\Unlike most transmembrane proteins, phospholipids can migrate from one leaflet of the membrane to the other. Because this spontaneous lipid translocation (flip-flop) tends to be very slow, cells facilitate the process with enzymes that catalyze the transmembrane movement and thereby regulate the transbilayer lipid distribution. Non-enzymatic membrane-spanning proteins with unrelated primary functions have also been found to accelerate lipid flip-flop in a non-specific manner and by various hypothesized mechanisms.
http://bit.ly/2sJi1aN
Πέμπτη 24 Ιανουαρίου 2019
Gramicidin increases lipid flip-flop in symmetric and asymmetric lipid vesicles
Cooperative changes in solvent exposure identify cryptic pockets, switches, and allosteric coupling
Proteins are dynamic molecules that undergo conformational changes to a broad spectrum of different excited states. Unfortunately, the small populations of these states make it difficult to determine their structures or functional implications. Computer simulations are an increasingly powerful means to identify and characterize functionally-relevant excited states. However, this advance has uncovered a further challenge: it can be extremely difficult to identify the most salient features of large simulation datasets.
http://bit.ly/2sIPodN
Influenza Hemagglutinin Modulates , Phosphatidylinositol(4,5)bisphosphate Membrane Clustering
The lipid phosphatidylinositol-4,5-bisphosphate (PIP2) forms nanoscopic clusters in cell plasma membranes; however, the processes determining PIP2 mobility and thus its spatial patterns are not fully understood. Using super-resolution imaging of living cells, we find that PIP2 is tightly colocalized with and modulated by overexpression of the influenza viral protein hemagglutinin (HA). Within and near clusters, HA and PIP2 follow a similar spatial dependence, which can be described by an HA-dependent potential gradient; PIP2 molecules move as if they are attracted to the center of clusters by a radial force of 0.079±0.002 pN in HAb2 cells.
http://bit.ly/2Mw4WL5
The Value of Prognostic Nutritional Index in Follicular Lymphoma
Objectives: Previous studies reported that prognostic nutritional index (PNI), a marker of host inflammatory and nutritional status, is associated with prognoses in a number of cancer types. Thus, we investigated PNI at diagnosis as a prognostic factor in FL. Methods: We reviewed FL patients in Tuen Mun Hospital, Hong Kong from 2000 to 2014 (n=88). PNI was calculated by serum albumin (g/L)+5×absolute lymphocyte count (109/L). We determined the best PNI cut-off value using receiver-operating characteristic curves. The extent to which progression-free survival (PFS) and overall survival differed by PNI cut-off was assessed using Kaplan-Meier and log-rank tests. Cox proportional hazards model was utilized to adjust for covariates. Results: The best cut-off value for PNI was determined to be 45. Patients with high PNI (>45) had a higher complete response (CR) rate after primary treatment, 46 of 61 (75.4%) patients with high PNI had CR, compared with 10 of 23 (43.5%) for low PNI (2-sample test of proportions P-value=0.006). Further, higher PNI at relapse as a continuous variable was associated with superior postprogression survival with a hazard ratio (HR) 0.88 (95% confidence interval [CI], 0.81-0.96). In multivariate analysis, high PNI at diagnosis had superior PFS (adjusted HR of 0.37; 95% CI, 0.15-0.93). Conclusions: PNI was shown to be independent prognostic factor of PFS in FL. It is a cheap and widely available biomarker. Future study is needed to validate its prognostic value and clinical utility in a prospective cohort.http://bit.ly/2RLY8yG
How to Optimize Cancer Treatment in Older Patients: An Overview of Available Geriatric Tools
Cancer is a disease of older people, but this age group has often been excluded from clinical trials of cancer, which leads to poor transportability of standardized treatments in older cancer patients. One of the main reasons for the exclusion is the heterogeneity of older people in several domains: social environment, comorbidities, dependency, functional status, nutritional status, cognition status, and mood status. Comprehensive geriatric assessment aims to assess this heterogeneity and has identified frequent health problems often unknown before therapeutic decisions, which allows for targeted geriatric interventions with or without follow-up and appropriate cancer treatment selection. Several tools and scores have been developed for a complementary approach. These tools have the following characteristics: they screen for vulnerability to select patients who may benefit from a comprehensive geriatric assessment; are predictive tools for survival, postoperative complications, or chemotherapy-related toxicity; are decisional algorithms for cancer treatment; or define a core set of geriatric data to be collected in clinical cancer trials. Here, we present an overview of the geriatric tools that were published in PubMed from 2000 to 2017, that could help in the therapeutic decision-making for older cancer patients.http://bit.ly/2CKQ5rC
Accelerated Hypofractionated Radiation Therapy for Elderly Frail Bladder Cancer Patients Unfit for Surgery or Chemotherapy
Purpose/Objectives: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. Materials and Methods: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. Results: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). Conclusions: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT.http://bit.ly/2RNJYNt
MGMT Testing in Glioblastomas: Pitfalls and Opportunities
Gliomas, that do not respond to alkylating agent chemotherapy, can be made more sensitive to chemotherapy through promotor mediated epigenetic silencing of the MGMT gene. MGMT is one of the important markers in glioblastomas as it not only predicts response to therapy but may also be used as an independent prognostic marker. As such, MGMT is gaining increasing traction in diagnosis, prognostication, and therapeutic decision-making for these highly malignant gliomas. Although, MGMT promotor methylation status is becoming more commonly used in neuro-oncology; this test remains imperfect. Because of its increasing use in clinical practice and research, it is integral that we are aware of its pitfalls and complications. Currently, there are many ways to detect a patient's MGMT promotor methylation status, including: quantitative PCR, methylation-specific PCR, pyrosequencing, real time PCR with high resolution melt, and the infinitum methylation EPIC beadChip. The technical aspects, shortcomings, and optimal approach to interpreting the results of each method will be discussed. Furthermore, given that none of these methods have been prospectively validated, the challenge of equivocal cases will be discussed, and technical and logistic strategies for overcoming these challenges will be proposed. Finally, the difficulty in validating these methods, establishing standardized practice, and considerations of the cost of these competing methods will be explored.http://bit.ly/2CHOzXh
Role of Stereotactic Body Radiation Therapy in Early Stage Small Cell Lung Cancer in the Era of Lung Cancer Screening: A Systematic Review
With the obvious benefit from low dose computed tomography to reduce the lung cancer-specific mortality, lung cancer screening is on the rise. With the implementation of the screening programs, diagnosis of early stage lung cancer is expected to increase, and small cell lung cancer (SCLC) would account for 10% of screen-detected lung cancer. Apart from Concurrent chemoradiation (CRT), the present guidelines virtually do not support other options for radiation (RT). There is a paucity of data addressing the role of Stereotactic Body Radiation Therapy (SBRT) in SCLC and we conducted the current systematic review on this topic. We systematically searched literature using the electronic databases PubMed and Embase with no language, year or publication status restrictions. After removal of duplicate records, 3469 screened, 3446 excluded with reasons, 23 full-text articles were assessed for eligibility, and 7 studies (8 reports) were included. Unsuitability for surgery or refusal for surgery was the most common reason for the use of SBRT in early stage SCLC in the included studies. Variable patterns of SBRT—chemotherapy (CT) sequencing including concurrent, pre-CT and post-CT and radiation doses were noted. Within the reported studies overall survival (OS) at 1 year, 2 year and 3 year varied from 63% to 87%, 37% to 72%, and 35% to 72%, respectively. Distant metastasis was the most common pattern of failure ranging from 38% to 53%. There was no increase in the reported grade III toxicity. SBRT could be a potential option in stage I SCLC with comparable outcomes with no added toxicity. Acknowledging the limitations and absence of high-quality data, presently cautious interpretation is warranted and further studies are needed to establish the role of SBRT in SCLC.http://bit.ly/2CFIbzE
Identification of Adenosquamous Carcinoma as a Rare Aggressive HER2-negative Subgroup of Esophageal/Gastroesophageal Junction Adenocarcinoma
Background: Our purpose was to evaluate the prognostic impact of pathologically confirmed esophageal adenosquamous carcinoma (ASC) and its association with HER2 status and clinicopathologic characteristics. Methods: Among 796 patients with esophageal or gastroesophageal junction adenocarcinoma who underwent curative resection, surgical pathology reports were reviewed, and suspected ASC was confirmed utilizing p63 and CK5/6 immunostaining. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization. Cox models were used to assess the impact of ASC on disease-specific survival and overall survival. Results: Overall, 2.0% (16/796) of patients had esophageal ASC, mostly demonstrating a close intermingling of squamous and adenocarcinoma cells within the same tumor. The percentage of squamous versus adenocarcinoma cells in the primary was generally recapitulated in nodal metastases, and intrapatient internodal heterogeneity was uncommon. Patients with esophageal ASC were statistically significantly more likely to be female (vs. male), have normal (vs. excess) body mass index, and harbor HER2-negative (vs. positive) tumors, as compared with patients with adenocarcinoma only. No ASC tumor was HER2-positive as compared with 16% of adenocarcinoma only tumors (P=0.018). Compared with patients with adenocarcinoma only, those with ASC demonstrated profoundly worse disease-specific survival (5-year event-free rate, 34% vs. 6%; multivariate hazard ratio, 2.87 [95% confidence interval, 1.59-4.76]; P=0.0010) and overall survival (P=0.0027) that was independent of known prognostic factors and HER2 status. Conclusion: ASC identifies a rare aggressive HER2-negative subgroup of esophageal/gastroesophageal junction adenocarcinoma.http://bit.ly/2RKOuwd
A Simplified Risk Stratification Method for Women With Stage I Endometrial Carcinoma
