Hypoxia mimetic agents (HMAs) have been shown to have a positive influence on cellular functions in a multitude of tissue regenerative strategies. Novel experimental approaches use biomaterials as carriers for controlled delivery of these HMAs. Here, the cytotoxic aspects of biocompatibility are of key relevance. The MTT assay is widely used to evaluate cytotoxicity and proliferation. Based on the implications from the proceeding research we hypothesized that specific HMAs such as deferoxamine at high concentrations can interfere with the MTT assay. Thus, the aim of this study was to test the repercussions of the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2 on the validity of the MTT assay. Murine MC3T3-E1 cells were cultured in serum-free alphaMEM and in alphaMEM supplemented with 10 % fetal bovine serum with the HMAs dimethyloxalylglycine, deferoxamine, L-mimosine, and CoCl2, respectively, at 3 mM-0.3 mM for 24 h (experimental groups). Cells without HMAs served as control (control groups). The same experiments were performed with medium and phosphate buffered saline (PBS) without cells. In all settings MTT solution was added to PBS-washed or unwashed culture plates for the last two hours of the incubation period. Then MTT solution was removed and dimethyl sulfoxide was added to dissolve the formazan crystals and absorption was measured. Our data show that the presence of deferoxamine can interfere with the MTT assay if not removed before the addition of MTT. This is particularly important when evaluating cell viability in setups where deferoxamine-loaded biomaterials are used.
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Σάββατο 17 Νοεμβρίου 2018
Deferoxamine but Not Dimethyloxalylglycine, L-Mimosine, or Cobalt Dichloride Can Interfere with the MTT Assay
Data-Driven-Based Approach to Identifying Differentially Methylated Regions Using Modified 1D Ising Model
Background. DNA methylation is essential for regulating gene expression, and the changes of DNA methylation status are commonly discovered in disease. Therefore, identification of differentially methylation patterns, especially differentially methylated regions (DMRs), in two different groups is important for understanding the mechanism of complex diseases. Few tools exist for DMR identification through considering features of methylation data, but there is no comprehensive integration of the characteristics of DNA methylation data in current methods. Results. Accounting for the characteristics of methylation data, such as the correlation characteristics of neighboring CpG sites and the high heterogeneity of DNA methylation data, we propose a data-driven approach for DMR identification through evaluating the energy of single site using modified 1D Ising model. Applied to both simulated and publicly available datasets, our approach is compared with other popular methods in terms of performance. Simulated results show that our method is more sensitive than competing methods. Applied to the real data, our method can identify more common DMRs than DMRcate, ProbeLasso, and Wang's methods with a high overlapping ratio. Also, the necessity of integrating the heterogeneity and correlation characteristics in identifying DMR is shown through comparing results with only considering mean or variance signals and without considering relationship of neighboring CpG sites, respectively. Through analyzing the number of DMRs identified in real data located in different genomic regions, we find that about 90% DMRs are located in CGI which always regulates the expression of genes. It may help us understand the functional effect of DNA methylation on disease.
https://ift.tt/2QYNIXO
Lead Environmental Pollution and Childhood Lead Poisoning at Ban Thi Commune, Bac Kan Province, Vietnam
Lead poisoning is a public health problem in many areas of the world. Children are at particularly high risk for adverse effects of lead exposure; even at low concentrations, lead can affect physical, mental, and behavioral development. Children living near lead-zinc mines are at high risk for environmental lead poisoning, especially the contaminated soil. We conducted a cross-sectional descriptive study in Ban Thi Commune, northern Vietnam. 195 children (92,9% participation) aged 3-14 years old (average: 7.69 ± 2.90) were randomly selected from a list of all children prepared by the village health collaborators. 109 (55.90%) were boys and 86 (44.10%) were girls. The research measures were the lead concentration in native soil and the children's total blood lead concentration determined by the inductively coupled plasma-mass spectrometry (ICP-MS) method. The results showed that lead content in soil was many times higher than American Environmental Protection Agency and Vietnam standards (average 2980.23 ± 6092.84 mg/kg dry weight of soil (range 80.05 – 33820.62)). Average blood lead levels for children were 15.42 ± 6.45 μg/dL (95% CI: 14.50 -16.33 μg/dL). The percentage of children with lead levels >10 μg/dL (value considered to be lead poisoning for children according to the Ministry of Health of Vietnam) was 79.49% of the total number of children. None of the children in this study had blood lead level (BLL) that required chelation treatment according to Vietnam MOH guideline (BLL ≥45 μg/dL). There is weakly evidence that lead exposure relates to the physical development of children. Children with low lead concentrations (less than 10 μg/dL) had height and weight of 1.47-3.51 cm and 1.19-2.81 kg, greater than those with BLL >10 μg/dL (p>0.05).
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A Comparison between the i-gel® and air-Q® Supraglottic Airway Devices Used for the Patients Undergoing General Anesthesia with Muscle Relaxation
Objectives. The aim of the present study was to compare two supraglottic airway (SGA) devices (i.e., the i-gel® © Intersurgical Ltd and air-Q® (Reusable) Cookgas company) in terms of the insertion time, amount of leak during ventilation with maximum positive pressure, and postoperative complications in patients referring to Modarres Hospital in Tehran. Method. The present double-blind clinical trial was performed on 60 patients undergoing elective surgeries that required general anesthesia with muscle relaxation. Patients were randomly assigned to either i-gel® (n = 30) or Air-Q® (n = 30) groups. Results. The mean age, body mass index, duration of surgery, duration of anesthesia, and gender ratio were not significantly different between the two groups. Mean ± SD values of the SGA devices' insertion time (in seconds) in the air-Q® and i-gel® groups were 4.87 ± 1.6 and 6.80 ± 1.2, respectively (P
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Ewing’s Sarcoma of the Head and Neck: Margins are not just for surgeons
We present a prospective large series (n = 47) of head and neck Ewing's sarcomas (HNES) homogeneously treated by the Euro‐Ewing 99 trial (EE99) from 1999 to 2014 in France. All our findings plead for a multidisciplinary approach of HNES in specialized centers from the diagnosis to maximize for these young patients the chance of cure with a minimum of sequelae. We highlight that margin interpretation is crucial to discuss postoperative radiotherapy indication and should be questioned by a multidisciplinary team beyond the only surgeon and pathologist opinion.
Abstract
Background, Methods
To describe the characteristics, treatments (systemic/local), and outcome (oncological/functional) of French patients with head and neck Ewing's sarcomas (HNES) registered in the Euro‐Ewing 99 (EE99) database. Specific patient‐level data were reviewed retrospective.
Results
Forty‐seven HNES patients in the EE99 database had a median age of 11 years, 89% had bone tumors (skull 55%, mandible 21%, maxilla 11%), 89% had small tumors (<200 mL), and they were rarely metastatic (9%). Local treatment was surgery radiotherapy (55%), exclusively surgery (28%), or radiotherapy (17%). Metastatic relapses occurred in five patients with high relapse risk factors (metastasis at diagnosis, poor histological response, large tumors). Local progression/relapses (LR) after exclusive radiotherapy occurred in three patients with persistent extra‐osseous residue and in four patients considered R0 margins (postchemotherapy surgery, without postoperative radiotherapy [PORT]), reclassified by pathological review as R1a. Pathological review reclassified 72% of R0 margins: 11/18 to R1a and 2/18 to R2. Five patients had confirmed R0 margins after postchemotherapy surgery without PORT and had no LR Eight patients had R2 margins (initial surgery without previous chemotherapy, with PORT) and had no LR With a median follow‐up of 9.3 years, the 3‐year LR rate, EFS, and OS were 84.8%, 78.6%, and 89.3%, respectively. Among the 5‐year survivors, 88% had long‐term sequelae.
