomes were recorded.
RESULTS: A total of 35 subjects (age range, 5 months to 20 years) were included, 18 (51%) of whom were found to have dorsal midbrain syndrome. Of those 18, 16 patients (89%) had limitation of upgaze, 15 (83%) had pupillary light-near dissociation, and 9 (50%) had convergence-retraction nystagmus. Convergence insufficiency was noted in 5 patients (28%); exotropia (either intermittent or constant), in 9 (50%). Improvement in dorsal midbrain syndrome findings following treatment was seen in 7 of 17 patients (41%), but only 2 (12%) experienced complete resolution. Treatment consisted of surgery, radiation, and/or chemotherapy.
CONCLUSIONS: In our study cohort of children with pineal tumors have a high incidence of dorsal midbrain syndrome. Most cases had residual findings after treatment.
PMID: 28069468 [PubMed - indexed for MEDLINE]
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet. 2017 02 04;389(10068):519-527
Authors: Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A
BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for patients with newly diagnosed myeloma. The combination of the proteasome inhibitor bortezomib with lenalidomide and dexamethasone has shown significant efficacy in the setting of newly diagnosed myeloma. We aimed to study whether the addition of bortezomib to lenalidomide and dexamethasone would improve progression-free survival and provide better response rates in patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.
METHODS: In this randomised, open-label, phase 3 trial, we recruited patients with newly diagnosed multiple myeloma aged 18 years and older from participating Southwest Oncology Group (SWOG) and National Clinical Trial Network (NCTN) institutions (both inpatient and outpatient settings). Key inclusion criteria were presence of CRAB (C=calcium elevation; R=renal impairment; A=anaemia; B=bone involvement) criteria with measurable disease (measured by assessment of free light chains), Eastern Cooperative Oncology Group (ECOG) performance status of 0-3, haemoglobin concentration 9 g/dL or higher, absolute neutrophil count 1 × 103 cells per mm3 or higher, and a platelet count of 80 000/mm3 or higher. We randomly assigned (1:1) patients to receive either an initial treatment of bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group). Randomisation was stratified based on International Staging System stage (I, II, or III) and intent to transplant (yes vs no). The VRd regimen was given as eight 21-day cycles. Bortezomib was given at 1·3 mg/m2 intravenously on days 1, 4, 8, and 11, combined with oral lenalidomide 25 mg daily on days 1-14 plus oral dexamethasone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was given as six 28-day cycles. The standard Rd regimen consisted of 25 mg oral lenalidomide once a day for days 1-21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22. The primary endpoint was progression-free survival using a prespecified one-sided stratified log rank test at a significance level of 0·02. Analyses were intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00644228.
FINDINGS: Between April, 2008, and February, 2012, we randomly assigned 525 patients at 139 participating institutions (264 to VRd and 261 to Rd). In the randomly assigned patients, 21 patients in the VRd group and 31 in the Rd group were deemed ineligible based mainly on missing, insufficient, or early or late baseline laboratory data. Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0·712, 96% CI 0·56-0·906; one-sided p value 0·0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0·709, 95% CI 0·524-0·959; two-sided p value 0·025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group.
INTERPRETATION: In patients with newly diagnosed myeloma, the addition of bortezomib to lenalidomide and dexamethasone resulted in significantly improved progression-free and overall survival and had an acceptable risk-benefit profile.
FUNDING: NIH, NCI, NCTN, Millennium Pharmaceuticals, Takeda Oncology Company, and Celgene Corporation.
PMID: 28017406 [PubMed - indexed for MEDLINE]
Effect of corneal cross-linking on contact lens tolerance in keratoconus.
Clin Exp Optom. 2017 Jul;100(4):369-374
Authors: Ünlü M, Yüksel E, Bilgihan K
BACKGROUND: The aim was to investigate changes in corneal sensation and rigid gas-permeable (RGP) contact lens tolerance after corneal cross-linking (CXL) on patients with keratoconus.
METHODS: Thirty eyes of 30 patients, who were RGP lens intolerant, were treated with CXL. The main outcome measures were corneal sensation evaluation by Cochet-Bonnet esthesiometry, sub-basal nerve fibre assessment by corneal in vivo confocal microscopy and RGP contact lens tolerance evaluation with the Likert scale and wearing time. All eyes were evaluated preoperatively and post-operatively at one, three and six months after CXL procedure.