Objectives: Available risk stratification methods for women with endometrial carcinoma are controversially defined. We sought to develop a simplified and an individualized prognostic index for cancer recurrence in women with International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial carcinoma, solely of endometrioid histology. Materials and Methods: We identified 976 women who underwent a hysterectomy and did not receive any adjuvant therapy. Cox proportional hazards model was used to identify independent predictors of recurrence. Prognostic groups were created based on the number of independent predictors of recurrence (0, 1, or 2 or 3 risk factors). These groups were then validated using a separate cohort of 611 women treated at another academic institution. The model's performance for predicting cancer recurrence was measured by the concordance probability estimate along with a 95% confidence interval. Results: Median follow-up was 65 months. The final recurrence model included 3 risk groups based on 3 independent predictors of recurrence (tumor grade 2 or 3, the presence of lymphovascular space invasion and stage IB). Five-year recurrence rates were 4%, 16%, and 44% for groups 0, 1, and 2 or 3, respectively. The performance of the model was very good with a concordance probability estimate of 0.72 and 0.80 for the development and validation cohorts, respectively. Conclusions: On the basis of 3 well-known prognostic factors, we have developed and externally validated a simplified prognostic model that accurately predicts cancer recurrence in women with stage I endometrial carcinoma. This simplified predictive tool may be helpful in estimating individualized risk of recurrence and guide counseling with regard to adjuvant treatment.http://bit.ly/2CJohnk
Prospective Evaluation of Multinational Association of Supportive Care in Cancer Risk Index Score for Gynecologic Oncology Patients With Febrile Neutropenia
Background: The Multinational Association of Supportive Care of Cancer (MASCC) risk-index score has been validated as a stratification tool for febrile neutropenia (FN) risk in a heterogeneous group of cancer patients; recently, it has been deemed a suitable tool in gynecologic oncology patients in a retrospective study. This is a prospective multi-institutional study wherein we sought to validate MASCC score for stratifying FN morbidity in gynecologic oncology patients. Methods: IRB approval was obtained at 4 institutions for prospective data collection of gynecologic cancer patients admitted with FN from 3/1/2013 to 9/1/2014. Participating institutions have a policy of inpatient management of FN patients receiving chemotherapy. Deidentified data was compiled and processed at the leading institution. Results: In total, 31 patients met inclusion criteria. Most had advanced stage disease (67%). 100% of patients were receiving chemotherapy (57% for primary, 43% for recurrent disease). 55% had a positive culture. Median MASCC score was 21 (range, 10 to 26); 58% of patients were considered low risk. High risk patients more often had one (11% vs. 38%, P=0.09) or multiple (6% vs. 23%, P=0.28) severe complications, ICU admission (0% vs. 15%, P=0.17), and delay in next chemotherapy cycle (33% vs. 54%, P=0.25). No patients died from FN during the study period. Conclusions: This pilot data suggests that MASCC score may be a promising tool for determining suitability of outpatient management of FN in gynecologic oncology patients. Larger studies are warranted to achieve statistically significant results, which may enable us to effectively utilize this risk stratification tool for cost containment and avoidance of nosocomial infections.http://bit.ly/2CK08Nn
Contemporary Approaches to High-risk, Early-Stage Serous Endometrial Cancer: Clinical Equipoise Persists
No abstract availablehttp://bit.ly/2RMp7do
Factors Affecting Racial Disparities in End-of-Life Care Costs Among Lung Cancer Patients: A SEER-Medicare–based Study
Objectives: Racial disparities exist in end-of-life lung cancer care, which could potentially lead to considerable racial differences in end-of-life care costs. This study for the first time estimates the racial differences in end-of-life care costs among lung cancer patients, and identifies and quantifies factors that contribute the most to these differences using a statistical decomposition method. Methods: This is a retrospective analysis of patients 66 years and older, diagnosed with stage I-IV lung cancer, who died on or before December 31, 2013, using the Surveillance Epidemiology and End Result-Medicare data from 1991 to 2013. Ordinary least square regression of logarithmically transformed cost was used to estimate racial differences in end-of-life care costs among lung cancer patients. Blinder-Oaxaca decomposition was used to identify and quantify factors that contributed the most to these differences. Results: Non-Hispanic blacks had 10% to 13% higher end-of-life care costs as compared with non-Hispanic whites. Geographic variations, baseline comorbidity indices and stage at diagnosis contributed the most to explaining the racial differences in costs, with geographic variation explaining most of the differences. However, the observed factors could only explain 25% to 32% of the racial differences in end-of-life care costs. Conclusions: Geographic differences in access to timely and appropriate care, and provider practice patterns, should be examined to understand the reasons behind geographic variations in racial disparity. Provider-level educational interventions to reduce small area practice variations and differential management of patients by race, as well as racially sensitive patient-level educational and navigational interventions might be critical in improving quality of care and reducing costs during end-of-life.http://bit.ly/2CIA5Gs
A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients
Objectives: Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies. Materials and Methods: Patients received gemcitabine 1000 mg/m² intravenously on days 1 and 8, capecitabine 1300 mg/m² oral daily from day 1 to 14, and dovitinib oral daily 5 days on and 2 days off, every 21-day cycle. The standard 3+3 dose escalation design was utilized and the study expanded to treat an additional 20 advanced pancreatic and biliary tract cancers patients at MTD. Results: A total of 29 patients were enrolled. One patient experienced dose-limiting grade 3 colitis. Two patients developed clinically significant neuropathy after the first cycle requiring dose reduction. The MTD was not reached and dovitinib 300 mg was declared the recommended dose for expansion. The most frequent grade 2 or worse adverse events were fatigue (45%), neutropenia (41%), thrombocytopenia (34%), anemia (24%), nausea (24%), and palmer-plantar erythrodysaesthesia syndrome (21%). Partial responses were observed in 5 patients. Pharmacokinetic studies showed no drug-drug interaction between dovitinib, capecitabine and gemcitabine. Fibroblast growth factor 23 plasma level increased in 4 of 5 patients during the first cycle of treatment. Conclusions: Dovitinib 300 mg daily is the recommended dose when combined with gemcitabine and capecitabine, achieving clinically relevant plasma concentrations. The study combination demonstrated encouraging efficacy signals in advanced pancreatic cancer.http://bit.ly/2RMp4hI
Management of Unresectable T4b Esophageal Cancer: Practice Patterns and Outcomes From the National Cancer Data Base
Purpose: Patients with unresectable cT4b esophageal cancer (EC) are rare and largely excluded from prospective trials. As a result, current treatment recommendations are based on limited evidence. This study sought to evaluate national practice patterns and outcomes for this population and evaluated 3 primary cohorts: patients receiving chemotherapy (CT) with or without subtherapeutic radiotherapy (RT), definitive chemoradiotherapy (CRT), or CT with or without RT followed by definitive surgery. Materials and Methods: The National Cancer Data Base was queried for cT4b Nany M0 EC. Exclusion criteria were patients with unspecified staging, palliative treatment, improper, or no histologic confirmation, or lack of CT. Multivariable logistic regression determined factors predictive of receiving surgical therapy. Kaplan-Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Results: Altogether, 519 patients met inclusion criteria; 195 (38%) underwent CT, 291 (56%) underwent definitive CRT, and 33 (6%) underwent surgical-based therapy. Surgery was more likely performed in patients residing in rural areas, living farther from the treating facility, and N1 status (Phttp://bit.ly/2CLmzSi
Outcomes and Characteristics of Patients Receiving Second-line Therapy for Advanced Pancreatic Cancer
Objectives: There is limited randomized data to guide second-line chemotherapy selection in advanced pancreatic cancer (APC). We aimed to characterize predictors and outcomes of second-line chemotherapy in patients with APC. Methods: We identified all patients with APC [locally advanced (LAPC) or metastatic (MPC)] who received ≥1 cycle of first-line chemotherapy between January 2012 and December 2015 across 6 cancer centers in British Columbia, Canada. Baseline characteristics and survival outcomes were summarized. Results: Of 676 patients with APC (31% LAPC, 69% MPC) who received ≥1 cycle of chemotherapy, 164 (24%) received second-line chemotherapy. These patients were younger, with lower ECOG and higher CA19-9 at presentation, compared with patients who did not receive second-line chemotherapy. There were no differences in rates of second-line chemotherapy between LAPC and MPC (28% vs. 23%; P=0.18). Only first-line FOLFIRINOX was associated with second-line chemotherapy. Median overall survival (OS) from second-line chemotherapy was longer with second-line gemcitabine/nab-paclitaxel than fluoropyrimidine or gemcitabine (7.9 vs. 5.1 vs. 4.3 mo; P=0.008). On multivariable analysis, longer OS from second-line chemotherapy was associated with gemcitabine/nab-paclitaxel, lower ECOG, and LAPC. Conclusions: In this population-based cohort, first-line FOLFIRINOX was the strongest predictor of second-line chemotherapy. Duration of therapy remains short and novel treatments are urgently needed.http://bit.ly/2RMp15w
An Evaluation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) Staging System for Retroperitoneal Sarcomas Using the National Cancer Data Base (NCDB): Does Size Matter?
Objectives: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the seventh edition AJCC size classification of 15 cm). We evaluated the prognostic ability of the eighth edition using the National Cancer Database (NCDB). Methods: Patients with RPS treated between 1998 and 2011 were identified from the NCDB; overall survival (OS) was compared. Results: Of the 6427 patients identified, 9% had tumors ≤5 cm (n=580), 19.4% 515 cm (n=3045). With the eighth edition, stage II patients (G2/3 ≤5 cm) have a similar OS to stage IIIA patients (G2/3 5 cm10 cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR, 1.004; P=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR, 1.3; Phttp://bit.ly/2CTIhE7
miR‐30e‐5p as predictor of generalization in ocular myasthenia gravis
Abstract
Objective
To determine a predictive factor for the risk of conversion from ocular myasthenia gravis (OMG) to generalized MG (GMG) in a prospective study.
Methods
RNA was isolated from serum samples and detection of microRNA (miRNA) expression analyzed with qPCR. In the discovery set, 179 human miRNAs were assayed for profiling of five OMG patients and four age‐ and gender‐matched healthy controls. Based on the specific accumulation pattern of 19 miRNAs from the discovery set, in addition to miRNAs previously found elevated in generalized MG (GMG; miR‐150‐5p and miR‐30e‐5p), 21 miRNAs were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow‐up visit (median duration 28 months from first visit).