Conclusion
To optimize HNES management, patients should be treated from diagnosis in expert centers with multidisciplinary committees to discuss treatment strategy (type of surgery, need for PORT) and validate surgical margins.
https://ift.tt/2qRDCwH
Updates on autoinflammatory diseases
Narcisa Martinez-Quiles | Raphaela Goldbach-Mansky
https://ift.tt/2zZSTQ3
Soft Tissue Disorders of the Mouth
Soft tissue disorders of the mouth encompass a wide expanse of pathophysiology. This article focuses on the identification, etiology, management, and complications of common infectious processes (candidiasis, dental caries, and herpes labialis), inflammatory lesions (sialolithiasis, oral lichen planus, and aphthous ulcer), and benign entities (bony tori and mucocele).
https://ift.tt/2PvEA0p
Tracheostomy Emergencies
Tracheostomy is a common procedure for long-term airway management. Although the overall complication rate is greater than 50%, the incidence of serious complications is low. These serious complications can, however, lead to significant morbidity and mortality and it is incumbent on the emergency provider to be prepared to deal with such tracheostomy-related emergencies. The greatest life threats to the tracheostomy patient are decannulation, obstruction, and hemorrhage. Other important but lower-acuity complications include tracheoesophageal fistula formation, tracheal stenosis, infection, and tracheocutaneous fistula formation.
https://ift.tt/2Pzx1Wv
Infections of the Oropharynx
This article reviews the presentation, diagnosis, and management of common and "can't miss" infections of the oropharynx, including streptococcal pharyngitis, infectious mononucleosis, peritonsillar abscess, retropharyngeal abscess, and epiglottitis.
https://ift.tt/2Pv7u0B
Dental Emergencies
Dental emergencies present frequently to the emergency department and urgent care centers. Trauma to the teeth includes fractures, luxations, and avulsions, which can be reduced in most cases. Avulsed primary teeth should never be replaced. Mouthguards should be worn in most youth sports to prevent many dental injuries. Dental caries can progress to worsening infection and should be diagnosed and promptly referred. More severe infections may require antibiotics, imaging, or incision and drainage. Dental blocks can assist with analgesia and patient comfort during other procedures.
https://ift.tt/2PzQypy
Peripheral Vertigo
This article summarizes the systematic assessment of the dizzy patient who presents with peripheral vertigo. It demonstrates the steps and tests necessary using the Triage-Timing-Trigger–Test (Triage + TiTraTe) method to accurately diagnose the underlying most probable cause while ruling out life-threatening causes. Using video support and just-in-time infographics, it demonstrates the Dix-Hallpike, Semont, Epley, and HINTS maneuvers.
https://ift.tt/2PvEnu2
Ear, Nose, and Throat Emergencies
EMERGENCY MEDICINE CLINICS OF NORTH AMERICA
https://ift.tt/2QNcSJ5
Foreign Bodies of the Ear, Nose and Throat
Foreign bodies to the ear, nose, and throat often can be managed in the emergency department, particularly if the patient offers a history consistent with foreign body and is calm and compliant with the examination and removal attempts. Tips for success include analgesia, adequate visualization, immobilization of the patient's head, dexterity and experience level of the provider, and minimizing attempts at removal. It is critical to recognize the risks involved with certain retained objects (button batteries or sharp objects) and when to call a consultant to help facilitate safe, successful removal of objects to the ear, nose, and throat.
https://ift.tt/2PylGpK
Sinusitis Update
Rhinosinusitis affects many pediatric patients as well as 1 in 6 adults in any given year, resulting in ambulatory care, pediatric, and emergency department visits. Uncomplicated rhinosinusitis requires no imaging or testing and does not require antibiotic treatment. Using strict clinical diagnostic criteria may minimize unnecessary antibiotics. When indicated, amoxicillin with or without clavulanate for 5 to 10 days remains the first-line antibiotic, despite increasing incidence of staphylococcal sinusitis in the post-pneumococcal conjugate vaccine era. Emergency providers also need to recognize atypical cases in which uncommon but serious complications of sinusitis cause both morbidity and mortality.
https://ift.tt/2PylE16
Ears, Nose, and Throat Emergencies
I just recently completed the painful process of taking my second recertification examination in emergency medicine. The process of reviewing the entire core curriculum of our specialty every 10 years is always an eye-opening process, as I have a chance to review so many aspects of the specialty that have fallen from my "regularly used memory." In the process of this review, I became keenly aware once again of just how much of our specialty resides above the shoulders, yet outside the brain. Unbelievably, the ears, nose, mouth, and throat (the "head holes") account for the fourth most important organ system in terms of numbers of questions on the board exam, following cardiovascular, abdominal/gastrointestinal, and thoracic/respiratory.
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Ear, Nose, and Throat Emergencies
The American Board of Emergency Medicine lists 30 specific Ear, Nose, and Throat disorders as well as five Otolaryngology-specific procedures in its 2016 Model of the Clinical Practice of Emergency Medicine. These disorders and their associated procedural skills range from critical in nature to lower acuity. As such, it is incumbent upon emergency providers to be prepared when these patients present for care. While specialty consultation with an otolaryngologist may be available at some centers, often timely access to such consultation is not possible.
https://ift.tt/2QP2wsa
Erratum
The following errors were found in the article, "Pediatric Sepsis" by Melanie K. Prusakowski and Audrey P. Chen in the Severe Sepsis Care in the Emergency Department issue of Emergency Medicine Clinics of North America (February 2017, Volume 35, Issue 1, p1-240):
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Epistaxis
Most anterior epistaxis originates primarily from the Kiesselbach plexus, whereas posterior epistaxis is less common and originates from branches of the sphenopalatine artery. Risk factors include local trauma, foreign body insertion, substance abuse, neoplasms, inherited bleeding diatheses, or acquired coagulopathies. Assessment of airway, breathing, and circulation precedes identification of bleeding source, pain control, and achieving hemostasis. Management options include topical vasoconstrictors, direct pressure, cautery, tranexamic acid, nasal tampons, Foley catheters, or surgical intervention. Specialty consultation may be pursued if interventions fail. Disposition is typically to home unless posterior epistaxis or significant comorbidities exist that warrant admission.
https://ift.tt/2PylCGw
The Diagnosis and Management of Facial Bone Fractures
Appropriate medical care for a patient with a facial fracture can not only optimize aesthetic outcomes but also prevent the potential morbidity and mortality of delayed treatment. In this article, we focus on the clinical presentations, physical examination findings, diagnostic imaging, consultations, and follow-up that patients with facial fractures need related to their emergency department management. Specifically, we address the nuances of evaluating frontal, orbital, nasal, maxillofacial, and mandibular fractures.
https://ift.tt/2QJRggC
Infections of the Neck
Infection of the neck is a relatively common emergency department complaint. If not diagnosed and managed promptly, it may quickly progress to a life-threatening infection. These infections can result in true airway emergencies that may require fiberoptic or surgical airways. This article covers common, as well as rare but emergent, presentations and uses an evidence-based approach to discuss diagnostic and treatment modalities.
https://ift.tt/2PylyXi
Traumatic Injuries of the Ear, Nose and Throat
This article reviews the presentation, diagnosis, and management of common traumatic injuries of the ear, nose, and throat, including laryngeal trauma, auricular and septal hematomas, and tympanic membrane rupture.
https://ift.tt/2QQLhGU
Transcriptional Profiling of Leucocyte Count Variation from Porcine Peripheral Blood Reveals Differential Gene Expression
Leucocytes have tremendous health-check importance related to the individual antiviral capacity of pigs and other mammals. However, the molecular mechanism of the immune response of blood leucocytes in pigs is not completely known. This study investigated the leucocyte-count variation before and after poly I:C stimulation in a Duroc–Erhualian F2 population. Pigs with increased and decreased differences in leucocyte counts were coded as increased responder (IR) and decreased responder (DR), respectively. Then, we used microarray technology to compare the gene-expression profiles of both groups of pigs. Transcriptomic analysis identified 129 differentially expressed genes (DEGs) in IR pigs and 136 DEGs in DR pigs. Forty-one common DEGs showed that both groups had similar expression patterns of immune responses. These results illustrated a differential expression in both groups. Furthermore, qPCR experiment was performed to verify the differential-expression profile. Functional annotation of the DEGs indicated that both IR and DR pigs were similar in several biological processes, including innate immune response, and also exhibited distinct differences in biological processes, molecular function, and pathways. These results provided insights into the mechanism underlying the antiviral capacity of pigs. Trial registration number is CAS Registry Number 24939-03-5.
