Histopathology, Volume 0, Issue ja, -Not available-.
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Τρίτη 4 Σεπτεμβρίου 2018
Heterogeneity of Programmed Cell Death‐Ligand 1 Expression in Thymic Epithelial Tumors Between Initial Specimen and Synchronous or Metachronous Metastases or Recurrences
Relative normalized luciferase activity for the recombinant vector constructs carrying the ancestral and variant alleles for XRCC2:rs3218550 and PHB:rs6917
The data presented herein represents the preliminary results of the functional assays of a recently conducted larger study in which two single nucleotide polymorphisms (SNPs) [XRCC2:rs3218550 and PHB:rs6917] were...
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Observations of extensive gene expression differences in the cerebellum and potential relevance to Alzheimer’s disease
In order to determine how gene expression is altered in disease it is of fundamental importance that the global distribution of gene expression levels across the disease-free brain are understood and how diffe...
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Outcomes in patients with Hirschsprung disease following definitive surgery
Several pull-through procedures have been described for Hirschsprung disease (HSCR) with varying outcomes. We aimed to describe the outcomes in HSCR patients
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Learning receptive awareness via neurofeedback in stressed healthcare providers: a prospective pilot investigation
Because physicians and nurses are commonly stressed, Bispectral Index™ (BIS) neurofeedback, following trainer instructions, was used to learn to lower the electroencephalography-derived BIS value, indicating t...
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Multicentric reticulohistiocytosis: a case report
Multicentric reticulohistiocytosis is a rare form of non-langerhans cell histiocytosis presenting with skin changes and erosive arthritis. Infiltration of histiocytes and multinucleated giant cells are typical...
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Colorectal Cancer Incidence Trends by Age, Stage, and Racial/Ethnic Group in California, 1990-2014
Background: The incidence of colorectal cancer in the United States declined substantially over the past 20 years, but evidence suggests that among younger adults (under 50 years at diagnosis), incidence is increasing. However, data on age- and stage-specific incidence trends across racial/ethnic groups are limited.
Methods: All incident cases of colorectal cancer diagnosed from 1990 through 2014 in adults aged 20 years and older were obtained from the California Cancer Registry. Incidence rates (per 100,000), incidence rate ratios, and triannual percent changes in incidence were estimated for each age group at diagnosis (20–49, 50–74, 75+ years), sex, stage, and race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and 7 Asian American groups).
Results: Of 349,176 incident colorectal cancer cases diagnosed from 1990 through 2014, 9% were in adults younger than 50 years. Increases in incidence of early-onset colorectal cancer, especially in regional/distant stage disease, were observed in most racial/ethnic groups (statistically significant for non-Hispanic whites and Hispanics, ranging from 0.9% to 2.9% every 3 years). Incidence also increased in Vietnamese and other Southeast Asian groups of screening age (50–74 years). The incidence of colorectal cancer in non-Hispanic blacks aged 50+ declined over the 25-year period, but remained significantly higher than in non-Hispanic whites.
Conclusions: Further research is needed to understand the causes of the increasing incidence of early-onset colorectal cancer. The rising incidence of colorectal cancer among Southeast Asians of screening age and the persistently high incidence in non-Hispanic blacks also warrant attention.
Impact: Our findings may have implications for revisiting screening guidelines in the United States. Cancer Epidemiol Biomarkers Prev; 27(9); 1011–8. ©2018 AACR.
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Causal Inference in Cancer Epidemiology: What Is the Role of Mendelian Randomization?
Observational epidemiologic studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) uses genetic variants to proxy modifiable exposures to generate more reliable estimates of the causal effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within cardio-metabolic epidemiology, but also holds much promise for identifying possible interventions for cancer prevention and treatment. However, some methodologic challenges in the implementation of MR are particularly pertinent when applying this method to cancer etiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies. In this review, we provide an overview of the key principles and assumptions of MR, focusing on applications of this method to the study of cancer etiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared with conventional epidemiological studies. Finally, limitations of MR and recent methodologic developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 995–1010. ©2018 AACR.
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Hepatocellular Carcinoma Outcome Is Predicted by Expression of Neuronal Calcium Sensor 1
Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. There is an urgent demand for prognostic biomarkers that facilitate early tumor detection, as the incidence of HCC has tripled in the United States in the last three decades. Biomarkers to identify populations at risk would have significant impact on survival. We recently found that expression of Neuronal Calcium Sensor 1 (NCS1), a Ca2+-dependent signaling molecule, predicted disease outcome in breast cancer, but its predictive value in other cancer types is unknown. This protein is potentially useful because increased NCS1 regulates Ca2+ signaling and increased Ca2+ signaling is a hallmark of metastatic cancers, conferring cellular motility and an increasingly aggressive phenotype to tumors.
Methods: We explored the relationship between NCS1 expression levels and patient survival in two publicly available liver cancer cohorts and a tumor microarray using data mining strategies.
Results: High NCS1 expression levels are significantly associated with worse disease outcome in Asian patients within these cohorts. In addition, a variety of Ca2+-dependent and tumor growth-promoting genes are transcriptionally coregulated with NCS1 and many of them are involved in cytoskeleton organization, suggesting that NCS1 induced dysregulated Ca2+ signaling facilitates cellular motility and metastasis.
Conclusions: We found NCS1 to be a novel biomarker in HCC. Furthermore, our study identified a pharmacologically targetable signaling complex that can influence tumor progression in HCC.