Results
Thirteen patients generalized 14.8 ± 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two miRNAs were significantly higher in secondary GMG (SGMG) patients compared to OMG patients with late onset MG: miR‐30e‐5p (9.1 ± 0.5 vs. 6.3 ± 0.9; P < 0.0001) and miR‐150‐5p (7.4 ± 1.1 vs. 6.4 ± 1.1; P = 0.01). The sensitivity for miR‐30e‐5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients.
Interpretation
This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG. Raised levels (>8) of miR‐30e‐5p at initial presentation in patients with ocular MG symptoms, give a predictive cut‐off for subsequent generalization of 96–100%.
http://bit.ly/2MxAdgv
miR-424-5p Regulates Hepatoma Cell Proliferation and Apoptosis
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
http://bit.ly/2FVdYQt
Imaging of HER2 with [89Zr]pertuzumab in Response to T-DM1 Therapy
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
http://bit.ly/2FMfy7R
Robotic Simulations, Simulations of Robots
Abstract
Simulation studies have been carried out in robotics for a variety of epistemic and practical purposes. Here it is argued that two broad classes of simulation studies can be identified in robotics research. The first one is exemplified by the use of robotic systems to acquire knowledge on living systems in so-called biorobotics, while the second class of studies is more distinctively connected to cases in which artificial systems are used to acquire knowledge about the behaviour of autonomous mobile robots. The two classes pertain to sub-areas of robotics which are apparently quite distant from one another in terms of goals, methodologies, technologies, and theoretical backgrounds. Still both are concerned with building, running, and experimenting on simulations of other systems. This paper aims to reveal and discuss some methodological commonalities between the two classes of studies. Philosophical literature on simulation methodologies has been traditionally focused on studies carried out in research fields other than robotics: this article may therefore contribute to shedding light on how the concept of simulation is used in robotics, and on the role simulation methodologies play in this research field.
http://bit.ly/2T8yWz6
Pancoast tumour presenting as shoulder pain with Horners syndrome
A 54-year-old man presented to the emergency department with a 4-week history of right shoulder pain radiating down his arm, with some associated sensory loss. Further questioning and examination in the department revealed a classical Horner's syndrome; miosis, partial ptosis and hemifacial anhidrosis. An initial chest X-ray was deemed to be unremarkable; however, further review by a radiologist noted asymmetrical right apical thickening. A subsequent high-resolution CT scan of the chest revealed a right-sided Pancoast tumour. This case highlights the importance of a thorough history and examination in identifying a rare cause of shoulder and/or back pain.
http://bit.ly/2B0IaGE
Multiple foreign bodies in the facial region from a penetrating stab injury
Penetrating injuries can lead to multiple retained foreign bodies. To present a case of a penetrating stab injury on to the right orbital region of a 37-year-old woman which resulted in lacerations on both eyelids, loss of vision in addition to the retention of glass particle and woven artificial hair strands at the anterior end of the floor of the orbit. The woven artificial hair strand, being flexible in nature, was apparently logged in by the penetrating force of the broken glass used as the stab injury object. Under local anaesthesia, a gentle intermittent pull on one hair strand led to the dislodgement of a piece of broken glass particle along with the other end of the hair strand. The resultant wound was repaired. Stab injuries can result in retained multiple foreign bodies. This possibility should be considered during assessment and management of facial injuries to avoid complications of retention.
http://bit.ly/2TbUcnx
Tissue-Specific Transcriptome Analysis Reveals Candidate Genes for Terpenoid and Phenylpropanoid Metabolism in the Medicinal Plant Ferula assafoetida
Ferula assafoetida is a medicinal plant of the Apiaceae family that has traditionally been used for its therapeutic value. Particularly, terpenoid and phenylpropanoid metabolites, major components of the root-derived oleo-gum-resin, exhibit anti-inflammatory and cytotoxic activities, thus offering a resource for potential therapeutic lead compounds. However, genes and enzymes for terpenoid and coumarin-type phenylpropanoid metabolism have thus far remained uncharacterized in Ferula assafoetida. Comparative de novo transcriptome analysis of roots, leaves, stems, and flowers was combined with computational annotation to identify candidate genes with probable roles in terpenoid and coumarin biosynthesis. Gene network analysis showed a high abundance of predicted terpenoid- and phenylpropanoid-metabolic pathway genes in flowers. These findings offer a deeper insight into natural product biosynthesis in F. assafoetida and provide genomic resources for exploiting the medicinal potential of this rare plant.
http://bit.ly/2Dxsegt
The mir-35 Family Links Maternal Germline Sex to Embryonic Viability in Caenorhabditis elegans
The germline sex determination pathway in C. elegans determines whether germ cells develop as oocytes or sperm, with no previously known effect on viability. The mir-35 family of microRNAs are expressed in the C. elegans germline and embryo and are essential for both viability and normal hermaphroditic sex determination, preventing aberrant male gene expression in XX hermaphrodite embryos. Here we show that combining feminizing mutations with partial loss of function of the mir-35 family results in enhanced penetrance embryonic lethality that preferentially kills XO animals. This lethal phenotype is due to altered signaling through the germline sex determination pathway, and maternal germline feminization is sufficient to induce enhanced lethality. These findings reveal a surprising pleiotropy of sperm-fate promoting pathways on organismal viability. Overall, our results demonstrate an unexpectedly strong link between sex determination and embryonic viability, and suggest that in wild type animals, mir-35 family members buffer against misregulation of pathways outside the sex determination program, allowing for clean sex reversal rather than deleterious effects of perturbing sex determination genes.
http://bit.ly/2UiXXb1
Environmental and Evolutionary Drivers of the Modular Gene Regulatory Network Underlying Phenotypic Plasticity for Stress Resistance in the Nematode Caenorhabditis remanei
Organisms can cope with stressful environments via a combination of phenotypic plasticity at the individual level and adaptation at the population level. Changes in gene expression can play an important role in both. Significant advances in our understanding of gene regulatory plasticity and evolution have come from comparative studies in the field and laboratory. Experimental evolution provides another powerful path by which to learn about how differential regulation of genes and pathways contributes to both acclimation and adaptation. Here we present results from one such study using the nematode Caenorhabditis remanei. We selected one set of lines to withstand heat stress and another oxidative stress. We then compared transcriptional responses to acute heat stress of both and an unselected control to the ancestral population using a weighted gene coexpression network analysis, finding that the transcriptional response is primarily dominated by a plastic response that is shared in the ancestor and all evolved populations. In addition, we identified several modules that respond to artificial selection by (1) changing the baseline level of expression, (2) altering the magnitude of the plastic response, or (3) a combination of the two. Our findings therefore reveal that while patterns of transcriptional response can be perturbed with short bouts of intense selection, the overall ancestral structure of transcriptional plasticity is largely maintained over time.
http://bit.ly/2UgtUk9
Identification of Suppressor of Clathrin Deficiency-1 (SCD1) and Its Connection to Clathrin-Mediated Endocytosis in Saccharomyces cerevisiae
Clathrin is a major coat protein involved in vesicle formation during endocytosis and transport in the endosomal/trans Golgi system. Clathrin is required for normal growth of yeast (Saccharomyces cerevisiae) and in some genetic backgrounds deletion of the clathrin heavy chain gene (CHC1) is lethal. Our lab defined a locus referred to as "suppressor of clathrin deficiency" (SCD1). In the presence of the scd1-v allele ("v" - viable), yeast cells lacking clathrin heavy chain survive but grow slowly, are morphologically abnormal and have many membrane trafficking defects. In the presence of scd1-i ("i"- inviable), chc1 causes lethality. As a strategy to identify SCD1, we used pooled linkage analysis and whole genome sequencing. Here, we report that PAL2 (YHR097C) is the SCD1 locus. pal2 is synthetic lethal with chc1; whereas a deletion of its paralog, PAL1, is not synthetic lethal with clathrin deficiency. Like Pal1, Pal2 has two NPF motifs that are potential binding sites for EH domain proteins such as the early endocytic factor Ede1, and Pal2 associates with Ede1. Also, GFP-tagged Pal2p localizes to cortical patches containing other immobile phase endocytic coat factors. Overall, our data show that PAL2 is the SCD1 locus and the Pal2 protein has characteristics of an early factor involved in clathrin-mediated endocytosis.
http://bit.ly/2Dy5Q6K
Alarming lack of knowledge about antithrombotic therapy among patients with atrial fibrillation
ABSTRACT Large population campaigns have been conducted in Brazil to improve knowledge about the signs and symptoms of stroke and the importance of time to care. Objective: Parallel to these important actions, we aimed to evaluate the lay knowledge of patients with atrial fibrillation, a well-recognized etiology of stroke, adequate treatment and management of which can prevent up to 30% of cerebrovascular events. Methods: We questioned 143 patients with atrial fibrillation about the risks associated with the disease. Results: Ninety-one percent were on anticoagulation treatment. Of the total, 63.6% reported having been informed about the risks and benefits of anticoagulants but only 46.9% were able to correctly mention one of these risks. Ischemic stroke was identified as a risk by only 25.9% and hemorrhagic stroke was not mentioned. A CHADS2 ≥ 2 was scored by 84.0% of the patients. Conclusions: Our study showed an alarming knowledge gap in patients with atrial fibrillation. Difficulty in adherence to treatment resulting from the failure of this communication is possibly one of the factors responsible for the high incidence and recurrence of stroke, and should not go unnoticed.