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Oxidative Modification of LDL by Various Physicochemical Techniques: Its Probable Role in Diabetes Coupled with CVDs
Background. Pro- and antiatherogenic properties of oxidised low density lipoprotein (Ox-LDL) are responsible for different chronic diseases including diabetes and cardiovascular diseases (CVD). The constant attack on the body from oxidative stress makes the quantification of various oxidation products necessary. In this study, the oxidative stress causing the structural and chemical changes occurring in the LDL molecule is comprehensively done. Moreover, the prevalence of the autoantibodies against the oxidised LDL is also determined. Methods. Our study made an attempt to see the effect of Ox-LDL as an enhancer of type 2 diabetes mellitus (T2DM) coupled with CVD. Primarily, we detected the oxidation of LDL with different concentration of Fenton reaction. The biochemical parameters were assessed for the changes occurring in the LDL molecule. In a clinical set up, 20 sera samples were taken from patients who are healthy, 30 from those with diabetes, 20 from those with CVD, and 30 from diabetes with CVD patients. Results. In biochemical assays there were markedly increased TBARS, carbonyl, and HMF content in Ox-LDL as compared to native LDL. The prevalence of autoantibodies against the T2DM was recorded to be 36%, while for CVD it was recorded to be 29%. However, it was found that 50% of the sera samples showed autoantibodies against oxidized LDL in the sera of T2DM with CVD complications as compared to the native analogue. Conclusion. There is significant change in the LDL molecule as revealed by various physicochemical analysis. The change in the LDL macromolecule as a result of oxidation triggered the development of the autoantibodies against it.
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Movement Velocity and Fluidity Improve after Armeo®Spring Rehabilitation in Children Affected by Acquired and Congenital Brain Diseases: An Observational Study
Background. Children with cerebral palsy (CP) and acquired brain injury (ABI) often exhibit upper limb impairment, with repercussions in their daily activities. Robotic rehabilitation may promote their functional recovery, but evidence of its effectiveness is often based on qualitative functional scales. The primary aim of the present work was to assess movement precision, velocity, and smoothness using numerical indices from the endpoint trajectory of Armeo®Spring. Secondly, an investigation of the effectiveness of robotic rehabilitation in CP and ABI children was performed. Methods. Upper limb functional changes were evaluated in children with CP (N=21) or ABI (N=22) treated with Armeo®Spring (20 45-minute sessions over 4 weeks) using clinical scales and numerical indices computed from the exoskeleton trajectory. Results. Functional scales (i.e., QUEST and Melbourne) were sensitive to changes produced by the treatment for the whole study group and for the two etiology-based subgroups (improvements above Minimal Clinically Importance Difference). Significant improvement was also observed in terms of velocity, fluidity, and precision of the movement through the numerical indices of kinematic performance. Differences in the temporal evolution of the motor outcome were highlighted between the ABI and CP subgroups, pointing toward adopting different rehabilitative protocols in these two populations. Conclusions. Robot-assisted upper limb rehabilitation seems to be a promising tool to promote and assess rehabilitation in children affected by acquired and congenital brain diseases.
https://ift.tt/2S2jDHh
The Critical Role of Biliary Candidiasis in Development of Surgical Site Infections after Pancreatoduodenectomy: Results of Prospective Study Using a Selective Culture Medium for Candida Species
In accordance with previous reports, the incidence of biliary candidiasis (BC) after pancreaticoduodenectomy (PD) was reported to be 0 to 5%, and the clinical significance of BC still has been elusive. In this study, we prospectively evaluated the precise incidence of BC after PD using the CHROMagar Candida plate in an attempt to elucidate whether BC has a significant impact on the clinical outcomes after PD. Patients and Method. From November 2014 to March 2016, the consecutive 51 patients who underwent PD were enrolled for this study. The bile juice was prospectively collected through the biliary stent tube on postoperative days (POD) 3, 7, and 14 and directly incubated onto the CHROMagar Candida plate for the cultivation of various Candida species. In the presence or absence of BC, we compared the incidence of SSIs. Results. The incidence of postoperative BC was 15% on POD 3, 24% on POD 7, and 39% on POD 14, respectively. Taken together, 22 patients out of 51 (43.1%) developed BC after PD. Moreover, the incidence of SSIs was significantly higher in patients with BC than in those without it (71% versus 7%, p=0.005). BC was selected as the only significant risk factor of SSIs after PD among the various risk factors. Even though a cause of BC is unknown, high level of alkaline phosphatase (cut-off line >300 IU/L) was selected as the only preoperative risk factor of the development of BC. Conclusion. We elucidated new evidence in which BC could be the independent cause of SSIs after PD and should not be recognized as just contamination artifacts. Preoperative assessment for identifying carriers of Candida species might be essential for reducing the incidence of SSIs after PD.
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Analysis of Titin in Red and White Muscles: Crucial Role on Muscle Contractions Using a Fish Model
Several studies have compared molecular components between red and white skeletal muscles in mammals. However, mammalian skeletal muscles are composed of mixed types of muscle fibers. In the current study, we analyzed and compared the distributions of titin, lipid, phosphate ions, and fatty acid levels in red and white muscles using a fish model (Tilapia), which is rich in red and white muscles, and these are well separated. Oil-red O staining showed that red muscle had more-abundant lipids than did white muscle. A time-of-flight secondary-ion mass spectrometric (TOF-SIMS) analysis revealed that red muscle possessed high levels of palmitic acid and oleic acid, but white muscle contained more phosphate ions. Moreover, elastica-van Gieson (EVG) and Mito-Tracker green FM staining showed that collagen and elastic fibers were highly, respectively, distributed in connective tissues and mitochondria in red muscle. An electron micrographic analysis indicated that red muscle had a relatively higher number of mitochondria and longer sarcomere lengths and Z-line widths, while myofibril diameters were thicker in white muscle. Myofibrillar proteins separated by SDS-PAGE showed that the major giant protein, titin, was highly expressed in white muscle than in red muscle. Furthermore, ratios of titin to myosin heavy chain (MHC) (titin/MHC) were about 1.3 times higher in white muscle than red muscle. We postulated that white muscle is fit for short and strong contractile performance due to high levels of titin and condensed sarcomeres, whereas red muscle is fit for low intensity and long-lasting activity due to high levels of lipids and mitochondria and long sarcomeres.
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Mimicry, Camouflage and Perceptual Exploitation: the Evolution of Deception in Nature
Abstract
Despite decades of study, mimicry continues to inspire and challenge evolutionary biologists. This essay aims to assess recent conceptual frameworks for the study of mimicry and to examine the links between mimicry and related phenomena. Mimicry is defined here as similarity in appearance and/or behavior between a mimic and a model that provides a selective advantage to the mimic because it affects the behavior of a receiver causing it to misidentify the mimic, and that evolved (or is maintained by selection) because of those effects. Mimics copy cues or signals that are already in use as part of a stable communication system, but offer misleading information to receivers. Mimicry overlaps, both conceptually and evolutionarily, with camouflage and perceptual exploitation but the overlap is only partial, which may create some confusion. Certain types of camouflage (e.g. masquerade) conform to the definition of mimicry, while others (e.g. background matching) are not considered mimicry because they prevent detection rather than recognition of the camouflaged animal. Mimicry, on the other hand, works by exploiting peculiarities of the receiver at higher stages of sensory processing involving recognition and classification of stimuli. Perceptual exploitation models of trait evolution are also closely related to mimicry, and sensory traps in particular may act as a precursor for true mimicry to evolve. The common thread through these diverse phenomena is deception of a receiver by a mimic. Thus receiver deception (i.e. perceptual error) emerges as a key characteristic of mimicry shared with some types of camouflage and perceptual exploitation.