Impact: These results lay the foundation for using NCS1 as a prognostic biomarker in prospective cohorts of HCC patients and for further functional assessment of the characterized signaling axis. Cancer Epidemiol Biomarkers Prev; 27(9); 1091–100. ©2018 AACR.
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Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer
Background: The early detection of colon cancer is one of the main prerequisites for successful treatment and mortality reduction. Circulating PIWI-interacting RNAs (piRNA) were recently identified as novel promising biomarkers. The purpose of the study was to assess the profiles of piRNAs in blood serum of colon cancer patients with the aim to identify those with high diagnostic potential.
Methods: Blood serum samples from 403 colon cancer patients and 276 healthy donors were included in this 3-phase biomarker study. Large-scale piRNA expression profiling was performed using Illumina small RNA sequencing. The diagnostic potential of selected piRNAs was further validated on independent training and validation sets of samples using RT-qPCR.
Results: In total, 31 piRNAs were found to be significantly deregulated in serum of cancer patients compared with healthy donors. Based on the levels of piR-5937 and piR-28876, it was possible to differentiate between cancer patients and healthy donors with high sensitivity and specificity. Moreover, both piRNAs exhibited satisfactory diagnostic performance also in patients with stage I disease and enabled detection of colon cancer with higher sensitivity than currently used biomarkers CEA and CA19-9. Finally, the expression of analyzed piRNAs in blood restored significantly 1 month after the surgical resection.
Conclusions: Based on our findings, piRNAs are abundant in human blood serum. Furthermore, their levels in colon cancer have been observed to be significantly deregulated. However, their involvement in carcinogenesis must be further established.
Impact: piRNAs could serve as promising noninvasive biomarkers for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1019–28. ©2018 AACR.
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A Rare Variant P507L in TPP1 Interrupts TPP1-TIN2 Interaction, Influences Telomere Length, and Confers Colorectal Cancer Risk in Chinese Population
Background: Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility.
Methods: In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case–control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development.
Results: The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T and p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04–8.07; P = 0.041], 2.50 (95% CI, 1.04–6.04; P = 0.042), and 2.66 (95% CI, 1.36–5.18; P = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1–TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development.
Conclusions: A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1–TIN2 interaction, impairing telomerase processivity, and shrinking telomere length.
Impact: These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1029–35. ©2018 AACR.
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Collaborative Method Performance Study of the Measurement of Nicotine, Its Metabolites, and Total Nicotine Equivalents in Human Urine
Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.
Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.
Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.
Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.
Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR.
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Rural-Urban Disparities in Time to Diagnosis and Treatment for Colorectal and Breast Cancer
Background: Longer cancer pathways may contribute to rural–urban survival disparities, but research in this area is lacking. We investigated time to diagnosis and treatment for rural and urban patients with colorectal or breast cancer in Victoria, Australia.
Methods: Population-based surveys (2013–2014) of patients (aged ≥40, approached within 6 months of diagnosis), primary care physicians (PCPs), and specialists were collected as part of the International Cancer Benchmarking Partnership, Module 4. Six intervals were examined: patient (symptom to presentation), primary care (presentation to referral), diagnostic (presentation/screening to diagnosis), treatment (diagnosis to treatment), health system (presentation to treatment), and total interval (symptom/screening to treatment). Rural and urban intervals were compared using quantile regression including age, sex, insurance, and socioeconomic status.
Results: 433 colorectal (48% rural) and 489 breast (42% rural) patients, 621 PCPs, and 370 specialists participated. Compared with urban patients, patients with symptomatic colorectal cancer from rural areas had significantly longer total intervals at the 50th [18 days longer, 95% confidence interval (CI): 9–27], 75th (53, 95% CI: 47–59), and 90th percentiles (44, 95% CI: 40–48). These patients also had longer diagnostic and health system intervals (6–85 days longer). Breast cancer intervals were similar by area of residence, except the patient interval, which was shorter for rural patients with either cancer in the higher percentiles.
Conclusions: Rural residence was associated with longer total intervals for colorectal but not breast cancer; with most disparities postpresentation.
Impact: Interventions targeting time from presentation to diagnosis may help reduce colorectal cancer rural–urban disparities. Cancer Epidemiol Biomarkers Prev; 27(9); 1036–46. ©2018 AACR.
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Transcriptomic Characterization of Endometrioid, Clear Cell, and High-Grade Serous Epithelial Ovarian Carcinoma
Background: Endometrioid carcinoma (EC) and clear cell carcinoma (CC) histotypes of epithelial ovarian cancer are understudied compared with the more common high-grade serous carcinomas (HGSC). We therefore sought to characterize EC and CC transcriptomes in relation to HGSC.
Methods: Following bioinformatics processing and gene abundance normalization, differential expression analysis of RNA sequence data collected on fresh-frozen tumors was completed with nonparametric statistical analysis methods (55 ECs, 19 CCs, 112 HGSCs). Association of gene expression with progression-free survival (PFS) was completed with Cox proportional hazards models. Eight additional multi-histotype expression array datasets (N = 852 patients) were used for replication.
Results: In the discovery set, tumors generally clustered together by histotype. Thirty-two protein-coding genes were differentially expressed across histotype (P < 1 x 10–10) and showed similar associations in replication datasets, including MAP2K6, KIAA1324, CDH1, ENTPD5, LAMB1, and DRAM1. Nine genes associated with PFS (P < 0.0001) showed similar associations in replication datasets. In particular, we observed shorter PFS time for CC and EC patients with high gene expression for CCNB2, CORO2A, CSNK1G1, FRMD8, LIN54, LINC00664, PDK1, and PEX6, whereas, the converse was observed for HGSC patients.