RESUMO Campanhas populacionais para melhorar o conhecimento sobre os sinais e sintomas do acidente vascular encefálico e a importância do tempo para o tratamento têm sido realizadas no nosso país, visando a melhoria da linha do atendimento. Objetivo: Paralelamente a estas relevantes ações, objetivamos avaliar o conhecimento leigo de pacientes portadores de fibrilação atrial, etiologia determinada e prevalente do acidente vascular encefálico, cujo tratamento e manejo adequado podem prevenir até 30% dos eventos cerebrovasculares. Métodos: Entrevistamos portadores de fibrilação atrial sobre os riscos associados à doença. Resultados: Noventa e um por cento estavam sob uso de anticoagulantes. Do total, 63,6% responderam terem sido informados sobre riscos e benefícios da terapia anticoagulante, mas apenas 46,9% souberam citar corretamente um desses riscos. Acidente vascular encefálico isquêmico foi associado ao risco por apenas 25,9% e acidente vascular encefálico hemorrágico não foi mencionado. CHADS2 ≥ 2 foi pontuado por 84,0% dos pacientes. Conclusões: Nosso estudo demonstra uma alarmante falha no conhecimento do risco de acidente vascular encefálico nos portadores de fibrilação atrial. Dificuldade na aderência ao tratamento resultante da falha dessa comunicação é fator relevante na incidência e recorrência do acidente vascular encefálico e não deve ser negligenciado.
http://bit.ly/2RQH0Ib
Intracranial pressure following decompressive hemicraniectomy for malignant cerebral infarction: clinical and treatment correlations
ABSTRACT Decompressive craniectomy (DC) reduces mortality and improves outcome in patients with massive brain infarctions. The role of intracranial pressure (ICP) monitoring following DC for stroke has not been well established. Methods: We evaluated 14 patients admitted to a tertiary hospital with malignant middle cerebral artery infarctions, from October 2010 to February 2015, who underwent DC and had ICP monitoring. Patients with and without episodes of ICP elevation were compared. Results: Fourteen patients were submitted to DC and had ICP monitoring following the procedure during the period. Ten patients (71.4%) had at least one episode of sustained elevated ICP in the first seven days after surgery. Maximal ICP levels had no correlation with age, time to hemicraniectomy or Glasgow Coma Scores at admission, but had a trend toward correlation with the National Institutes of Health Stroke Scale score at admission (p = 0.1). Ventriculitis occurred in 21.4% of the patients. Conclusions: High ICP episodes and ventriculitis were common in patients following hemicraniectomy for malignant middle cerebral artery strokes. Therefore, the implications of ICP and benefits of the procedure should be firmly established.
RESUMO Craniectomia descompressiva (CD) reduz a mortalidade e melhora o desfecho em pacientes com infartos malignos de artéria cerebral média (ACM). O papel da monitorização da pressão intracraniana (PIC) após CD para infartos malignos de ACM não está bem estabelecido. Métodos: Avaliamos pacientes consecutivos internados em um hospital terciário com infartos malignos de ACM de outubro/2010 a fevereiro/2015 tratados com CD e submetidos à monitorização da PIC. Foram comparados pacientes com e sem episódios de elevação de PIC. Resultados: Quatorze pacientes (idade média 49,0 ± 12,4 anos, 42,9% do sexo masculino) foram avaliados. Dez pacientes (71,4%) tiveram pelo menos um episódio de elevação da PIC nos primeiros sete dias após a cirurgia. A PIC máxima média foi de 26,71 ± 11,64 mmHg. Os níveis máximos de PIC não apresentaram correlação com a idade, o tempo de hemicraniectomia ou com a pontuação na Escala de Coma de Glasgow na admissão, mas houve tendência a ser correlacionada com a pontuação da National Institutes of Health Stroke Scale na admissão (p = 0,1). Ventriculite ocorreu em 21,4% dos pacientes. Conclusões: Os episódios de aumento da PIC foram comuns em pacientes tratados com CD por infarto maligno de MCA e ventriculite foi evento adverso frequente nesses pacientes. Portanto, as implicações da monitorização da PIC sobre o resultado funcional, bem como os riscos e benefícios do procedimento, devem ser melhor estabelecidos.
http://bit.ly/2CGLuGW
Exclusion of mimics does not influence Willis-Ekbom disease diagnosis among recent medical graduates
ABSTRACT In view of the diagnostic challenge posed by restless legs syndrome/Willis-Ekbom disease (RLS/WED) to health professionals and the challenge of its recognition by patients, the diagnostic criteria have been revised and updated to facilitate identification of this disease. However, in a previous study, we found that self-diagnosis of RLS/WED depends on the very name used to describe the condition. Objective: To ascertain whether the presence of the fifth diagnostic criterion of the International Restless Legs Syndrome Study Group (IRLSSG), is necessary for RLS/WED diagnosis when the term "Willis-Ekbom disease" is used. Methods: We randomly distributed 705 forms to recent medical graduates, asking them to self-assess whether they had "Willis-Ekbom disease" (WED). In one questionnaire model, we excluded the fifth criterion suggested by the IRLSSG, while in the other, all five criteria were included. No forms contained the term RLS; only WED was used throughout. Results: Seven hundred and five recent medical graduates participated in the study. Among the 332 who received the form without the fifth criterion, 8 (2.41%) self-diagnosed as having WED (95%CI: 0.8%-4.1%). Of the 373 who received the form with all five of the 2014 IRLSSG criteria, 9 (2.41%) self-diagnosed as having WED (95%CI: 0.8%-4.0%) (p > 0.05). Conclusion: Our data show that presence of the fifth IRLSSG criterion did not influence self-diagnosis of WED among recent medical graduates, suggesting that the name WED reduces the odds of mimics (confounding conditions) being misinterpreted as symptoms of this disease. This finding indicates that for the diagnosis of RLS/WED only four criteria and a systematic use of the name WED are necessary.
RESUMO Frente ao desafio diagnóstico da síndrome das pernas inquietas/doença de Willis-Ekbom (SPI/DWE) pelos profissionais de saúde e também seu reconhecimento pelos pacientes, os critérios de diagnóstico vêm sendo revisados e atualizados para facilitar a identificação dessa doença, porém, em estudo anterior, observamos que o autodiagnóstico da SPI/DWE depende do próprio nome utilizado para descrevê-la. Objetivo: Verificar se a presença do quinto critério do International Restless Legs Syndrome Study Group (IRLSSG) é necessária para o diagnóstico da SPI/DWE quando utilizamos apenas a expressão/denominação DWE. Métodos: Distribuímos aleatoriamente 705 formulários solicitando a médicos recém-formados que avaliassem se eles tinham DWE. Em um tipo de questionário, excluímos o quinto critério diagnóstico sugerido pelo IRLSSG e no outro mantivemos os cinco critérios. Em nenhum formulário apresentamos o termo SPI, apenas DWE. Resultados: Setecentos e cinco médicos recém-formados participaram do estudo. Dentre os 332 médicos que receberam o formulário sem o quinto critério, 8 (2,41%) autodiagnosticaram-se com DWE (IC 95%: 0,8%-4,1%). Trezentos e setenta e três médicos receberam o formulário com os 5 critérios do IRLSSG (2014) e 9 (2,41%) autodiagnosticaram-se como tendo DWE (IC 95%: 0,8%-4,0%) (p > 0.05). Conclusão: Nossos dados mostraram que a presença do quinto critério do IRLSSG não influenciou a realização do autodiagnóstico da DWE entre médicos recém-formados, sugerindo que a denominação DWE reduz a chance de condições confundidoras serem tomadas como sintomas desta doença. Este achado está de acordo com dados anteriores, onde mostramos que o autodiagnóstico da SPI/DWE é dependente da denominação utilizada para descrever a doença.
http://bit.ly/2RQH0rF
Epidemiological and clinical aspects of a sample of Brazilian patients with primary dystonia and the impact of the new classification on their clinical evaluation
ABSTRACT Dystonia is a relatively common movement disorder but some of its epidemiological and clinical aspects have not been well characterized in Brazilian patients. Also, a new clinical classification for the disorder has been proposed and its impact on clinical practice is unclear. We aimed to describe the clinical and demographic characteristics of a Brazilian series of patients with primary dystonia, to estimate its local prevalence, and to explore the impact of using a new classification for dystonia. We identified 289 patients with primary dystonia over a 12-month period, of whom235 underwent a detailed evaluation. Patients with primary dystoniamade up one-sixth of all patients evaluated at the service where the study was conducted, with an estimated local prevalence of 19.8/100,000 inhabitants. The clinical and demographic characteristics of the patients were similar to those described elsewhere, with blepharospasm as the most common focal dystonia and most patients using sensory tricks that they judged useful on a day-to-day basis. The application of the new classification was easy and simple, and the systematic approach allowed for a better clinical characterization of our patients. We recognized two dystonic syndromes that were not described in the original article that proposed the classification, and suspected that the arbitrary distinction between generalized and multifocal dystonia seems not to be useful for patients with primary dystonia. In conclusion, the prevalence and clinical characteristics of our patients were not distinct from other studies and the new classification was shown to be practical and useful to characterize patients with dystonia.
RESUMO A distonia é um distúrbio de movimento relativamente comum e alguns de seus aspectos epidemiológicos e clínicos ainda não foram bem caracterizados em pacientes brasileiros. Além disso, uma nova classificação clínica para o transtorno foi proposta e seu impacto na prática clínica não é claro. Nosso objetivo é descrever as características clínicas e demográficas de uma série brasileira de pacientes com distonia primária, estimar sua prevalência local e explorar o impacto do uso de uma nova classificação para distonia. Foram identificados 289 pacientes com distonia primária (PDYS) durante um período de 12 meses, dos quais 235 foram submetidos a uma avaliação detalhada. Os pacientes com PDYS corresponderam a um sexto de todos os pacientes avaliados no serviço em que o estudo foi realizado, com uma prevalência local estimada de 19,8/100.000 habitantes. As características clínicas e demográficas dos pacientes foram semelhantes àquelas descritas em outros locais, com o blefaroespasmo como distonia focal mais comum e a maioria dos pacientes apresentando truques sensoriais que julgaram úteis no dia-a-dia. A aplicação da nova classificação foi fácil e simples, e a abordagem sistemática permitiu uma melhor caracterização clínica de nossos pacientes. Reconhecemos duas síndromes distônicas que não foram descritas no artigo original que propôs a classificação e suspeitamos que a distinção arbitrária entre distonia generalizada e multifocal parece não ser útil para pacientes com PDYS. Em conclusão, a prevalência e as características clínicas de nossos pacientes não foram distintas de outras amostras e a nova classificação mostrou-se prática e útil para caracterizar pacientes com distonia.
http://bit.ly/2CFmOOW
Restless legs syndrome in end-stage renal disease patients undergoing hemodialysis
ABSTRACT Restless legs syndrome (RLS) is a frequent complication of hemodialysis that has been associated with poor quality of life and increased risk for complications. Nevertheless, few studies regarding this entity exist in resource-limited settings. Objectives: To determine the prevalence of RLS among Mexican patients on hemodialysis; and compare these patients with a control group of the same population. Methods: We recruited 105 hemodialysis patients. Restless legs syndrome was diagnosed according to the updated criteria set out by the International RLS Study Group. We selected patients who did not meet the criteria, as controls. Results: We found an RLS prevalence of 18%. The RLS patients had a significantly higher prevalence of iron deficiency anemia and uremic pruritus. None of the patients reported RLS symptoms prior to hemodialysis initiation. Conclusions: Restless legs syndrome is common among Mexican patients on hemodialysis. Larger studies are required to address the impact of RLS in hemodialysis patients.