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pVAX1-A20 alleviates colitis in mice by promoting regulatory T cells
To investigate whether the intrarectal administration of the ubiquitin E3 ligase A20 (A20) attenuates intestinal inflammation and influences regulatory T cells in experimental colitis.
https://ift.tt/2DuNBQd
Epidemiology of Primary Biliary Cholangitis in Italy: Evidence From a Real-world Database
Primary biliary cholangitis is an autoimmune disease affecting the interlobular bile ducts. Limited information is available on its epidemiology and treatment in Italy.
https://ift.tt/2Q1RmTU
Phase I/II trial of helical IMRT-based stereotactic body radiotherapy for hepatocellular carcinoma
To report the results of a phase I/II study of helical IMRT-based stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC).
https://ift.tt/2Q1RmDo
Salivary markers of hepato-metabolic comorbidities in pediatric obesity
The pediatric obesity epidemic calls for the noninvasive detection of individuals at higher risk of complications.
https://ift.tt/2DqF6Wd
Relationship among different skin dose definitions in high-dose-rate (HDR) balloon breast brachytherapy
Abstract
Objective
To establish the relationship among various skin dosimetric indices and different volumetric definitions of skin in high-dose-rate (HDR) balloon breast brachytherapy.
Methods
Fifty breast cancer patients were treated with HDR balloon brachytherapy. The MammoSite® applicator was used for 40 patients and the Contura® applicator for 10 patients. Skin structure was retrospectively defined by expanding the skin surface internal to the body with a thickness of 1, 2, 3, 4, or 5 mm in one method. In another method, the skin was defined by expanding its external to the body to demonstrate the maximum point dose on the skin surface. For each skin structure defined by six different methods, three dosimetric data points extracted from dose-volume histograms were compared. Dmax was defined as the maximum point dose, and D1cc and D0.1cc were defined as the minimum dose to 1 cm3 and 0.1 cm3 of the most irradiated skin volume, respectively. The relationship among 18 dosimetric parameters was presented in graphs, and linear curve fitting was performed to provide mathematical formulas.
Results
For each skin definition, the Dmax, D1cc, and D0.1cc values show a linear relationship such that Dmax is the largest, D0.1cc is the next, and D1cc is the smallest value. For each dosimetric parameter, there was a linear relationship among the dosimetric indices for 6 different skin definitions. For clinical use, all linear relationships were displayed in graphs and two parameters for linear fitting were provided. Average R2 value for curve fitting was 0.978.
Conclusion
The presented relationships can be developed in each individual institution and convert one dosimetric index to another for different skin definitions.
https://ift.tt/2FnRwAG
Alkaline extracellular conditions promote the proliferation and mineralization of a human cementoblast cell line
Abstract
Aim
To investigate the proliferation and mineralization of a human cementoblast cell line under alkaline conditions.
Methodology
A human cementoblast cell line was cultured in alkaline media with several pHs (pH 7.6, 8.0 and 8.4) without CO2. Cell numbers, phospho‐p44/42 expression, alkaline phosphatase (ALP) activity, and mineralization were evaluated. The significance of differences between groups was assessed using a two‐way analysis of variance 15 (ANOVA) followed by Bonferroni's multiple comparison test (α=0.01).
Results
Cell numbers increased in a time‐dependent manner in the high pH medium groups. Western blot analysis revealed the up‐regulated expression of phospho‐p44/42 under alkaline conditions. ALP activity was also increased at pH 8.0 and 8.4. Alizarin red staining showed increased mineralization in the high pH medium groups. The incorporation of the transient receptor potential ankyrin subfamily member 1 (TRPA1) antagonist HC030031 markedly negated the effect on proliferation and mineralization.
Conclusions
Extracellular alkaline conditions promoted the proliferation and mineralization of human cementoblasts in vitro via TRPA1.
This article is protected by copyright. All rights reserved.
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Moderate hypofractionation in intermediate and high risk, localized prostate cancer: Health-related quality of life from the randomized, phase 3 HYPRO trial
The randomized phase 3 HYPRO trial compared hypofractionated radiotherapy of 64.6 Gy in 19 fractions of 3.4 Gy versus conventionally fractionated treatment of 79 Gy in 39 fractions of 2 Gy in patients with localized prostate cancer. Quality of life was measured using the validated EORTC-QLQ-PR 25 questionnaire. Non-inferiority of hypofractionation could not be demonstrated for genitourinary and gastrointestinal quality of life, but was demonstrated for androgen-deprivation therapy-related symptoms, sexual activity and sexual function.
https://ift.tt/2RXT4CY
Image-guided brachytherapy for cancer of the nasal vestibule: achieving high local-regional control while preserving cosmesis
We examined 102 patients with Wang T1-T2 squamous cell carcinoma of the nasal vestibule to assess local-regional control rates and patient satisfaction after image guided brachytherapy. Furthermore, tumor volume was explored as prognostic factor for recurrence. We found that brachytherapy offers excellent local control with high patient satisfaction. Tumor volume was found to be an adequate predictive factor for patients at risk of regional recurrence.
https://ift.tt/2RWp9eg
Administration of dendritic cells and anti-PD-1 antibody converts X-ray irradiated tumors into effective in situ vaccines
Although localized X-ray therapy can induce a systemic anti-tumor immune response, radiation alone may not be sufficient to control both primary and metastatic tumors. Using B16/BL6 and LLC mouse models, controls of primary and metastatic tumors were evaluated after X-ray irradiation followed by administrations of bone marrow derived dendritic cells and anti-PD1 antibody. This triple combination induced a remarkable CD8 mediated anti-tumor immune response inhibiting both local and metastatic tumor growth and extending survival significantly.
https://ift.tt/2DKQJbg
Inorganic nitrate alleviates total body irradiation-induced systemic damage by decreasing reactive oxygen species levels
Conventional radiotherapy is a common strategy for treating cancer patients, but it can induce multiple organ damage. The effect of supplementation with inorganic nitrate, a novel radioprotectant, on systemic damage was evaluated in a mouse model of total body gamma irradiation. Inorganic nitrate delivery was shown to effectively prevent systemic irradiation-induced damage, and nitrate-mediated decreases in reactive oxygen species levels may contribute to this radioprotective effect.
https://ift.tt/2DHnu9m
Do Elevated Autoantibodies in Patients With Multiple Sclerosis Matter ?
Abstract
Objectives
The incidence and clinical impact of serum autoantibodies in patients with multiple sclerosis (MS) is controversially discussed. The aim of the study is to reassess the value of elevated serum autoantibodies in our MS study cohort.
Material & Methods
176 MS patients were retrospectively analyzed for coexistence and clinical impact of increased serum autoantibody levels.
Results
18.8% of the MS cohort showed elevated serum autoantibody levels, but only 10.2% of all MS patients were diagnosed with a further autoimmune disease (AI). Patients with elevated serum autoantibodies (AABS) were not significantly more often diagnosed with a clinical manifest AI as compared to patients with negative autoantibodies (p = 0.338). MS patients with disease duration of more than 10 years showed no significant increase of positive autoantibodies as compared to patients with a more recent disease onset (p = 1). MS patients with elevated serum autoantibodies did not exhibit a significantly worse disease course (p = 0.428).
Conclusions
According to our data, elevated serum autoantibodies do not have the potential to serve as a prognostic tool for disease severity in patients with MS. Since MS patients with positive serum AABS did not significantly more often suffer from clinical manifest AIs than MS patients with negative serum AABS, the role of routine testing of serum AABS in MS patients should be critically called into question.
This article is protected by copyright. All rights reserved.
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Early sensitivity of evoked potentials to surface and volumetric structure during the visual perception of three‐dimensional object shape
Abstract
This study used event‐related potentials (ERPs) to elucidate how the human visual system processes three‐dimensional (3D) object shape structure. In particular, we examined whether the perceptual mechanisms that support the analysis of 3D shape are differentially sensitive to higher‐order surface and volumetric part structure. Observers performed a whole‐part novel object matching task in which part stimuli comprised sub‐regions of closed edge contour, surfaces or volumetric parts. Behavioural response latency data showed an advantage in matching surfaces and volumetric parts to whole objects over contours, but no difference between surfaces and volumes. ERPs were analysed using a convergence of approaches based on stimulus dependent amplitude modulations of evoked potentials, topographic segmentation and spatial frequency oscillations. The results showed early differential perceptual processing of contours, surfaces and volumetric part stimuli. This was first reliably observed over occipitoparietal electrodes during the N1 (140‐200ms) with a mean peak latency of 170ms, and continued on subsequent P2 (220‐260ms) and N2 (260‐320ms) components. This differential sensitivity in perceptual processing during the N1 was accompanied by distinct microstate patterns that distinguished among contours, surfaces and volumes, and predominant theta band activity around 4‐7Hz over right occipitoparietal and orbitofrontal sites. These results provide the first evidence of early differential perceptual processing of higher‐order surface and volumetric shape structure within the first 200ms of stimulus processing. The findings challenge theoretical models of object recognition that do not attribute functional significance to surface and volumetric object structure during visual perception.