Conclusions: The results suggest important histotype differences that may aid in the development of treatment options, particularly those for patients with EC or CC.
Impact: We present replicated findings on transcriptomic differences and how they relate to clinical outcome for two of the rarer ovarian cancer histotypes of EC and CC, along with comparison with the common histotype of HGSC. Cancer Epidemiol Biomarkers Prev; 27(9); 1101–9. ©2018 AACR.
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The Efficacy of Direct Mail, Patient Navigation, and Incentives for Increasing Mammography and Colonoscopy in the Medicaid Population: A Randomized Controlled Trial
Background: Despite lower cancer screening rates and survival rates in the Medicaid population compared with those with private insurance, there is a dearth of population-based, evidence-based interventions targeting Medicaid clients to address this problem.
Methods: This study reports results of a population-based randomized controlled trial (RCT) among all individuals enrolled in Minnesota's Medicaid program who were overdue for breast cancer (n = 22,113) and/or colorectal cancer (n = 94,294) screening. Individuals were randomized to intervention or control groups. The intervention group received persuasive and innovative direct mail materials coupled with a $20 incentive for using their Medicaid benefit to get screened. Direct mail materials provided a phone number to a call center staffed by patient navigators who addressed barriers and scheduled appointments via three-way calls. The control group received the intervention 15 months later. Primary outcomes were completion of mammography or colonoscopy within 12 weeks of the intervention. Billing claims served as evidence of screening.
Results: Multivariate logistic regression showed significant differences for both breast cancer (P < 0.001) and colorectal cancer (P < 0.01). The odds of receiving a mammogram for the treatment group were significantly higher than the control group [OR = 1.30; 95% confidence interval (95% CI) = 1.16–1.46], and the treatment group was more likely to receive a colonoscopy than the control group (OR = 1.12; 95% CI = 1.04–1.21).
Conclusions: This population-based intervention increased breast cancer and colorectal cancer screening in a Medicaid population overdue for screening.
Impact: These findings may have broad application for reaching individuals who generally remain outside the health care system despite having public health insurance. Cancer Epidemiol Biomarkers Prev; 27(9); 1047–56. ©2018 AACR.
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Identification and Characterization of Transcripts Regulated by Circadian Alternative Polyadenylation in Mouse Liver
Dynamic control of gene expression is a hallmark of the circadian system. In mouse liver, approximately 5-20% of RNAs are expressed rhythmically, and over 50% of mouse genes are rhythmically expressed in at least one tissue. Recent genome-wide analyses unveiled that, in addition to rhythmic transcription, various post-transcriptional mechanisms play crucial roles in driving rhythmic gene expression. Alternative polyadenylation (APA) is an emerging post-transcriptional mechanism that changes the 3'-ends of transcripts by alternating poly(A) site usage. APA can thus result in changes in RNA processing, such as mRNA localization, stability, translation efficiency, and sometimes even in the localization of the encoded protein. It remains unclear, however, if and how APA is regulated by the circadian clock. To address this, we used an in silico approach and demonstrated in mouse liver that 57.4 % of expressed genes undergo APA and each gene has 2.53 poly(A) sites on average. Among all expressed genes, 2.9 % of genes alternate their poly(A) site usage with a circadian (i.e., approximately 24 hours) period. APA transcripts use distal sites with canonical poly(A) signals (PASs) more frequently; however, circadian APA transcripts exhibit less distinct usage preference between proximal and distal sites and use proximal sites more frequently. Circadian APA transcripts also harbor longer 3'UTRs, making them more susceptible to post-transcriptional regulation. Overall, our study serves as a platform to ultimately understand the mechanisms of circadian APA regulation.
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Time spent lying, sitting, and upright during hospitalization after stroke: a prospective observation study
Early mobilization has been an important part of acute stroke unit treatment. However, early and intense mobilization within the first 24 h post stroke may cause an unfavorable outcome. Recently, objective mea...
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Dexmedetomidine for Sedation of Neonates with HIE Undergoing Therapeutic Hypothermia: A Single-Center Experience
AJP Rep 2018; 08: e168-e173
DOI: 10.1055/s-0038-1669938
Hypoxic-ischemic encephalopathy (HIE) is a significant cause of morbidity and mortality in neonates. Therapeutic hypothermia reduces the risk of death or disability. Providing optimal sedation while neonates are undergoing therapeutic hypothermia is likely beneficial but may present therapeutic challenges. There are limited data describing the use of dexmedetomidine for sedation in patients undergoing therapeutic hypothermia. The objective of this study is to evaluate the efficacy and short-term safety of dexmedetomidine infusion for sedation in term neonates undergoing therapeutic hypothermia for HIE.
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Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Article in Thieme eJournals:
Table of contents | Abstract | open access Full text
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Pulse wave response characteristics for thickness and hardness of the cover layer in pulse sensors to measure radial artery pulse
Piezo-resistive pressure sensors are widely used for measuring pulse waves of the radial artery. Pulse sensors are generally fabricated with a cover layer because pressure sensors without a cover layer are fra...
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Contribution of Adrenal Glands to Intra-tumor Androgens and Growth of Castration Resistant Prostate Cancer
Purpose: Tumor androgens in castration resistant prostate cancer (CRPC) reflect de novo intra-tumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy. We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Results: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, AED and T in castrated mice became undetectable after adrenalectomy (all p<0.05). Adrenalectomy prolonged median survival (days) in both CRPC models (33 vs 179; 25 vs 301) and suppressed tumor steroids vs castration alone (T 0.64 vs 0.03pg/mg; DHT 2.3 vs 0.23pg/mg; and T 0.81 vs 0.03pg/mg, DHT 1.3 vs 0.04pg/mg; all p=<0.001). A subset of tumors recurred with increased steroid levels, and/or induction of AR, truncated AR variants, and GR. Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and 9 expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3 and HSD17B3). Conclusions:Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of adrenalectomy-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical adrenalectomy than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true 'non-surgical ADX' are warranted.