RESUMEN El síndrome de piernas inquietas (SPI) es una complicación de la hemodiálisis que se ha asociado con menor calidad de vida y riesgo aumentado de complicaciones. Sin embargo, existen pocos estudios acerca de esta entidad en escenarios de recursos limitados. Objetivos: Determinar la prevalencia de SPI en pacientes mexicanos en hemodiálisis, y comparar las características con un grupo control de la misma población. Métodos: Reclutamos 105 pacientes en hemodiálisis. El SPI se diagnosticó de acuerdo con los criterios actualizados del grupo de estudio internacional del síndrome de piernas inquietas. Seleccionamos a los pacientes que no cumplieron dichos criterios como controles. Resultados: Encontramos una prevalencia de SPI del 18%. Los pacientes con SPI tenían una prevalencia más alta de anemia ferropénica, y prurito urémico. Ninguno de los pacientes reportó síntomas de SPI previo a iniciar la hemodiálisis. Conclusiones: El SPI es frecuente en pacientes mexicanos en hemodiálisis; se requieren estudios más grandes para evaluar el impacto del síndrome en ésta población.
http://bit.ly/2RMtJQJ
Genes related to maintenance of autophagy and successful aging
ABSTRACT Considering aging as a phenomenon in which there is a decline in essential processes for cell survival, we investigated the autophagic and proteasome pathways in three different groups: young, older and oldest old male adults. The expression profile of autophagic pathway-related genes was carried out in peripheral blood, and the proteasome quantification was performed in plasma. No significant changes were found in plasma proteasome concentrations or in correlations between proteasome concentrations and ages. However, some autophagy- and/or apoptosis-related genes were differentially expressed. In addition, the network and enrichment analysis showed an interaction between four of the five differentially expressed genes and an association of these genes with the transcriptional process. Considering that the oldest old individuals maintained both the expression of genes linked to the autophagic machinery, and the proteasome levels, when compared with the older group, we concluded that these factors could be considered crucial for successful aging.
RESUMO Considerando o envelhecimento como um fenômeno em que há um declínio nos processos essenciais a sobrevivência celular, investigamos as vias autofágica e proteassômica em três grupos: jovens, idosos e longevos. O perfil de expressão dos genes relacionados à via autofágica foi analisado em sangue periférico, e a quantificação do proteassoma realizada em plasma. Não foram encontradas alterações significativas nas concentrações plasmáticas de proteassoma ou na correlação entre as concentrações de proteassoma e as idades. No entanto, alguns genes relacionados a autofagia e / ou apoptose foram expressos diferencialmente. Além disso, as análises de rede e de enriquecimento mostraram uma interação entre quatro dos cinco genes diferencialmente expressos e a associação desses ao processo transcricional. Considerando que os indivíduos longevos mantiveram tanto a expressão de genes ligados à maquinaria autofágica, quanto os níveis de proteassoma quando comparados aos idosos, concluímos que esses fatores poderiam ser considerados cruciais para o envelhecimento bem-sucedido.
http://bit.ly/2CGLjLM
Apomorphine in the treatment of Parkinson's disease: a review
ABSTRACT Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.
RESUMO A optimização do tratamento da doença de Parkinson idiopática se faz um desafio, pois tem impacto direto na qualidade de vida do paciente. O melhor esquema terapêutico é o que permite o melhor controle motor com os menores efeitos adversos, através de terapêutica individualizada. A apomorfina é o único medicamento antiparkinsoniano que pode ser comparável à potência da levodopa no controle dos sintomas motores. Trata-se de um agonista dopaminérgico empregado na terapia de resgate em pacientes com flutuações motoras e também contribui para a melhora de muitos sintomas não motores. A via subcutânea, com injeções intermitentes, ou com infusão contínua, parece ser a melhor opção pela eficácia e tolerabilidade. Essa revisão resume aspectos históricos, estrutura da molécula, mecanismo de ação, indicação, contra-indicação e efeitos colaterais, compara a terapia de infusão com apomorfina com outros tratamentos, como a terapia oral, estimulação cerebral profunda e infusão enteral contínua de levodopa/carbidopa gel, e fornece instruções práticas de como iniciar o tratamento.
http://bit.ly/2RMCIBu
The convergence of stroke and dementia
ABSTRACT Neurological disorders account for the most Disability Adjusted Life Years (DALY's) -of the Global Burden of Disease (10%). More than half of neurological DALY's result from the combination of stroke (42%) and dementia (10%). The two pose risk for each other and share the same predisposing factors. A stroke doubles the risk of dementia. The close interactions call for convergent approaches. Stroke and dementia also converge at the microscopic level. The neurovascular unit has emerged as a key organizational structure of the brain. Involvement of any of its elements affects all the others. Thus, neurodegeneration impairs the microcirculation and disturbances of the microcirculation accelerate neurodegeneration. Evolving technologies allow "in vivo" imaging of the usual mixture of vascular and neurodegenerative pathology of the elderly that makes them prone to stroke and dementia. Since they occur together, they should be prevented together with a multimodal approach of lifestyle changes and mechanistic therapeutic targets. The two fields are also converging at the policy level. The World Stroke Organization has updated its Proclamation to include potentially preventable dementias that has been endorsed by Alzheimer Disease International, The World Federation of Neurology, the American Academy of Neurology and 20 international, regional and national organizations. Those interested in stroke and those dealing with dementia should work together where they can, differ where they must, with the common aim of preventing jointly, both stroke and dementia.
RESUMO As doenças neurológicas são responsáveis pela maior parte dos Anos de Vida Ajustados por Incapacidade (DALY's) segundo o Estudo da Carga Global de Doença (10%). Mais da metade dos DALY's de origem neurológica resultam da combinação de acidente vascular cerebral-AVC (42%) e demência (10%). Estas duas condições representam risco uma para a outra e compartilham dos mesmos fatores predisponentes. Um AVC quase triplica o risco de demência. Esta grande interação demanda abordagens convergentes. AVC e demência também convergem em nível microscópico. A unidade neurovascular emergiu como estrutura de organização chave da saúde do cérebro. O envolvimento de qualquer um dos seus elementos afeta todos os outros. Desse modo, a neurodegeneração compromete a microcirculação, enquanto distúrbios da microcirculação aceleram a neurodegeneração. Novas tecnologias permitem a obtenção de imagens "in vivo" da combinação usual entre patologia vascular e neurodegenerativa de idosos, que os torna vulneráveis ao AVC e à demência. Como estas duas condições ocorrem associadas, devem ser prevenidas em conjunto, com uma abordagem multimodal que conjugue mudanças de hábitos de vida e alvos terapêuticos mecanísticos. Estes dois campos também estão convergindo no campo das políticas de saúde. A Organização Mundial do AVC atualizou sua Proclamação de modo a incluir demências potencialmente passíveis de prevenção, que foi endossada pela Associação Internacional da Doença de Alzheimer, pela Federação Mundial de Neurologia, pela Academia Americana de Neurologia, e por 20 outras organizações internacionais, regionais e nacionais. Os colegas interessados em AVC e aqueles que lidam com demência devem trabalhar juntos onde puderem, diferindo onde devem, com o objetivo comum da prevenção conjunta tanto do AVC quanto da demência.
http://bit.ly/2CO7kIm
The remarkable pioneering contribution of Gaspar Vianna to the study of the neuropathology of Chagas disease
ABSTRACT Gaspar Vianna is considered one of the great names in Medicine and Science in Brazil. Yet, little prominence has been given to his studies in Neuropathology. He was the first to describe, in 1911, the histopathology and pathogenesis of chagasic encephalitis in the acute phase of Chagas disease, as well as the intracellular life cycle of Trypanosoma cruzi. Over 100 years have elapsed and Gaspar Vianna's pioneering study remains an example of a meticulous and still up-to-date description of central nervous system involvement in the acute phase of Chagas disease.
RESUMO Gaspar Vianna é considerado um dos grandes nomes da Medicina e da Ciência no Brasil. Contudo, pouco destaque tem sido dado aos seus estudos em Neuropatologia. Ele foi o primeiro a descrever a histopatologia e a patogênese da encefalite chagásica na fase aguda da doença de Chagas, bem como o ciclo evolutivo intracelular do Trypanosoma cruzi, em 1911. Passados mais de 100 anos, o estudo pioneiro de Gaspar Vianna permanece como exemplo de descrição minuciosa e ainda atual do envolvimento do sistema nervoso central na fase aguda da doença de Chagas.
http://bit.ly/2RQGYA3
Persistent craniopharyngeal canal
ABSTRACT Gaspar Vianna is considered one of the great names in Medicine and Science in Brazil. Yet, little prominence has been given to his studies in Neuropathology. He was the first to describe, in 1911, the histopathology and pathogenesis of chagasic encephalitis in the acute phase of Chagas disease, as well as the intracellular life cycle of Trypanosoma cruzi. Over 100 years have elapsed and Gaspar Vianna's pioneering study remains an example of a meticulous and still up-to-date description of central nervous system involvement in the acute phase of Chagas disease.