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The Prodromes of Parkinson's disease
Abstract
Whilst the diagnosis of Parkinson's disease (PD) relies on the motor triad of bradykinesia, rigidity and tremor, the underlying pathological process starts many years before these signs are overt. In this prodromal phase of PD, a diverse range of non‐motor and motor features can occur. Individually they do not allow a diagnosis of PD, but when considered together, they reflect the gradual development of the clinical syndrome. Different subgroups within the prodromal phase may exist and reflect different underlying pathology. Here we summarise the evidence on the prodromal phase of PD in patient groups at increased of PD with well described prodromal features: patients with idiopathic Rapid Eye Movement (REM) Sleep Behaviour Disorder (RBD), patients with idiopathic anosmia, and families with monogenic mutations that are closely linked to PD pathology. In addition, we discuss the information on prodromal features from ongoing studies aimed at detecting prodromal PD in the general population. It is likely that better delineation of the clinical prodromes of PD and their progression in these high‐risk groups will improve understanding of the underlying pathophysiology.
This article is protected by copyright. All rights reserved.
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Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABAA and GABAB receptors
Abstract
GABA is the most abundant neurotransmitter in the circadian pacemaker circuits of mammals and insects. In the Madeira cockroach the accessory medulla (AME) in the brain′s optic lobes is the circadian clock that orchestrates rest‐activity rhythms in synchrony with light dark cycles. Three prominent GABAergic tracts connect the AME to termination sites of compound eye photoreceptors in the lamina and medulla. Parallel GABAergic light entrainment pathways were suggested to either advance or delay the clock for adjustment to changing photoperiods. In agreement with this hypothesis GABA activated or inhibited AME clock neurons, allowing for distinction of three different GABA response types. Here, we examined which GABA receptors are responsible for these response types. We found that both ionotropic GABAA receptors and metabotropic GABAB receptors were expressed in AME clock cells. Via different signaling pathways, either one of them could account for all three GABA response types. The muscimol‐dependently activated GABAA receptor formed a chloride channel, while the SKF 97541‐dependently activated GABAB receptor signaled via G‐proteins, apparently targeting potassium channels. Expression of chloride exporters or –importers determined whether GABAA receptor activation hyper‐ or depolarized AME neurons. For GABAB receptor responses second messenger gated channels present in the clock cells appeared to decide about the polarity of the GABA response. In summary, circadian clock neurons co‐expressed inhibitory and/or excitatory GABAA and GABAB receptors in various combinations, while cotransporter expression and the set of second messenger gated ion channels present allowed for distinct signaling in different clock neurons.
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An epidemiological survey of bovine viral diarrhea infection in calves in Egypt with identification of high prevalence of persistent infected animals
Abstract
In the present study, we identified the persistent infection by bovine viral diarrhea virus (BVDV) in 45 clinically suspected persistent infected (PI) calves and 260 apparently healthy calves from Damietta governorate (North) in Egypt during 2016 using enzyme-linked immunosorbent assay (ELISA), serum neutralization test (SNT), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction (RT-PCR). The identification of PI calves was performed after vaccination by CattleMaster® 4. The age of PI calves in the current study was ranged from 2 to 4 months (n = 7) and from 5 to 8 months (n = 38). ELISA revealed the infection in 4 clinically suspected PI calves (57.14%) aged 2 to 4 months. While the infection did not approve in any of the calves within this age using RT-PCR, for calves aged from 5 to 8 months old, ELISA showed the infection in 30 calves (78.94%), and from these calves, the infection was confirmed in 6 calves (15.79%) only using RT-PCR. For apparently clinically healthy animals, 11 transiently infected calves were identified by IHC (positive), SNT (positive), and RT-PCR (negative) at 2 months' post-vaccination. Collectively, the persistent infection was confirmed in 9 calves (2.95%) out of 305 calves. In summary, our study detected a high prevalence of PI calves with BVDV in Damietta province in Egypt, which highlights the importance of introducing effective prevention and control strategies throughout Egypt to minimize the prevalence of BVDV.
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The Galleria mellonella Waxworm Infection Model for Disseminated Candidiasis
Galleria mellonella serves as an invertebrate model for disseminated candidiasis. Here, we detail the infection protocol and provide supporting data for the model's effectiveness.
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Visualization of 3D White Adipose Tissue Structure Using Whole-mount Staining
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Enrich and Expand Rare Antigen-specific T Cells with Magnetic Nanoparticles
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LDL Cholesterol Uptake Assay Using Live Cell Imaging Analysis with Cell Health Monitoring
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Quantitative Polymerase Chain Reaction-based Analyses of Murine Intestinal Microbiota After Oral Antibiotic Treatment
Here we provide detailed protocols for the oral administration of antibiotics to mice, collection of fecal samples, DNA extraction and quantification of fecal bacteria by qPCR.
https://ift.tt/2RZYf5s
Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice
Objective
Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease.
DesignInterleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).
ResultsIn a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g–/– mice.
ConclusionEthanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.
https://ift.tt/2OPA2fZ
Iron-containing micronutrient powders modify the effect of oral antibiotics on the infant gut microbiome and increase post-antibiotic diarrhoea risk: a controlled study in Kenya
Objective
Many African infants receiving iron fortificants also receive antibiotics. Antibiotic efficacy against enteropathogens may be modified by high colonic iron concentrations. In this study, we evaluated the effect of antibiotics on the infant gut microbiome and diarrhoea when given with or without iron-containing micronutrient powders (MNPs).
DesignIn a controlled intervention trial, four groups of community-dwelling infants (n=28; aged 8–10 months) received either: (A) antibiotics for 5 days and iron-MNPs for 40 days (Fe+Ab+); (B) antibiotics and no-iron-MNPs (Fe–Ab+); (C) no antibiotics and iron-MNPs (Fe+Ab–); or (D) no antibiotics and no-iron-MNPs (Fe–Ab–). We collected a faecal sample before the first antibiotic dose (D0) and after 5, 10, 20 and 40 days (D5–D40) to assess the gut microbiome composition by 16S profiling, enteropathogens by quantitative PCR, faecal calprotectin and pH and assessed morbidity over the 40-day study period.
ResultsIn Fe+Ab+, there was a decrease in Bifidobacterium abundances (p<0.05), but no decrease in Fe–Ab+. In Fe–Ab+, there was a decrease in abundances of pathogenic Escherichia coli (p<0.05), but no decrease in Fe+Ab+. In Fe–Ab+, there was a decrease in pH (p<0.05), but no decrease in Fe+Ab+. Longitudinal prevalence of diarrhoea was higher in Fe+Ab+ (19.6%) compared with Fe–Ab+ (12.4%) (p=0.04) and compared with Fe+Ab– (5.2%) (p=0.00).
ConclusionOur findings need confirmation in a larger study but suggest that, in African infants, iron fortification modifies the response to broad-spectrum antibiotics: iron may reduce their efficacy against potential enteropathogens, particularly pathogenic E. coli, and may increase risk for diarrhoea.
Trial registration numberNCT02118402; Pre-results.