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Classes of ITD predict outcomes in AML patients treated with FLT3 inhibitors
Purpose: Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of FLT3-ITD mutations, we investigated the effects of FLT3-ITD structural features on the response of AML patients to treatment. Experimental Design: We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in FLT3-ITD-positive AML patients. Results: HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wildtype FLT3 whereas an atypical ITD's insert contains nucleotides exogenous to the wildtype FLT3. Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical FLT3-ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical FLT3-ITDs. Conclusions:These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing towards personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.
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Synergistic interaction of HOXB13 and CIP2A predispose to aggressive prostate cancer
Purpose: Distinguishing aggressive prostate cancer (PrCa) from indolent disease improves personalized treatment. Although, only few genetic variants are known to predispose to aggressive PrCa, synergistic interactions of HOXB13 G84E high-risk PrCa susceptibility mutation with other genetic loci remains unknown. The purpose of this study was to examine the interplay of HOXB13 rs138213197 (G84E) and CIP2A rs2278911 (R229Q) germline variants on PrCa risk. Experimental Design: Genotyping was done in Finnish discovery cohort (n=2738), validated in Swedish (n=3132) and independent Finnish (n=1155) PrCa cohorts. Expression pattern analysis was followed by functional studies in PrCa cell models. Results: Interplay of HOXB13 (G84E) and CIP2A (R229Q) variants results in highest observed inherited PrCa risk (OR 21.1; p=0.000024). In addition, this synergism indicates a significant association of HOXB13 T and CIP2A T dual carriers with elevated risk for high Gleason score (OR 2.3; p=0.025) and worse PrCa specific life expectancy (HR 3.9; p=0.048), and it is linked with high PSA at diagnosis (OR 3.30; p=0.028). Furthermore, combined high expression of HOXB13-CIP2A correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates PrCa cell growth and migration. In addition, we observed strong chromatin binding of HOXB13 at CIP2A locus, and revealed that HOXB13 functionally promotes CIP2A transcription. The study is limited to retrospective Nordic cohorts. Conclusions:Simultaneous presence of HOXB13 T and CIP2A T alleles confers for high PrCa risk and aggressiveness disease, earlier biochemical relapse, lower disease-specific life expectancy. HOXB13 protein binds to CIP2A gene and functionally promotes CIP2Atranscription.
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Screening the Pathogen Box against Plasmodium sexual stages using a new nanoluciferase based transgenic line of P. berghei identifies transmission-blocking compounds. [Susceptibility]
Malaria remains an important parasitic disease with a large morbidity and mortality burden. Plasmodium transmission-blocking (TB) compounds are essential for achieving malaria elimination efforts. Recent efforts to develop high-throughput screening (HTS) methods to identify compounds that inhibit or kill gametocytes, the Plasmodium sexual stage infectious to mosquitoes, have yielded insight into new TB compounds. However, the activities of these compounds against gametes, formed in the first minutes of mosquito infection, are typically not assessed, unless screened in a standard membrane feeding assay (SMFA), a labor intensive assay. Here we demonstrate the generation of a Plasmodium model for drug screens against gametes and fertilization. The new P. berghei line, named Ookluc, was genetically and pharmacologically validated and scalable for HTS. Screening the Pathogen Box from the Medicines for Malaria Venture (MMV) using the new model identified promising TB compounds. The use of Ookluc in different libraries of compounds may aid in the identification of transmission-blocking drugs not assessed in screens against asexual stages or gametocytes.
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Pharmacodynamic Evaluation of Rezafungin (CD101) Against Candida auris in the Neutropenic Mouse Invasive Candidiasis Model [Experimental Therapeutics]
Rezafungin (CD101) is a novel echinocandin under development for once-weekly intravenous (IV) dosing. We evaluated the pharmacodynamics (PD) of rezafungin against four Candida auris strains using the neutropenic mouse invasive candidiasis model. AUC/MIC was a robust predictor of efficacy (R2 0.76). The stasis free-drug 24-h AUC/MIC target exposure for the group was 1.88; whereas the 1-log kill free-drug 24-h AUC/MIC target exposure was 5.77. These values are very similar to previous rezafungin PD studies with other Candida spp. Based on recent surveillance susceptibility data, AUC/MIC targets are likely to be exceeded for >90% of C. auris isolates using the previously studied human dose of 400 mg IV once weekly.