RESUMO Gaspar Vianna é considerado um dos grandes nomes da Medicina e da Ciência no Brasil. Contudo, pouco destaque tem sido dado aos seus estudos em Neuropatologia. Ele foi o primeiro a descrever a histopatologia e a patogênese da encefalite chagásica na fase aguda da doença de Chagas, bem como o ciclo evolutivo intracelular do Trypanosoma cruzi, em 1911. Passados mais de 100 anos, o estudo pioneiro de Gaspar Vianna permanece como exemplo de descrição minuciosa e ainda atual do envolvimento do sistema nervoso central na fase aguda da doença de Chagas.
http://bit.ly/2CIBUDl
Disseminated necrotizing leukoencephalopathy
ABSTRACT Gaspar Vianna is considered one of the great names in Medicine and Science in Brazil. Yet, little prominence has been given to his studies in Neuropathology. He was the first to describe, in 1911, the histopathology and pathogenesis of chagasic encephalitis in the acute phase of Chagas disease, as well as the intracellular life cycle of Trypanosoma cruzi. Over 100 years have elapsed and Gaspar Vianna's pioneering study remains an example of a meticulous and still up-to-date description of central nervous system involvement in the acute phase of Chagas disease.
RESUMO Gaspar Vianna é considerado um dos grandes nomes da Medicina e da Ciência no Brasil. Contudo, pouco destaque tem sido dado aos seus estudos em Neuropatologia. Ele foi o primeiro a descrever a histopatologia e a patogênese da encefalite chagásica na fase aguda da doença de Chagas, bem como o ciclo evolutivo intracelular do Trypanosoma cruzi, em 1911. Passados mais de 100 anos, o estudo pioneiro de Gaspar Vianna permanece como exemplo de descrição minuciosa e ainda atual do envolvimento do sistema nervoso central na fase aguda da doença de Chagas.
http://bit.ly/2RMtN2V
BRCA Exchange Launches [News in Brief]
Open-access database provides one-stop shop for information on BRCA variants.
http://bit.ly/2B35wvf
Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment [Review]
Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specific molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profiling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical–pathologic features, may help improve risk stratification of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.
Significance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identification of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population.
http://bit.ly/2TkrBME
Ultrasensitive immunoprofiling of plasma extracellular vesicles identifies syndecan-1 as a potential tool for minimally invasive diagnosis of glioma
Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for non-invasive diagnosis of glioma. Experimental design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay (PEA)-based, ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n=82). Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high grade glioblastoma multiforme (GBM, WHO grade IV) and low grade glioma (LGG, WHO grade II) (AUC: 0.81; sensitivity: 71%; specificity: 91%). These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased post-operatively depending on extent of surgery. Conclusion: Our studies support the concept of circulating plEVs as a tool for non-invasive diagnosis and monitoring of gliomas, and should move this field closer to the goal of improving the management of cancer patients.
http://bit.ly/2B2KJrv
LIMS1 Promotes Pancreatic Cancer Cell Survival Under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation
Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by immunohistochemical staining and analysing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics. Results: LIMS1 expression was drastically elevated in PDAC. High LIMS1 level was associated with advanced TNM stage and poor prognosis of tumour patients. Increased LIMS1 expression was pivotal for tumour cells to survive in the oxygen-glucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signalling, while HIF1 transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumour growth. Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygen-glucose deprivation conditions and is a promising therapeutic target for cancer treatment.
http://bit.ly/2T9gk1D
Oestradiol measurement during fulvestrant treatment for breast cancer
Oestradiol measurement during fulvestrant treatment for breast cancer
Oestradiol measurement during fulvestrant treatment for breast cancer, Published online: 25 January 2019; doi:10.1038/s41416-019-0378-9
Oestradiol measurement during fulvestrant treatment for breast cancer
https://go.nature.com/2Wfc6HY
Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours
Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours
Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours, Published online: 25 January 2019; doi:10.1038/s41416-019-0377-x
Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours
https://go.nature.com/2ReFavk
Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance
Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance
Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance, Published online: 25 January 2019; doi:10.1038/s41416-019-0380-2
Diet quality and Gleason grade progression among localised prostate cancer patients on active surveillance
https://go.nature.com/2WddZ89
Flu-Like Illness Tied to Increased Relative Mortality in ESRD
THURSDAY, Jan. 24, 2019 -- Community activity for influenza-like illness (ILI) is associated with seasonal variation in all-cause mortality among patients with end-stage renal disease (ESRD), according to a study published online Jan. 24 in the...
http://bit.ly/2CFh8V8
Fried Chicken, Fish Linked to All-Cause, Cardiovascular Death
THURSDAY, Jan. 24, 2019 -- Among postmenopausal women, fried food consumption, especially fried chicken and fish/shellfish, is associated with an increased risk for all-cause and cardiovascular mortality, according to a study published online Jan....
http://bit.ly/2RQACkb
Gun Injury Hospitalization Cost Over $911 Million 2010 to 2015
THURSDAY, Jan. 24, 2019 -- The average annual cost of inpatient hospitalizations for firearm injury exceeded $911 million from 2010 to 2015, with 9.5 percent of that amount due to readmissions, according to a study published online Jan. 24 in PLOS...
http://bit.ly/2CGrNPq
Measles Outbreak Prompts Public Emergency in Washington State
THURSDAY, Jan. 24, 2019 -- An ongoing measles outbreak has led to a public health emergency being declared in Clark County, Washington. The latest update from the county's health department said that 23 measles cases have been confirmed and two more...
http://bit.ly/2RNfJGA
CDC: Proportion of Increased-Risk Deceased Organ Donors on Rise
THURSDAY, Jan. 24, 2019 -- Among deceased organ donors, there has been an increase in the proportion at increased risk for transmitting hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV to recipients, according to research published in the...
http://bit.ly/2CHzrZT
Spatial distribution and temporal trends in social fragmentation in England, 2001-2011: a national study
Objective
Social fragmentation is commonly examined in epidemiological studies of mental illness as high levels of social fragmentation are often found in areas with high prevalence of mental illness. In this study, we examine spatial and temporal patterns of social fragmentation and its underlying indicators in England over time.
SettingData for social fragmentation and its underlying indicators were analysed over the decennial Censuses (2001–2011) at a small area geographical level (mean of 1500 people). Degrees of social fragmentation and temporal changes were spatially visualised for the whole of England and its 10 administrative regions. Spatial clustering was quantified using Moran's I; changes in correlations over time were quantified using Spearman's ranking correlation.
ResultsBetween 2001 and 2011, we observed a strong persistence for social fragmentation nationally (Spearman's r=0.93). At the regional level, modest changes were observed over time, but marked increases were observed for two of the four social fragmentation underlying indicators, namely single people and those in private renting. Results supported our hypothesis of increasing spatial clustering over time. Moderate regional variability was observed in social fragmentation, its underlying indicators and their clustering over time.
ConclusionPatterns of social fragmentation and its underlying indicators persisted in England which seem to be driven by the large increases in single people and those in private renting. Policies to improve social cohesion may have an impact on the lives of persons who experience mental illness. The spatial aspect of social fragmentation can inform the targeting of health and social care interventions, particularly in areas with strong social fragmentation clustering.
http://bit.ly/2RRIG3Z
Pediatric Palliative Care in the Multi-Cultural Context: Findings from a workshop conference
In our increasingly multicultural society, providing sensitive and respectful pediatric palliative care is vital.
http://bit.ly/2Td99Wl
Lipids, Apolipoproteins, and Risk of Atherosclerotic Cardiovascular Disease in Persons With CKD
A large residual risk for atherosclerotic cardiovascular disease (ASCVD) remains in the setting of chronic kidney disease (CKD) despite treatment with statins. We sought to evaluate the associations of lipid and apolipoprotein levels with risk for ASCVD in individuals with CKD.
http://bit.ly/2FMcjx8
Dietary Phosphate and the Forgotten Kidney Patient: A Critical Need for FDA Regulatory Action
Careful dietary management that reduces high phosphate intake is recommended to slow the progression of chronic kidney disease (CKD) and prevent complications of CKD and may help reduce chronic disease risks such as incident CKD associated with high phosphate intake in the healthy general population. For patients treated with maintenance dialysis, control of serum phosphorus levels is considered a marker of good care and requires a coordinated plan that limits dietary phosphate intake, uses oral phosphate binders, and provides an adequate dialysis prescription.
http://bit.ly/2FYnnGL
Data Science for Child Health
Data science has revolutionized industry and academic fields including marketing,1 astronomy,2 and computer vision.3 It has not yet impacted medicine and biomedical research to the same degree. However, many observers4-6 believe that data science will improve the ability of health care systems to deliver personalized medicine,7 population health,8 and public health.9
http://bit.ly/2CSXi9d
Frizzled 2‐induced EMT correlates with vasculogenic mimicry, stemness and Hippo signaling in hepatocellular carcinoma
Abstract
Prior observation has indicated that Frizzled 2 (FZD2)‐induced epithelial‐mesenchymal transition (EMT) may be a key step in metastasis and early recurrence of hepatocellular carcinoma (HCC). However, the mechanism underlying tumor development and progression due to aberrant FZD2 expression is poorly defined. Here, we provide evidence that FZD2 is a driver for EMT, cancer stem cell (CSC) property, and vasculogenic mimicry (VM) in HCC. We found that FZD2 was highly expressed in two cohorts of Chinese hepatitis B virus‐related HCC patients, and that high FZD2 expression was associated with poor prognosis. Concerning the mechanism, gain‐ and loss‐of function experiments showed the oncogenic action of FZD2 in HCC cell proliferation, apoptosis, migration, and invasion. Further investigations in vitro and in vivo suggested that FZD2 promotes the EMT process, enhances stem‐like properties, and confers VM capacity to HCC cells. Notably, integrative RNA‐seq analysis of FZD2‐knockdown cells indicated the enrichment of Hippo signaling pathway. Taken together, our data suggest for the first time that FZD2 may promote clinically relevant EMT, CD44(+) stem‐like properties, and the VM phenotype in HCC involving a potential Hippo signaling pathway‐dependent mechanism, and should be considered as a promising therapeutic target for the treatment of HCC.