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Authors reply: treatment strategy for necrotising pancreatitis
We thank the authors for their interest in our randomised trial.1 2 First, the patient population: The treatment algorithm outlined in our study is different from the TENSION trial and other preceding trials from the Netherlands.3 In patients with large collections (>120 mm in size), the multigate technique was adopted (20% of patient cohort). In patients with persistent or ongoing systemic inflammatory response syndrome (SIRS) after initial drainage, a CT scan was obtained at 72 hours to assess treatment response. If there was <25% decrease in size of the necrotic collection, then additional interventions were undertaken (another 40% of patient cohort): more drainage tracts were created or necrosectomy was performed depending on contents of the necrotic cavity and/or percutaneous drains were placed. In essence, 60% of study cohort required advanced/additional interventions. We believe that necrosectomy was not required, not because the study population constituted a different patient subset, but because...
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Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink
Objective
To evaluate the association between statin use and risk of biliary tract cancers (BTC).
DesignThis is a nested case–control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders.
ResultsWe included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long-term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007).
ConclusionCompared with non-use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention.
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NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study
Objectives
Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).
DesignNKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies.
ResultsNKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo.
ConclusionNKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
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In Vivo Imaging of Reactive Oxygen Species in a Murine Wound Model
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Analyzing Spatial Learning and Prosocial Behavior in Mice Using the Barnes Maze and Damsel-in-Distress Paradigms
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In Reply to Dr. Lambein et al “HER2 protein overexpression in non‐amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry?”
Abstract
We were pleased to read Dr. Lambein and colleagues' insightful and thought‐provoking correspondence. We acknowledge that there are alternatives to the three mechanisms we proposed to explain the discordant HER2 findings. The transcriptional mechanisms broached by Lambein et al. constitute a plausible explanation for our collective findings and are soundly supported by the literature [1‐2].
This article is protected by copyright. All rights reserved.
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Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor
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Cyclodestructive Procedures in Glaucoma: A Review of Current and Emerging Options
Abstract
The first surgical modalities to reduce aqueous humor production by damaging the ciliary body date back to the early twentieth century. Until recently, however, cyclodestructive procedures (e.g., cyclocryotherapy and transscleral diode laser photocoagulation) have been reserved as last option procedures in refractory glaucoma patients with poor visual potential. Emerging technologic innovation has led to the development of promising, safer and less destructive techniques, such as micropulse diode cyclophotocoagulation, endoscopic cyclophotocoagulation and ultrasound cyclodestruction. Consequently, an emerging paradigm shift is under way with the selection of these surgical options in eyes with less severe glaucoma and good visual potential. Although existing evidence has not, as yet, adequately defined the role and value of these procedures, their emergence is a welcome expansion of available options for patients with moderate-to-severe glaucoma. This article reviews the pertinent evidence on both established and evolving cyclodestructive techniques and describes their growing role in the management of glaucoma.
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A Randomized Controlled Clinical Trial Comparing 20 Gauge and 23 Gauge Vitrectomy for Patients with Macular Hole or Macular Pucker
Abstract
Introduction
To compare the transconjunctival sutureless 23 gauge (G) pars plana vitrectomy (PPV) with 20 G PPV regarding inflammation, safety, visual outcome and patient comfort.
Methods
We included 103 patients with symptomatic macular hole or macular pucker, scheduled for vitrectomy in this prospective, randomized, controlled, mono-center clinical trial. Patients were randomized 1:1 to either 20G PPV (n = 51) or 23G PPV (n = 52). All eyes underwent standard 20G or 23G PPV with membrane peeling. Primary outcome measure was change in aqueous humor flare 3 weeks after surgery compared with baseline. Secondary outcome measures were flare values 2 days and 26 weeks after surgery, subjective discomforts measured with a visual analog scale, best-corrected visual acuity, duration of surgery, intraocular pressure (IOP) and adverse events.
Results
There was no significant difference in change of flare 3 weeks after PPV [− 1.7, 95% CI (− 6.3 to 2.9), p = 0.466]. Both groups showed a significant increase in flare 2 days after surgery (20G: p < 0.001, 23G: p = 0.002), but only the 20G group after 3 weeks (p = 0.011). The gain in visual acuity after 3 weeks was higher after 23G PPV (4.2 95% CI (0.4–8.0, p = 0.029), but without a difference after 6 months. The duration of surgery was shorter in the 23G group (p < 0.001). Patient comfort 3 weeks after surgery was greater after 23G PPV (foreign body sensation p = 0.002; itching: p = 0.021). However, the rate of complications did not differ between the groups.
Conclusion
The primary aim, showing the superiority of the 23G group regarding the change of flare value from baseline to 3 weeks after surgery, was not met, but the level of inflammation decreased faster after 23G PPV. Clear advantages of the 23G PPV were a lower risk of postoperative IOP elevation, a shorter surgery time, faster visual recovery and greater patient comfort in the early postoperative phase.
Clinical Trial Registration Number
ClinicalTrials.gov NCT01969929.
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iCatch: a new strategy for capturing large DNA fragments using homing endonucleases
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Integrating anatomo‐physiological changes and pharmacogenomics in anti‐infective therapy management: is it a major concern?
Success of anti‐infective therapy is a major challenge in some patients given anatomo‐physiological changes and genetic variations. In this case anecdote, we report the management strategy of a patient suffering from chronic pulmonary aspergillosis in a context of anorexia nervosa and genetic polymorphism.
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The impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX
Summary
Studies have demonstrated an association between UDP‐glucuronosyltransferase‐1A1 (UGT1A1) genetic polymorphisms and irinotecan‐induced toxicity. We conducted this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients administered with FOLFIRINOX in the JASPAC06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (Oxaliplatin85mg/m2, Irinotecan180mg/m2, Leucovorin200mg/m2, bolus5‐FU400mg/m2, and continuous5‐FU2,400mg/m2) or a modified FOLFIRINOX (Oxaliplatin85mg/m2, Irinotecan150mg/m2, Leucovorin200mg/m2, and continuous5‐FU2,400mg/m2) as first‐line chemotherapy were included. Of 199patients eligible for this analysis, 79patients were administered the original FOLFIRINOX regimen and 120patients were administered the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 wild type, and 25 were UGT1A1 heterozygous type (−/*6, 12patients; −/*28, 13patients). In the modified FOLFIRINOX group, 64 were UGT1A1 wild type, and 56 were UGT1A1 heterozygous type (−/*6, 33patients; −/*28, 23patients).
In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 wild type, and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6 tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. On the other hand, for patients administered the modified FOLFIRINOX, there was no difference in frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with wild type UGT1A1.
This article is protected by copyright. All rights reserved.
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Identification of genes involved in the regulation of Telomerase Reverse Transcriptase in hepatocellular carcinoma
Summary
Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We conducted a genome‐wide short‐hairpin RNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55‐ and C7orf43‐responsive sites exist between base pairs ‐58 and +36 and ‐169 and ‐59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression via YAP1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non‐tumor tissues, compared to normal liver tissues from non‐HCC patients. Analysis of 377 HCC patients in the Cancer Genome Atlas (TCGA) dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment.
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Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model
Lenvatinib is a multitargeted tyrosine kinase inhibitor that selectively inhibits VEGFR1‐3, FGFR1‐4, PDGFRα, RET and KIT. Here, we show that lenvatinib has immunomodulatory activity, which plays a role in the antitumor activity of single lenvatinib treatment, and enhances the antitumor activity of anti‐PD‐1 antibody in the combination treatment in the Hepa1‐6 mouse HCC syngeneic tumor model.
Abstract
Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐4, platelet‐derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti‐programmed cell death 1 (PD‐1) antibody in the Hepa1‐6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti‐PD‐1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single‐cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti‐PD‐1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti‐PD‐1 antibody. Combination treatment of lenvatinib plus anti‐PD‐1 antibody therefore warrants further investigation against advanced HCC.
https://ift.tt/2DstXUP
Diagnostic performance of 18 F-choline PET-CT in prostate cancer
Abstract
Objectives
To evaluate the diagnostic performance of 18F-choline PETCT in staging prostate cancer (PC) and whether the use of this imaging modality changes the therapeutic decision in patients previously staged by conventional imaging. The secondary aim was to determine the prognostic factors associated with positive choline PETCT findings in both detection of disseminated disease and in changes in the therapeutic indication.