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The effect of plasma protein binding on the anti-HBV activity and pharmacokinetic properties of NVR 3-778. [Antiviral Agents]
High plasma protein binding (PPB) not only affects drug-target engagement but can also impact exposure of hepatocytes to antivirals and thereby affect antiviral activity. In this study, we assessed the effect of PPB on the antiviral activity of NVR 3-778, a sulfamoylbenzamide capsid assembly modulator (CAM). To this end, primary human hepatocyte (PHH) medium was spiked with plasma proteins. At first, the effect of plasma proteins on the HBV-infection assay was evaluated. The addition of plasma proteins neither decreased cell viability nor affected HBV DNA secretion or intracellular HBV RNA accumulation. In contrast, the secretion and intracellular amount of HBV proteins were induced with increasing amounts of plasma proteins. Next, the antiviral activity of NVR 3-778 was demonstrated by multiple assays while PPB and the time-dependent disappearance of the parent drug were quantified by LC-MS/MS. Plasma proteins strongly decreased the free fraction of NVR 3-778 resulting in a physiologically relevant in vitro hepatocyte exposure. NVR 3-778 displayed high PPB, while the antiviral activity was only approximately 4-fold reduced. The disconnect between the high PPB and the only moderate shift of the antiviral activity was explained by the rapid hepatic clearance of NVR 3-778 in the absence of plasma proteins. This study highlights the use of PHHs as a model to accurately determine the antiviral activity by capturing PPB, clearance and liver distribution. It is advantageous to consider both pharmacokinetics and pharmacodynamics for selection of HBV antiviral drug candidates and successful extrapolation of in vitro data to clinical studies.
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In vitro and in vivo assessment of FK506 analogs as novel antifungal drug candidates [Pharmacology]
FK506 (tacrolimus) is an FDA-approved immunosuppressant indicated for the prevention of allograft rejections in patients undergoing organ transplants. In mammals, FK506 inhibits the calcineurin-Nuclear factor of activated T-cells (NFAT) pathway to prevent T-cell proliferation by forming a ternary complex with its binding protein, FKBP12, and calcineurin. FK506 also exerts antifungal activity by inhibiting calcineurin, which is essential for the virulence of human pathogenic fungi. Nevertheless, FK506 cannot be used directly as an antifungal drug due to its immunosuppressive action. In this study, we analyzed the cytotoxicity, immunosuppressive activity, and antifungal activity of four FK506 analogs, 31-O-demethyl-FK506, 9-deoxo-FK506, 9-deoxo-31-O-demethyl-FK506, and 9-deoxo-prolyl-FK506, in comparison with FK506. The four FK506 analogs generally possess lower cytotoxicity and immunosuppressive activity than FK506. The FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against Cryptococcus neoformans and Candida albicans, which are two major invasive pathogenic yeasts, due to the inhibition of the calcineurin pathway. Furthermore, the FK506 analogs, except for 9-deoxo-prolyl FK506, have strong antifungal activity against the invasive filamentous fungus Aspergillus fumigatus. Notably, 9-deoxo-31-O-demethyl-FK506 and 31-O-demethyl-FK506 exhibited robust synergistic antifungal activity with fluconazole, similar to FK506. Considering the antifungal efficacy, cytotoxicity, immunosuppressive activity, and synergistic effect with commercial antifungal drugs, we selected 9-deoxo-31-O-demethyl-FK506 for further evaluation of in vivo antifungal efficacy in the murine model of systemic cryptococcosis. Although 9-deoxo-31-O-demethyl-FK506 alone was not sufficient to treat the cryptococcal infection, its combination treatment with fluconazole significantly extended the survival of C. neoformans-infected mice, confirming synergistic in vivo antifungal efficacy between these two agents.
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First report of an OXA-48 and CTX-M-213-producing Kluyvera spp. clone recovered from patients admitted in a University Hospital in Madrid, Spain [Mechanisms of Resistance]
Enterobacterales species other than Klebsiella pneumoniae also contribute to OXA-48 carbapenemase endemicity. We study the emergence of OXA-48-producing Kluyvera spp., which expresses the novel CTX-M-213, colonizing patients in our Hospital. Rectal swabs from patients admitted in four wards (March-2014-March 2016, R-GNOSIS project) were seeded on ESBL and CARB/OXA-48 chromogenic agar plates. Carbapenemases and ESBLs were characterized (PCR, sequencing, cloning, site-directed mutagenesis) and antibiotic susceptibility was determined. Clonal relatedness was established (XbaI-PFGE) and plasmid content was studied [transformation, S1-PFGE, SB-Hybridization, RFLP (DraI, HpaI) and PCR (incompatibility group and repA, traU and parA genes)]. Whole genome sequencing (WGS, IlluminaHISeq-2500) and further bioinformatics analysis of plasmids (PLACNET, Plasmid SPAdes) were performed. Patients' charts were reviewed. Six unrelated patients (median age 75 years, range 59-81; 4/6 male) colonized with OXA-48-Kluyvera spp. (>95% similarity PFGE-pattern) were detected. Nosocomial acquisition was demonstrated. In two patients, OXA-48-Kluyvera spp. co-existed with OXA-48-producing Raoultella ornithinolytica, K. pneumoniae and Escherichia coli. The blaOXA-48 gene was located on a ~60kb IncL plasmid related to IncL/M-pOXA-48a and the novel blaCTX-M-213 in a conserved chromosomal region of Kluyvera spp. isolates. CTX-M-213 different from CTX-M-13 (K56E) but conferring a similar β-lactam resistance profile, was identified. Genomic analysis also revealed a 177 kb IncF plasmid (class I integronsul1 and aadA2) and an 8 kb IncQ (IS4-blaFOX-8). We describe the first blaOXA-48 plasmid in Kluyvera spp. and the novel chromosomal CTX-M-213 enzyme and highlight further nosocomial dissemination of blaOXA-48 through clonal lineages or plasmids related to IncL/M-pOXA-48a.
https://ift.tt/2wHI0AO
The small compound inhibitor K22 displays broad antiviral activity against different members of the family Flaviviridae and offers potential as pan-viral inhibitor [Antiviral Agents]
The virus family Flaviviridae encompasses several viruses, including (re)-emerging viruses which cause widespread morbidity and mortality throughout the world. Members of this virus family are positive-strand RNA viruses and replicate their genome in close association with reorganized intracellular host cell membrane compartments. This evolutionary conserved strategy facilitates efficient viral genome replication and contributes to evasion from host cell cytosolic defense mechanisms.