This article is protected by copyright. All rights reserved.
http://bit.ly/2FORWzm
Preparation and spectroscopic characterization of a Si‐coated vegetable oils and its application in in‐situ curing of hybrid coatings
Abstract
The modification of natural oils with heteroatoms leads to materials that can be employed in various areas thanks to their specific properties. Here, a solventless chemical modification of epoxidized linseed oil with an aminosilane without a catalyst is developed, and a detailed study of the chemical reactions involved during the process is reported. The mechanism results in two competitive reactions: the ring‐opening of epoxides and trans‐amidification of triglycerides with the amine functional group of aminosilane. These competitive reactions are shown by infrared spectroscopy (FTIR) and 1H, 13C and 2D nuclear magnetic resonance (NMR). Even if the epoxy ring‐opening remains the major route, the trans‐amidification cannot be ignored. These modified oils are very reactive under atmospheric conditions by cross‐linking according to a polycondensation of the ‐Si(OMe)3 moieties or via a sol‐gel process and lead to a rapid hardening. The final material gives hydrophobic and glossy coatings on cellulose and glass.
Practical applications: This paper detailed the easy route to convert vegetable oils into coatings by crosslinking under mild conditions. These bio‐based materials can be applied as oil‐based impregnating products for exterior wood protection and in the hydrophobization of paper.
http://bit.ly/2Mvus2P
Development and validation of nomograms integrating immune‐related genomic signatures with clinicopathologic features to improve prognosis and predictive value of triple‐negative breast cancer: A gene expression‐based retrospective study
Immune‐related genomic signatures provide independent and complementary prognostic information for triple‐negative breast cancer (TNBC), and the developed nomogram might be a practical predictive tool to identify TNBC patients who would benefit from chemotherapy, radiotherapy, and upcoming popularity of immunotherapy.
Abstract
Purpose
Accumulating evidence indicated that triple‐negative breast cancer (TNBC) can stimulate stronger immune responses than other subtypes of breast cancer. We hypothesized that integrating immune‐related genomic signatures with clinicopathologic factors may yield a predictive accuracy exceeding that of the currently available system.
Methods
Ten signatures that reflect specific immunogenic or immune microenvironmental features of TNBC were identified and re‐analyzed using bioinformatic methods. Then, clinically annotated TNBC (n = 711) with the corresponding expression profiles, which predicted a patient's probability of disease‐free survival (DFS) and overall survival (OS), was pooled to evaluate their prognostic values and establish a clinicopathologic‐genomic nomogram. Three and two immune features were, respectively, selected out of 10 immune features to construct nomogram for DFS and OS prediction based on multivariate backward stepwise Cox regression analyses.
Results
By integrating the above immune expression signatures with prognostic clinicopathologic features, clinicopathologic‐genomic nomograms were cautiously constructed, which showed reasonable prediction accuracies (DFS: HR, 1.79; 95% CI, 1.46‐2.18, P < 0.001; AUC, 0.71; OS: HR, 1.96; 95% CI, 1.54‐2.49; P < 0.001; AUC, 0.73). The nomogram showed low‐risk subgroup had higher immune checkpoint molecules (PD‐L1, PD‐1, CTLA‐4, LAG‐3) expression and benefited from radiotherapy (HR, 0.2, 95% CI, 0.05‐0.89; P = 0.034) rather than chemotherapy (HR, 1.26, 95% CI, 0.66‐2.43; P = 0.485).
Conclusions
These findings offer evidence that immune‐related genomic data provide independent and complementary prognostic information for TNBC, and the nomogram might be a practical predictive tool to identify TNBC patients who would benefit from chemotherapy, radiotherapy, and upcoming popularity of immunotherapy.
http://bit.ly/2MzjLfS
Why does my tooth still hurt after a filling?
Some tooth sensitivity after a filling is normal. In this article, we look at the reasons why this occurs, when to see a doctor, and treatments to help relieve tooth sensitivity.
http://bit.ly/2B2fbSu
Psychopathic Traits in Adulthood Up With Child Lead Exposure
THURSDAY, Jan. 24, 2019 -- Higher childhood blood lead levels are associated with more psychopathy during the life course, according to a study published online Jan. 23 in JAMA Psychiatry. Aaron Reuben, from Duke University in Durham, North...
http://bit.ly/2CLh71S
Plasma Marker Predicts Allograft Failure in Lung Transplant
THURSDAY, Jan. 24, 2019 -- Donor-derived cell-free DNA (ddcfDNA) is a potential biomarker that can predict allograft failure after lung transplantation, according to a study published online Jan. 23 in EBioMedicine. Sean Agbor-Enoh, M.D., Ph.D.,...
http://bit.ly/2RPkZJM
Initiative Tied to Decreased Racial Inequity in Breastfeeding
THURSDAY, Jan. 24, 2019 -- A hospital-based initiative in Southern states is associated with increases in breastfeeding rates among African-American infants, according to a study published online Jan. 18 in Pediatrics. Anne Merewood, Ph.D., M.P.H.,...
http://bit.ly/2CHOh2v
Short Duration Between Dinner, Bed Has No Effect on HbA1c
THURSDAY, Jan. 24, 2019 -- Ensuring a short duration between dinner and bedtime has no effect on hemoglobin A1c (HbA1c) levels in middle-aged and older Japanese adults, according to a study published online Jan. 22 in BMJ Nutrition, Prevention &...
http://bit.ly/2ROT7Fm
BP >120/80 mm Hg Linked to Lower Gray Matter Volume
THURSDAY, Jan. 24, 2019 -- In young adults, lower gray matter volume (GMV) is seen in individuals with blood pressure (BP) >120/80 mm Hg, according to a study published online Jan. 23 in Neurology. H. Lina Schaare, from the International Max...
http://bit.ly/2CGOS4D
Time to Breast Cancer Surgery Delayed for Non-Hispanic Blacks
THURSDAY, Jan. 24, 2019 -- The time to surgery (TTS) after a breast cancer diagnosis is delayed for non-Hispanic black (NHB) versus non-Hispanic white (NHW) women, according to a study published online Jan. 23 in JAMA Surgery. Yvonne L. Eaglehouse,...
http://bit.ly/2RPkOhA
Body Size, Physical Activity Could Impact Odds of Reaching 90
THURSDAY, Jan. 24, 2019 -- Height, body mass index (BMI), and physical activity are associated with longevity, with correlations differing by sex, according to research published online Jan. 21 in the Journal of Epidemiology & Community...
http://bit.ly/2CHxmwY
Levodopa + Carbidopa Does Not Modify Disease in Early Parkinson
THURSDAY, Jan. 24, 2019 -- For patients with early Parkinson disease, treatment with levodopa combined with carbidopa has no disease-modifying effect, according to a study published in the Jan. 24 issue of the New England Journal of...
http://bit.ly/2ROT2l2
Smoking Tied to Peripheral Artery Disease in African-Americans
THURSDAY, Jan. 24, 2019 -- Cigarette smoking is associated with measures of subclinical peripheral artery disease (PAD) in African-Americans, according to a study published online Jan. 23 in the Journal of the American Heart Association. Donald...
http://bit.ly/2CFvNj7
Three-Week Immobilization Feasible for Some Ankle Fractures
THURSDAY, Jan. 24, 2019 -- For patients with stable, isolated Weber B-type fibula fractures, a three-week immobilization period is noninferior to a six-week cast, according to a study published online Jan. 23 in The BMJ. Tera Kortekangas, M.D.,...
http://bit.ly/2RLGr29
Effect of continuous venovenous hemodialysis on outcome and pharmacokinetics of arsenic species in a patient with acute promyelocytic leukemia and acute kidney injury
Abstract
This study presented outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous hemodialysis (CVVHD). Of three acute promyelocytic leukemia (APL) patients receiving CVVHD in management of acute kidney injury (AKI), only one patient was included. The patient presented disseminated intravascular coagulation (DIC) and AKI before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analyzed using high performance liquid chromatography‐hydride generation‐atomic fluorescence spectrometry. Plasma concentrations of AsIII, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) with CVVHD were lower than those without CVVHD. AUC0‐t of AsIII without CVVHD was significantly higher than that with CVVHD (292.10 ng*h/mL versus 195.86 ng*h/mL, P=0.037), which were not observed for MMAV and DMAV. Dialysate saturation of arsenic species was remarkable, especially for AsIII. Complete remission was achieved and renal function was recovered. In this study, ATO can be used safely and effectively to treat APL patients undergoing CVVHD without dose adjustment.
http://bit.ly/2B0YU08
A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis
Brain metastases are more common than primary CNS tumors and confer grave prognosis on patients, as existing treatments have very limited efficacy. The tumor microenvironment has a central role in facilitating tumorigenesis and metastasis. In recent years, there has been much progress in our understanding of the functional role of the brain metastatic microenvironment. In this review, we discuss the latest advances in brain metastasis research, with special emphasis on the role of the brain microenvironment and neuroinflammation, integrating insights from comparable findings in neuropathologies and primary CNS tumors. In addition, we overview findings on the formation of a hospitable metastatic niche and point out the major gaps in knowledge toward developing new therapeutics that will cotarget the stromal compartment in an effort to improve the treatment and prevention of brain metastases.
http://bit.ly/2sKaDMn
Is Adjuvant Chemotherapy Efficient in Colon Cancer with High Microsatellite Instability? A Look Towards the Future
The high microsatellite instability (MSI-H) is frequently observed in localized colorectal adenocarcinoma. MSI-H is a good prognostic factor in nonmetastatic colon adenocarcinoma. However, MSI-H is not a predictive factor because it is not related with better survival in patients with colon cancer with adjuvant chemotherapy. MSI-H should be a predictive factor because it is associated with a higher expression of enzymes, which are inhibited by cytotoxic agents. Here, we analyze this controversy. We conclude MSI-H is not a predictive factor because the adjuvant therapy based on traditional cytotoxic agents does not act on either immune signaling pathways or BRAF mutation.