Materials and methods
Multicentre, retrospective, observational study of 269 patients diagnosed with PC. Mean age was 69 ± 9.2 years. Of the 269 patients, 62 (23%) had high-risk localized PC (group 1), 118 (43.9%) biochemical failure after radical prostatectomy (group 2), and 89 (33.1%) biochemical failure after radiotherapy (group 3). None of the patients showed clear evidence of distant disease on computed tomography or bone scans. The following potential prognostic factors were assessed: PSA level at diagnosis; primary and secondary Gleason; Gleason score (GS); clinical and pathologic T and N stage; number of positive cylinders in the biopsy; presence of vascular or lymphatic invasion; status of surgical margins; androgen deprivation therapy (ADT); time to biochemical recurrence; and PSA, PSA doubling time (PSADT), and PSA velocity (PSAV) at failure. Univariate and multivariate analyses were performed, and receiver-operating curves calculated.
Results
The mean PSA by groups was, group 1: 31.22 ng/ml, group 2: 2.52 ng/ml and group 3: 5.85 ng/ml. The tumor detection rate with 18F-choline PETCT was 74% (group 1: 85.5%, group 2: 55.1% and group 3: 91%). Prognostic factors for positive 18F-choline PETCT were identified only in group 2: PSA at failure and PSADT. 18F-choline PETCT changed the therapeutic indication in 62.8% (group 1: 71%, group 2: 55.2% and group 3: 70.1%). The prognostic factors for a change in treatment were identified only in group 1: secondary Gleason ≤ 4 and GS ≤ 7 and in group 2: PSA at failure, PSA nadir after surgery and pathologic stage N0. 18F-choline PETCT identified lymph node and/or metastatic disease in 32.7% (group 1: 25.8%, group 2: 29.7% and group 3: 41.6%). Prognostic factors for detecting lymph node/metastasis were identified in the group 2: PSA failure ≥ 1.37 ng/ml and PSADT < 4 months and in the group 3: PSADT < 4.6 months and time to failure < 5 years.
Conclusion
These findings support the clinical use de 18F-choline PET-CT in staging high-risk patients with a secondary Gleason ≤ 4 and GS ≤ 7, in restaging patients with biochemical recurrence after RP if PSA at failure ≥ 1.37 ng/ml or PSADT ≤ 4 months and in patients with biochemical failure after RT, if PSADT ≤ 4.6 months and time to failure < 5 years, because it determines a change in the therapeutic indication.
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High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer
Abstract
Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes β-catenin to activate Wnt/β-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and ApcMin/+ mice. Our findings provide important insights into a previously unrecognized oncogenic role of Tob1 in colon cancer and suggest that Tob1 is an adverse prognostic factor and therapeutic target for colon cancer.
https://ift.tt/2qROeeR
Role of the NLRP3 inflammasome in cancer
Abstract
Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.
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Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers
Abstract
The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.
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Deep learning-based preoperative predictive analytics for patient-reported outcomes following lumbar diskectomy: Feasibility of center-specific modelling
Publication date: Available online 16 November 2018
Source: The Spine Journal
Author(s): Victor E. Staartjes, Marlies P. de Wispelaere, W. Peter Vandertop, Marc L. Schröder
Abstract
Background Context
There is considerable variability in patient-reported outcome measures (PROM) following surgery for lumbar disk herniation (LDH). Individualized prediction tools that are derived from center- or even surgeon-specific data could provide valuable insights for shared decision-making.
Purpose
To evaluate the feasibility of deriving robust deep learning-based predictive analytics from single-center, single-surgeon data.
Study Design
Derivation of predictive models from a prospective registry.
Patient Sample
Patients who underwent single-level tubular microdiskectomy for LDH.
Outcome Measures
Numeric rating scales (NRS) for leg and back pain severity and Oswestry Disability Index (ODI) scores at 12 months postoperatively.
Methods
Data were derived from a prospective registry. We trained deep neural network-based and logistic regression-based prediction models for PROM. The primary endpoint was achievement of the minimum clinically important difference (MCID) in NRS and ODI, defined as a 30% or greater improvement from baseline. Univariate predictors of MCID were also identified using conventional statistics.
Results
A total of 422 patients were included (mean [SD] age: 48.5 [11.5] years; 207 [49%] female). After 1 year, 337 (80%), 219 (52%), and 337 (80%) patients reported a clinically relevant improvement in leg pain, back pain, and functional disability, respectively. The deep learning models predicted MCID with high area-under-the-curve (AUC) of 0.87, 0.90, and 0.84, as well as accuracy of 85%, 87%, and 75%. The regression models provided inferior performance measures for each of the outcomes.
Conclusions
Our study demonstrates that generating personalized and robust deep learning-based analytics for outcome prediction is feasible even with limited amounts of center-specific data. With prospective validation, the ability to preoperatively and reliably inform patients about the likelihood of symptom improvement could prove useful in patient counselling and shared decision-making.
https://ift.tt/2Q3vHut
Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis
Abstract
Purpose
Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance.
Methods
We retrospectively collected data on 270 patients [median age 76 (range 48–92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously.
Results
Patients received an overall median of 6 (range 1–25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1–21) months [T1 7 (1–21), T2 5.5 (1–19) and T3 4 (1–19) months] and median overall survival 9 (range 1–36) months [T1 10 (1–31), T2 8 (1–36) and T3 6.5 (2–29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7–36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine.
Conclusion
We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy.
https://ift.tt/2QaOWT3
Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers
Abstract
The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-γ upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-γ exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-γ were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity.
https://ift.tt/2BcWWdD
Treatment of Femoral Neck Fractures in Patients 45 to 64 Years of Age
Publication date: Available online 16 November 2018
Source: Injury
Author(s): Joey P. Johnson, Justin Kleiner, Avi D. Goodman, Joseph A. Gil, Alan H. Daniels, Roman A. Hayda
Abstract
Introduction
Young patients with femoral neck fractures are optimally treated with reduction and stable fixation, while patients over the age of sixty-five are often treated with arthroplasty. This study analyzes in-hospital outcomes associated with total hip arthroplasty, hip hemiarthroplasty and internal fixation for treatment of femoral neck fractures in patients aged 45-64.
Methods
Records of patients between the ages of 45-64, from 2002 to 2014, sustaining femoral neck fractures and treated with internal fixation, hip hemiarthroplasty or total hip arthroplasty were obtained from the Nationwide Inpatient Sample (NIS). Examined variables were age, sex and Charlson Comorbidity Index (CCI). Outcome measures included hospital length of stay (LOS), complications, and inpatient hospitalization charge.
Results
From 2002-2014 74,678 femoral neck fractures were available for analysis. THA use increased from 5.3% of operatively managed fractures in 2002 to 22.3% of operatively managed fractures in 2014 (p < 0.0001). Patients undergoing THA had higher hospital cost, higher in hospital complication rates and longer length of stay than patients undergoing internal fixation (p < 0.0001). The in-hospital mortality for patients undergoing a hip hemiarthroplasty was higher (1.2%) than either total hip arthroplasty (0.2%) or internal fixation (0.5%) (P = 0.007).
Conclusion
This study demonstrates that the use of total hip arthroplasty in treatment of femoral neck fractures in patients from the age of 45-64 increased 4.2-fold over the study period. This treatment is associated with increased hospital cost, length of stay and complications. Additionally, as age increased in our study population, there was a stepwise increase in the use of arthroplasty, and it appears that hemiarthroplasty is being used with a different patient population.
https://ift.tt/2S1Ozr7
Head, face and neck camel-related injuries: biomechanics and severity
Publication date: Available online 16 November 2018
Source: Injury
Author(s): Mohamed A. Al-Ali, Ashraf F. Hefny, Fikri M. Abu-Zidan
Abstract
Introduction
Large animal-related human injuries are associated with high morbidity and mortality. There are no studies on biomechanics of the camel-related head, face, and neck (HFN) injuries. We aimed to study the mechanism, anatomical distribution and severity of camel-related HFN injuries.
Methods
We analyzed our prospectively collected data of patients who were admitted to Al Ain Hospital with camel-related HFN injury during the period of October 2001 to January 2010.