We have previously described the identification of a small compound inhibitor, K22, which exerts a potent antiviral activity against a broad range of coronaviruses by targeting membrane-bound viral RNA replication. To analyze the antiviral spectrum of this inhibitor, we assessed the inhibitory potential of K22 against several members of the Flaviviridae family, including the re-emerging Zika virus (ZIKV). We show that ZIKV is strongly affected by K22. Time of addition experiments revealed that K22 acts during a post-entry phase of the ZIKV life cycle, and combination regimens of K22 together with ribavirin (RBV) or interferon alpha (IFN-α) further increased the extent of viral inhibition. Ultrastructural electron microscopy studies revealed severe alterations of ZIKV-induced intracellular replication compartments upon infection of K22-treated cells. Importantly, the antiviral activity of K22 was demonstrated against several other members of the Flaviviridae family. It is tempting to speculate that K22 exerts its broad antiviral activity against several positive-strand RNA viruses via a similar mechanism, and thereby represents an attractive candidate for the development of a pan-viral inhibitor.
https://ift.tt/2wFWsJN
Mechanism of macrolide-induced inhibition of pneumolysin release involves impairment of autolysin release in macrolide-resistant Streptococcus pneumoniae [Mechanisms of Action]
Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Over the past two decades, macrolide resistance among S. pneumoniae has been increasing steadily and has escalated at an alarming rate worldwide. However, the use of macrolides in the treatment of community-acquired pneumonia has been reported to be effective regardless of antibiotic susceptibility of the causative pneumococci. Although previous studies suggested that sub-minimum inhibitory concentrations of macrolides inhibit the production of pneumolysin, a pneumococcal pore-forming toxin, by macrolide-resistant S. pneumoniae (MRSP), the underlying mechanisms of the inhibitory effect have not been fully elucidated. Here, we showed that the release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, was inhibited by treatment with azithromycin and erythromycin, whereas replenishing recombinant autolysin restored the release of pneumolysin from MRSP. Additionally, macrolides significantly downregulated ply transcription followed by a slight decrease of intracellular pneumolysin level. These findings suggested the mechanisms involved in the inhibition of pneumolysin in MRSP, which may provide additional explanation for the benefits of macrolides on the outcome of treatment for pneumococcal diseases.
https://ift.tt/2oHVTvu
Clinicians Should Learn to Engage With Transgender Patients
TUESDAY, Sept. 4, 2018 -- Clinicians should learn how to engage with transgender patients and be prepared to manage unique clinical issues, according to a review published online Aug. 27 in JAMA Internal Medicine. Noting that there are an estimated...
https://ift.tt/2CkMsf3
FDA: Montelukast Tablet Bottles Recalled
TUESDAY, Sept. 4, 2018 -- Some bottles of montelukast (Singulair) tablets for asthma have been recalled by Camber Pharmaceuticals because they contain the wrong medication, the U.S. Food and Drug Administration says. Bottles labeled as containing 30...
https://ift.tt/2wICTRO
Enrollment in High-Deductible Health Plans Up From '07 to '17
TUESDAY, Sept. 4, 2018 -- Enrollment in high-deductible health plans (HDHPs) has increased among adults with employment-based insurance coverage, according to an August data brief published by the U.S. Centers for Disease Control and Prevention's...
https://ift.tt/2wEirAI
When designing vaccines, consider the starting material: the human B cell repertoire
Colin Havenar-Daughton | Robert K. Abbott | William R. Schief | Shane Crotty
https://ift.tt/2Q3mYW6
Screening and Whole-Genome Sequencing of Two Streptomyces Species from the Rhizosphere Soil of Peony Reveal Their Characteristics as Plant Growth-Promoting Rhizobacteria
Two bacteria, Streptomyces albireticuli MDJK11 and S. alboflavus MDJK44, which are potential plant growth-promoting rhizobacteria against pathogenic fungi were isolated from the rhizosphere soil of peony in Shandong, China. Their biological characteristics and complete genome sequences were reported in this study. The total genome size of MDJK11 was only 8.14 Mb with 6,550 protein-coding genes and a high GC content of 72.8 mol%. The MDJK44 genome comprises a 9.62 Mb chromosome with 72.1 mol% GC content, 7,285 protein-coding genes, and two plasmids. Some gene sequences in these two genomes were analyzed to be heterologously obtained by horizontal transfer. Gene or gene cluster candidates responding to secondary metabolites production, antimicrobial activities, and plant growth-promoting capacities were also analyzed in this paper. The genomic information and biological characteristics will facilitate the understanding and application of S. albireticuli and S. alboflavus species as biocontrol agents in future agriculture.
https://ift.tt/2Cm0NrH
Impact of microbial Aetiology on mortality in severe community-acquired pneumonia
The impact of different classes of microbial pathogens on mortality in severe community-acquired pneumonia is not well elucidated. Previous studies have shown significant variation in the incidence of viral, b...
https://ift.tt/2PBEgbT
Characteristics of peripheral Vγ2Vδ2 T cells in interferon-γ release assay negative pulmonary tuberculosis patients
It is not fully explained why some active tuberculosis patients show negative interferon-γ release assays (IGRAs). In this study, we tried to explore associations of IGRAs with the characteristics of periphera...