http://bit.ly/2Munvz4
Anti-PD-L1 treatment results in functional remodeling of the macrophage compartment
Checkpoint inhibitors like anti-PD1/PD-L1 have demonstrated significant therapeutic efficacy in a subset of patients partly through reinvigoration of CD8 T cells. However, their impact on myeloid cells remains largely unknown. Here we report that anti-PD-L1 treatment favorably impacts the phenotype and function of tumor macrophages by polarizing the macrophage compartment towards a more pro-inflammatory phenotype. This phenotype was characterized by a decrease in Arginase-I (ARG1) expression and an increase in iNOS, MHCII, and CD40 expression. Whole-transcriptome profiling further confirmed extensive polarization of both tumor monocytes and macrophages from a suppressive to a pro-inflammatory, immuno-stimulatory phenotype. This polarization was driven mainly through IFNγ and was associated with enhanced T cell activity. Transfer of monocytes into anti-PD-L1-treated tumor-bearing mice led to macrophage differentiation into a more pro-inflammatory phenotype, with an increase in CD8 T cells expressing granzyme B and an increase in the CD8/Treg ratio compared to control-treated mice. While in responsive tumor models anti-PD-L1 treatment remodeled the macrophage compartment with beneficial effects on T cells, both macrophage reprogramming and depletion were needed to maximize anti-PD-L1 responses in a tumor immune contexture with high macrophage burden. Our results demonstrate that anti-PD-L1 treatment can favorably remodel the macrophage compartment in responsive tumor models towards a more pro-inflammatory phenotype, mainly through increased IFNγ levels. They also suggest that directly targeting these cells with reprogramming and depleting agents may further augment the breadth and depth of response to anti-PD-L1 treatment in less responsive or more macrophage-dense tumor microenvironments.
http://bit.ly/2sSLEGN
IDO1 and kynurenine pathway metabolites activate PI3K-Akt signaling in the neoplastic colon epithelium to promote cancer cell proliferation and inhibit apoptosis
The tryptophan-metabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) is frequently overexpressed in epithelial-derived malignancies, where it plays a recognized role in promoting tumor immune tolerance. We previously demonstrated that the IDO1-kynurenine pathway (KP) also directly supports colorectal cancer (CRC) growth by promoting activation of β-catenin and driving neoplastic growth in mice lacking intact adaptive immunity. In this study, we sought to delineate the specific role of epithelial IDO1 in colon tumorigenesis and define how IDO1 and KP metabolites interact with pivotal neoplastic signaling pathways of the colon epithelium. We generated a novel intestinal epithelial-specific IDO1 knockout mouse and utilized established CRC cell lines containing β-catenin-stabilizing mutations, human CRC samples, and human-derived epithelial organoids (colonoids and tumoroids). Mice with intestinal epithelial-specific knockout of IDO1 developed fewer and smaller tumors than wild type littermates in a model of inflammation-driven colon tumorigenesis. Moreover, their tumors exhibited reduced nuclear β-catenin and neoplastic proliferation but increased apoptosis. Mechanistically, kynurenine pathway metabolites (except kynurenic acid) rapidly activated PI3K-Akt signaling in the neoplastic epithelium to promote nuclear translocation of β-catenin, cellular proliferation, and resistance to apoptosis. Together, these data define a novel cell-autonomous function and mechanism by which IDO1 activity promotes CRC progression. These findings may have implications for the rational design of new clinical trials which exploit a synergy of IDO1 inhibitors with conventional cancer therapies for which Akt activation provides resistance such as radiation.
http://bit.ly/2Mvg7Ua
Tumour pH and protein concentration contribute to the signal of amide proton transfer magnetic resonance imaging
Abnormal pH is a common feature of malignant tumours and has been associated clinically with sub-optimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to non-invasively measure tumour pH, yet multiple factors collectively make quantification of tumour pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumours. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumour pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumour hypoxia was associated with a shift in tumour pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumours as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.
http://bit.ly/2sKaCrN
Pleiotropic effects of PPARD accelerate colorectal tumorigenesis, progression, and invasion
APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer (CRC), however, CRC progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in CRC. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and CRC. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in CRC. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed CRC, respectively. Depletion of PPARD in human CRC organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced CRC tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human CRC invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other pro-invasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote CRC progression and invasiveness.
http://bit.ly/2MunsmS
Utility of cytomorphology in distinguishing solid pseudopapillary neoplasm of pancreas from pancreatic neuroendocrine tumor with emphasis on nuclear folds and nuclear grooves
Background
Pancreatic solid pseudopapillary tumor (SPN) and pancreatic neuroendocrine tumors (Pan‐NET) have close resemblance on imaging and cytomorphology, though they differ in their prognosis and treatment strategy. SPNs are low‐grade indolent tumors while Pan‐NETs harbor malignant potential with propensity to metastasize. We aim to differentiate SPN from Pan‐NET based on cyto‐morphology; to classify nuclear membrane (NM) irregularities or nuclear folds into four grades and see whether they bear any difference with respect to the two entities.
Methods
Eighteen and ten confirmed cases of SPN and Pan‐NET were included in the study. Smears were assessed for architecture, background changes, cellular, and nuclear features, which were compared between the two study groups. Nuclear folds were classified into four grades. Nuclear folds and nuclear grooves were also compared between the two groups.
Results
All SPN patients were females; mean age of 28 years. Pan‐NET patients had equal male to female ratio; mean age of 46 years. Both SPN (78%) and Pan‐NET (71%) showed predilection for pancreatic head. Mean size of lesion was 4.8 cm and 3.1 cm in SPN and Pan‐NET groups. Papillary pattern, branching capillaries, degenerative background were significantly more prominent in SPN; sudden anisonucleosis and cytoplasmic granularity in Pan‐NET. Metachromatic matrix, hyaline globules, and nuclear grooves were noted exclusively in SPNs. Nuclear fold grades 2 and 3 were more characteristic of SPN than Pan‐NET (P = 0.041 and 0.002, respectively).
Conclusions
Cytomorphology is vital in differentiating SPN from Pan‐NET with nuclear folds being an important nuclear feature.
http://bit.ly/2FPcFmO
Changes in skeletal muscle area and lean body mass during pazopanib vs sunitinib therapy for metastatic renal cancer
Abstract
Purpose
To evaluate whether sunitinib and pazopanib treatments are associated with change in skeletal muscle area (SMA) and total lean body mass (LBM) as well as to compare their efficacies and safety profiles in patients with metastatic renal cell cancer (mRCC).
Methods
Thirty-six patients treated with a tyrosine kinase inhibitor were included. Eighteen of them received sunitinib and the rest/remaining received pazopanib in the first line of mRCC treatment. Baseline and follow-up computed tomography studies of the patients were performed to measure cross-sectional areas (cm2) of muscle tissues.
Results
About 69% of patients were male and median age was 60 (49–68) years. Median time interval between two CT imagings was 6.1 (3.1–7.7) months and it was similar between the two groups (for sunitinib, 4.9 (2.5–6.9) months vs for pazopanib, 7.3 (3.2–9.5) months, p = 0.16, respectively). Disease control rate was 77.7% in all patients. Of these, 66.6% in sunitinib group was consisted of four partial responses and eight stable diseases. In addition, 88.8% in pazopanib group was consisted of three partial responses and 13 stable diseases. A significant decrease in SMA and LBM was observed after sunitinib therapy, whereas SMA and LBM values of pazopanib group did not change significantly (p = 0.02 and p = 0.70, respectively). No significant differences were observed between patients with sunitinib, and pazopanib group median PFS [11.9 (95% CI 6.1–17.6) vs 8.1 months (95% CI 7.2–9.1), respectively; p = 0.28] and median OS [28.6 (95% CI 24.3–32.9) vs 25.5 months (95% CI 18.9–52.7), respectively; p = 0.42]. Dose-limiting toxicities were significantly more frequent in sunitinib group than in pazopanib group (66.7% vs 22.2%, p = 0.02, respectively).
Conclusions
Loss of SMA and LBM with sunitinib was more substantial than with pazopanib. Treatment efficacies of both drugs were similar, but dose-limiting toxicity was more frequent in sunitinib group. Loss of SMA had no significant association with prognosis. Further studies are needed to clarify the possible association between SMA and prognosis in mRCC patients who receive sunitinib or pazopanib.
http://bit.ly/2FZgRzB
Effect of aprepitant administration on CINV caused by cisplatin multi-day chemotherapy and pharmacokinetics of docetaxel
Abstract
Purpose
To compare efficacy and safety of postponing administration of aprepitant and routine triple-antiemetic treatment for chemotherapy-induced nausea and vomiting in patients who received docetaxel and cisplatin multi-day chemotherapy treatment, and to evaluate the effect of aprepitant on docetaxel pharmacokinetics in the Chinese population.
Methods
A total of 24 cancer patients (including 5 females and 19 males, 22–74 years old) received two cycles of high-emetic DP (docetaxel 75 mg/m2 on day 1 + cisplatin 25 mg/m2 on days 1–3) regimen. A randomized, two-period and cross-over study was applied for prevention of chemotherapy-induced nausea and vomiting. The patients in group A took aprepitant 125 mg on day 1 and 80 mg on days 2–3 (administered aprepitant 1 h before chemotherapy). In group B, the patients took aprepitant 125 mg on day 2, 80 mg on days 3–4, which was delayed 1 day than group A. Efficacy and safety in overall phase were evaluated within 5 days after initiation of chemotherapy. Simultaneously, the differences in the pharmacokinetic parameters of docetaxel between two different antiemetic treatments are compared.
Results
The CR rate of delayed-phase nausea was compared between the routine triple-antiemetic treatment (group A) and the aprepitant delayed 1-day administration treatment (group B), and the difference was statistically significant (16.7% vs 45.8% P < 0.05), despite there were similar for two groups in the CR rate of acute-phase nausea and vomiting, and delayed-phase vomiting. In two groups, the area under the docetaxel curve (AUC0−t values) (mean ± SD) of docetaxel was 1134.21 ± 732.55 (ng h/mL) and 1080.94 ± 585.09 (ng h/mL), and the geometric means were 944.82 and 902.10 (ng h/mL), respectively. There was no significant difference in AUC values between the two antiemetic treatments (P > 0.05), as well as Cmax, CLz, T1/2z, MRT and Tmax.
Conclusions
Delayed administration of aprepitant provided superior delayed-phase nausea protection for patients who received cisplatin-based chemotherapy in comparison with the routine triple-antiemetic treatment. In addition, in the routine triple-antiemetic treatment, aprepitant did not significantly affect the main pharmacokinetic parameters of docetaxel.
http://bit.ly/2FLLYPM
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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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