Results
Seventy-three patients were studied; all were males having a median (range) age of 28 (5-89) years. Camel kick was the most common mechanism of injury (45%) followed by falling from a camel (22%). Facial fractures were significantly more common in patients who were kicked by a camel. Severe head injuries were significantly more in patients who fell from a camel or who had a car collision with a camel. Car collision with a camel was significantly associated with lower cervical spine fractures (p = 0.017) and severe cervical spine injuries (p = 0.004). Two patients died (overall mortality 3%)
Conclusions
Our study provides an insight into the complex biomechanics and severity of camel-related HFN injuries. It is essential to adopt protective measures in our community so as to reduce camel-related HFN injuries.
https://ift.tt/2DIXY3M
Risk factors for early readmission due to surgical complications after treatment of proximal femoral fractures – a Finnish National Database study of 68,800 patients
Publication date: Available online 16 November 2018
Source: Injury
Author(s): Tero T. Yli-Kyyny, Reijo Sund, Mikko Heinänen, Antti Malmivaara, Heikki Kröger
Abstract
Introduction
Hip fracture surgery is associated with a considerable amount medical and surgical complications, which adversely impacts the patient's outcome and/or increases costs. We evaluated what risk factors were associated with the occurrence of early readmission due to surgical complications after hip fracture surgery.
Material and methods
A nationwide database with 68,800 hip fracture patients treated between 1999 and 2011 was studied to uncover the association of readmissions with co-morbidities, fracture types, different hospital types and treatment methods using the Cox proportional hazards model.
Results
Early readmission within three months due to hip fracture surgery complications occurred at a rate of 4.6%. Increased occurrence of readmission was found among patients with: heavy alcoholism (HR 1.38; 95% CI: 1.23–1.53); Parkinson's disease (PD; HR 1.22; 95% CI: 1.05–1.42); pre-existing osteoarthritis (HR 2.02; 95% CI: 1.83–2.23); rheumatic disease (HR 1.44; 95% CI: 1.27–1.65); as well as those with a fracture of the femur neck, depression, presence of a psychotic disorder, an operative delay of at least three days, or previous treatment with total hip arthroplasty.
Conclusion
Our results indicate that there are several factors associated with an increased risk of early readmission. We suggest that in the presence of these factors, the surgical treatment method and postoperative protocol should be carefully planned and performed.
https://ift.tt/2RWBX4o
Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis
Abstract
Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
https://ift.tt/2Bctapp
Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: an immunohistochemical study with clinicopathological and prognostic implications
Abstract
Several cancers, especially non-small cell lung cancer (NSCLC), are able to escape the immunosurveillance of tumor-infiltrating lymphocytes (TILs); among the molecules involved, the indoleamine 2,3-dioxygenase 1 (IDO-1) and the programmed cell death ligand-1 (PD-L1) play a crucial role. These aspects are of great interest in the current immunotherapeutic era, therefore the current study analyses the TILs, IDO-1, and PD-L1 interactions and their correlations with clinicopathological parameters and prognosis in NSCLC. One hundred ninety-three NSCLC surgical specimens, formalin-fixed, and paraffin-embedded were assessed for TILs density, TILs localization, IDO-1 (clone 4.16H1), and PD-L1 (clone E1L3N) immunohistochemical expressions. This data was correlated with clinicopathological parameters, disease free, and overall survivals. IDO-1 and PD-L1 high expressions were related to the solid pattern of adenocarcinomas (respectively p = 0.036 and p = 0.026); high PD-L1 expression was correlated with squamous histotype (p = 0.048). IDO-1 overexpression correlated with former smokers (p = 0.041), higher adenocarcinoma stages (p = 0.039), and with both higher TILs density and PD-L1 expression (respectively p = 0.025 and p = 0.0003). A better prognosis was associated with TILs intratumoral or mixed localizations (p = 0.029). TILs localization affects NSCLC prognosis; the higher expression of IDO-1 and PD-L1 in poorly differentiated and more aggressive lung adenocarcinomas, as well as the correlation between high PD-L1 expression and squamous cell histotype, confirm the more efficient immunoescaping of these NSCLC subgroups.
https://ift.tt/2KbN5HQ
Prevalence of comorbidities and effect on survival in survivors of human papillomavirus–related and human papillomavirus–unrelated head and neck cancer in the United States
Abstract
Background
The increasing incidence of human papillomavirus (HPV)–related head and neck cancer (HNC) has led to the increasing prevalence of survivors, yet to the best of the authors' knowledge the prevalence of comorbidities during the survivorship period and their effects on survival are relatively unknown.
Methods
In this retrospective cross‐sectional study, individuals with a first incident primary diagnosis of HNC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)–Medicare‐linked databases were included in the analysis and classified as patients with HPV‐related or HPV‐unrelated HNC. The presence of 30 comorbid conditions of interest was identified. Associations between comorbidity and treatment group as well as overall survival were evaluated.
Results
The study population consisted of 8025 patients with HPV‐unrelated HNC and 2499 patients with HPV‐related HNC. Hypertension, congestive heart failure, cerebrovascular disease, and chronic obstructive pulmonary disease all were found to be highly prevalent at the time of the cancer diagnosis and increased over time for both groups. These comorbidities were found at significantly lower rates in the HPV‐related HNC population, yet were associated with an increased risk of death in both groups. The probabilities of developing cancer‐related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in both groups after treatment but were more likely in patients with HPV‐related HNC. In both groups of patients, the presence of each comorbidity either at the time of diagnosis or during survivorship was associated with a significantly increased risk of death.
Conclusions
There is a large burden of comorbidities in both patients with HPV‐related and HPV‐unrelated HNC, both of which are associated with decreased survival. Oncologic surveillance should not be limited to the evaluation of disease status, but also should include screening for the highly prevalent conditions associated with the risk of death.
https://ift.tt/2QL6br2
FISHing for the Miracle of Eicosapentaenoic Acid
New England Journal of Medicine, Ahead of Print.
https://ift.tt/2PzBFDJ
Challenges in Assessing the Sunscreen‐Melanoma Association
Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen‐melanoma association in humans to 28.02.2018. We then used random‐effects meta‐analysis to combine estimates of the association, stratified by study design. Stratified meta‐analysis and meta‐regression were used to identify sources of heterogeneity. We included 21'069 melanoma cases from 28 studies published 1979‐2018: 23 case‐control (11 hospital‐based, 12 population‐based), 1 ecological, 3 cohort and 1 randomized controlled trial (RCT). There was marked heterogeneity across study designs and among case‐control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates towards decreased melanoma risk amongst sunscreen users. Ever‐ vs. never‐use of sunscreen was inversely associated with melanoma in hospital‐based case‐control studies (adjusted odds ratio (OR)=0.57, 95%confidence interval (CI) 0.37‐0.87, pheterogeneity<0.001), the ecological study (rate ratio=0.48, 95%CI 0.35‐0.66), and the RCT (hazard ratio (HR)=0.49, 95%CI 0.24‐1.01). It was not associated in population‐based case‐control studies (OR=1.17, 95%CI 0.90‐1.51, pheterogeneity<0.001) and was positively associated in the cohort studies (HR=1.27, 95%CI 1.07‐1.51, pheterogeneity=0.236). The association differed by latitude (pinteraction=0.042), region (pinteraction=0.008), adjustment for naevi/freckling (pinteraction=0.035), and proportion of never‐sunscreen‐users (pinteraction=0·012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen.
This article is protected by copyright. All rights reserved.
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Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U‐CLL). Subset #6 (IGHV1‐69/IGKV3‐20) is less aggressive compared to subset #8 (IGHV4‐39/IGKV1(D)‐39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome‐wide DNA methylation profiles in subsets #6 and #8 as well as other U‐CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U‐CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional non‐subset U‐CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro‐survival effect was also supported by siRNA‐mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.
This article is protected by copyright. All rights reserved.
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FISHing for the Miracle of Eicosapentaenoic Acid
New England Journal of Medicine, Ahead of Print.
https://ift.tt/2PzBFDJ
Risk Factors for 1-Year Mortality and Hospital Utilization Patterns in Critical Care Survivors: A Retrospective, Observational, Population-Based Data Linkage Study
https://ift.tt/2K9xHMg
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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