https://ift.tt/2MObfgo
First co-infection case of melioidosis and Japanese encephalitis in China
Melioidosis is endemic in Southeast Asia and northern Australia. Infection usually follows percutaneous inoculation or inhalation or ingestion of the causative bacterium, Burkholderia pseudomallei, which is prese...
https://ift.tt/2NPpoWY
Understanding value and how it relates to EMS costs
EMS should utilize a data-driven approach to value management that considers both quality and costs
https://ift.tt/2CjTKQ7
Innate immune sensor LGP2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma
Cancer Science, Volume 0, Issue ja, -Not available-.
https://ift.tt/2NP6U97
The effect of temperature increase on microbial carbon fluxes in the Adriatic Sea: an experimental approach
ABSTRACT
An assessment of the temperature increase effect on processes within the microbial food web provides a better insight into the carbon transfer and energy flow processes in marine environments in the global warming perspective. Modified laboratory dilution experiments that allow simultaneous estimates of protozoan grazing and viral lysis on picoplankton groups (bacteria, Prochlorococcus, Synechococcus and pico-eukaryotic algae) under in situ and 3°C above in situ temperatures were performed at seasonal scale. Picoplankton mortality due to grazing was generally higher than that caused by viral lysis, especially in the cold months. The largest part of HNF carbon demand was satisfied by grazing on bacteria throughout the year. Although ciliates satisfied their carbon demand predominantly through grazing on HNF and bacteria, the role of autotrophic picoplankton (APP) as their prey increased significantly in the cold months. Bacteria constituted the most important host for viruses throughout the year. However, during the warm months, APP groups were also significant hosts for viral infection. Under the warming condition the amount of picoplankton biomass transferred to protozoan grazers exceeded the lysed biomass, suggesting that global warming could further increase picoplankton carbon flow toward higher trophic levels in the Adriatic Sea.https://ift.tt/2wIk9lq
The marine bacterium Phaeobacter inhibens secures external ammonium by rapid buildup of intracellular nitrogen stocks
ABSTRACT
Reduced nitrogen species are key nutrients for biological productivity in the oceans. Ammonium is often present in low and growth-limiting concentrations, albeit peaks occur during collapse of algal blooms or via input from deep sea upwelling and riverine inflow. Autotrophic phytoplankton exploit ammonium peaks by storing nitrogen intracellularly. In contrast, the strategy of heterotrophic bacterioplankton to acquire ammonium is less well understood. This study revealed the marine bacterium Phaeobacter inhibens DSM 17395, a Roseobacter group member, to have already depleted the external ammonium when only ∼⅓ of the ultimately attained biomass is formed. This was paralleled by a three-fold increase in cellular nitrogen levels and rapid buildup of various nitrogen-containing intracellular metabolites (and enzymes for their biosynthesis) and biopolymers (DNA, RNA and proteins). Moreover, nitrogen-rich cells secreted potential RTX proteins and the antibiotic tropodithietic acid, perhaps to competitively secure pulses of external ammonium and to protect themselves from predation. This complex response may ensure growing cells and their descendants exclusive provision with internal nitrogen stocks. This nutritional strategy appears prevalent also in other roseobacters from distant geographical provenances and could provide a new perspective on the distribution of reduced nitrogen in marine environments, i.e. temporary accumulation in bacterioplankton cells.https://ift.tt/2CjlKTW
Front cover story: Eur. J. Immunol. 9'18
European Journal of Immunology, Volume 48, Issue 9, September 2018.
https://ift.tt/2Q5bscL
Journal roundup
European Journal of Immunology, Volume 48, Issue 9, Page 1427-1427, September 2018.
https://ift.tt/2LZE9EM
Contents: Eur. J. Immunol. 9'18
European Journal of Immunology, Volume 48, Issue 9, Page 1421-1424, September 2018.
https://ift.tt/2Q4IBFu
Upcoming EFIS‐EJI sponsored Meetings
European Journal of Immunology, Volume 48, Issue 9, Page 1428-1429, September 2018.
https://ift.tt/2LXb6lu
Editorial Board: Eur. J. Immunol. 9'18
European Journal of Immunology, Volume 48, Issue 9, September 2018.
https://ift.tt/2Q34a9s
Impressum
European Journal of Immunology, Volume 48, Issue 9, Page 1595-1595, September 2018.
https://ift.tt/2M3cNOo
In this issue
European Journal of Immunology, Volume 48, Issue 9, Page 1425-1426, September 2018.
https://ift.tt/2Q4Ivh6
The utility of rapid on-site evaluation of touch imprint cytology from endoscopic and cholangioscopic forceps biopsy (with video)
Rapid on-site evaluation of touch imprint cytology (ROSE-TIC) is a simple and rapid method used for the diagnosis of benign and malignant lesions. We evaluated the diagnostic accuracy of ROSE-TIC for advanced intestinal luminal and indeterminate pancreatobiliary lesions during endoscopy.
https://ift.tt/2PBnklP
Neuroimmune mechanisms of psychostimulant and opioid use disorders
European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.
https://ift.tt/2NJaeT4
Understanding value and how it relates to EMS costs
EMS should utilize a data-driven approach to value management that considers both quality and costs
https://ift.tt/2CjTKQ7
Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility
International Journal of Cancer, Volume 0, Issue ja, -Not available-.