RESULTS: The mean age was 25.3 ± 6.2 years. Preoperatively, the maximum keratometry (Kmax) in study eyes was 56.89 ± 4.60 D. Six months after CXL, it reduced to 56.03 ± 4.85 D (p = 0.01). Preoperative mean corneal sensation was 0.44 ± 0.05 g/mm2 , (range: 0.40 to 0.55); it was significantly decreased at the first month and increased to preoperative values after six months. The sub-basal nerve plexus could not be visualised in 90 per cent of the patients by confocal microscopy at one month post-operatively. Gradual restoration of corneal innervation with almost similar preoperative levels at post-operative month six was noted. There were significant differences in Likert scores between preoperative and third and sixth months after CXL. Likert scale scores correlated significantly with corneal sensitivity.
CONCLUSION: It can be concluded that increased RGP contact lens tolerance after CXL may be associated with the potential role of decreased corneal sensitivity and corneal flattening after CXL.
PMID: 27654998 [PubMed - indexed for MEDLINE]
Dasatinib-loaded albumin nanoparticles possess diminished endothelial cell barrier disruption and retain potent anti-leukemia cell activity.
Oncotarget. 2016 Aug 02;7(31):49699-49709
Authors: Dong C, Li B, Li Z, Shetty S, Fu J
Dasatinib (DAS), a second-generation tyrosine kinase inhibitor, is highly effective in treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, its clinical use is limited due to serious adverse effects. DAS can disrupt endothelial barrier integrity and increase endothelial permeability which may cause peripheral edema and pleural effusion. Albumin nanoparticles (NPs) as a drug carrier may serve as a useful tool for cell-selective drug delivery to reduce DAS-induced endothelial hyperpermeability and maintain endothelial barrier integrity. In this study, we reported that DAS-loaded NPs exhibited potent anti-leukemia efficacy as DAS alone. Importantly, albumin NPs as a drug carrier markedly reduced DAS-induced endothelial hyperpermeability by restraining the inhibition of Lyn kinase signaling pathway in endothelial cells. Therefore, albumin NPs could be a potential tool to improve anti-leukemia efficacy of DAS through its cell-selective effects.
PMID: 27391073 [PubMed - indexed for MEDLINE]
Local hyperthermia in head and neck cancer: mechanism, application and advance.
Oncotarget. 2016 Aug 30;7(35):57367-57378
Authors: Gao S, Zheng M, Ren X, Tang Y, Liang X
Local hyperthermia (HT), particularly in conjunction with surgery, radiotherapy and chemotherapy was useful for the treatment of human malignant tumors including head and neck cancer. However, at present it suffered from many limitations such as thermal dose control, target treatment regions and discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials to local HT of head and neck cancer that basically take advantage of various targeting approaches. The aim of this paper is to give a brief review of the mechanism, methods and clinical applications of local HT in head and neck cancer, mainly focusing on photothermal therapy (PTT) and nanoparticle-based hyperthermia.
PMID: 27384678 [PubMed - indexed for MEDLINE]
The effects of an early motor skill intervention on motor skills, levels of physical activity, and socialization in young children with autism spectrum disorder: A pilot study.
Autism. 2017 May;21(4):481-492
Authors: Ketcheson L, Hauck J, Ulrich D
Despite evidence suggesting one of the earliest indicators of an eventual autism spectrum disorder diagnoses is an early motor delay, there remain very few interventions targeting motor behavior as the primary outcome for young children with autism spectrum disorder. The aim of this pilot study was to measure the efficacy of an intensive motor skill intervention on motor skills (Test of Gross Motor Development-2), physical activity (accelerometers), and socialization (Playground Observation of Peer Engagement) in young children with autism spectrum disorder. A total of 20 children with autism spectrum disorder aged 4-6 years participated. The experimental group ( n = 11) participated in an 8-week intervention consisting of motor skill instruction for 4 h/day, 5 days/week. The control group ( n = 9) did not receive the intervention. A repeated-measures analysis of covariance revealed statistically significant differences between groups in all three motor outcomes, locomotor ( F(1, 14) = 10.07, p < 0.001, partial η2 = 0.42), object control ( F(1, 14) = 12.90, p < 0.001, partial η2 = 0.48), and gross quotient ( F(1, 14) = 15.61, p < 0.01, partial η2 = 0.53). Findings shed light on the importance of including motor programming as part of the early intervention services delivered to young children with autism spectrum disorder.
PMID: 27354429 [PubMed - indexed for MEDLINE]