https://ift.tt/2NQWG8l
Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol‐induced liver damage, steatosis and inflammation in mice
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2MQwyxW
NLRP3 inflammasome activation in hepatic stellate cells induces murine liver fibrosis
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2LZWS3c
Hepatitis B Virus Induces Autophagy to Promote its Replication by the Axis of miR‐192‐3p‐XIAP via NF‐κB Signaling
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2NizzGC
Limitations of Fractional Excretion of Urea in Clinical Practice
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2LWNv4p
Burden of Illness and Economic Model for Patients with Non‐Alcoholic Steatohepatitis (NASH) in the United States
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2Nn89zv
Global Perspectives on Non‐alcoholic Fatty Liver Disease and Non‐alcoholic Steatohepatitis
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2wI6uKo
From hepatocyte to cholangiocyte: the remarkable potential of transdifferentiation to treat cholestatic diseases
Hepatology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2wI64ng
Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women
Experimental Physiology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2PBokXe
EDSS progression assessment heterogeneity in MS according to geographical areas
Annals of Neurology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2PzXNte
The association between carotid atheroma and cerebral cortex structure at age 73
Annals of Neurology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2oFpe9G
Low‐Voltage Fast Seizures in Humans Begin With Increased Interneuron Firing
Annals of Neurology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2PwqqHG
Facioscapulohumeral dystrophy in childhood: a nationwide natural history study
Annals of Neurology, Volume 0, Issue ja, -Not available-.
https://ift.tt/2oFp02k
Mass Production of Large‐Sized, Nonlayered 2D Nanosheets: Their Directed Synthesis by a Rapid “Gel‐Blowing” Strategy, and Applications in Li/Na Storage and Catalysis
Advanced Materials, EarlyView.
https://ift.tt/2NiupdI
Rapidly Progressing Fatal High-Altitude Illness in a Patient with Hyperthyroidism
High Altitude Medicine &Biology, Ahead of Print.
https://ift.tt/2wJ9ffj
Two Drugs Work Together to Block ‘Master Regulator’ of Breast, Other Cancers
Arsenic trioxide and retinoic acid work together to target the master regulator protein Pin1, a new study shows. In cancer cell lines and mice, the drug combination slowed the growth of triple-negative breast cancer tumors.
https://ift.tt/2MMnav2
Breast Cancer Surgery Outcomes Poor for Nursing Home Residents
TUESDAY, Sept. 4, 2018 -- For female nursing home residents who undergo breast cancer surgery, rates of one-year mortality and functional decline are high, according to a study published online Aug. 29 in JAMA Surgery. Victoria Tang, M.D., from the...
https://ift.tt/2NPA3B8
Uninsured CV Hospitalization Down With Medicaid Expansion
TUESDAY, Sept. 4, 2018 -- States that expanded Medicaid had a greater reduction in the proportion of uninsured hospitalizations for major cardiovascular events, according to a study published online Aug. 24 in JAMA Network Open. Ehimare Akhabue,...
https://ift.tt/2wGdJDw
Remission of Schizophrenia Seen With Amisulpride, Clozapine
TUESDAY, Sept. 4, 2018 -- Remission can be achieved for most cases of schizophrenia and schizophreniform disorder with amisulpride and clozapine, according to a study published online Aug. 13 in the The Lancet Psychiatry. René S. Kahn, M.D., from...
https://ift.tt/2wKggfN
Relapse-Free Cure From MDR-TB Higher Than Anticipated
TUESDAY, Sept. 4, 2018 -- The frequency of relapse-free cure from multidrug-resistant tuberculosis (MDR-TB) is higher than previously anticipated, according to a study published in the Aug. 1 issue of the American Journal of Respiratory and Critical...
https://ift.tt/2NMYZJs
Adding Pharmacist to Team Can Improve Patient Outcomes
TUESDAY, Sept. 4, 2018 -- Integration of pharmacists into team-based care practice models can improve patient outcome, especially in chronic diseases, such as diabetes, according to a report published in the American Medical Association's AMA...
https://ift.tt/2CjI9Rb
Nalbuphine Can Relieve Opioid-Induced Urine Retention
TUESDAY, Sept. 4, 2018 -- Nalbuphine can relieve opioid-induced urine retention, according to a case report published online Sept. 4 in the Annals of Internal Medicine. Abdisamad M. Ibrahim, M.D., from the Southern Illinois University School of...
https://ift.tt/2oGsnWG
CDC: Increase in Rate of STDs for Fourth Consecutive Year in U.S.
TUESDAY, Sept. 4, 2018 -- Nearly 2.3 million cases of chlamydia, gonorrhea, and syphilis were diagnosed in the United States in 2017, marking a fourth consecutive year of sharp increases in these sexually transmitted diseases (STDs), according to a...
https://ift.tt/2CgWPAA.
August 2018 Briefing - Geriatrics
Here are what the editors at HealthDay consider to be the most important developments in Geriatrics for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are...
https://ift.tt/2oGsjWW
August 2018 Briefing - Allergy
Here are what the editors at HealthDay consider to be the most important developments in Allergy for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...
https://ift.tt/2CugvkD
August 2018 Briefing - Anesthesiology
Here are what the editors at HealthDay consider to be the most important developments in Anesthesiology for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
https://ift.tt/2Cjzluy
August 2018 Briefing - Hematology & Oncology
Here are what the editors at HealthDay consider to be the most important developments in Hematology & Oncology for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory...
https://ift.tt/2wKeRpn
August 2018 Briefing - Cosmetic Surgery
Here are what the editors at HealthDay consider to be the most important developments in Cosmetic Surgery for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
https://ift.tt/2wDRXQH
August 2018 Briefing - Pain Management
Here are what the editors at HealthDay consider to be the most important developments in Pain Management for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
https://ift.tt/2NM1ATL
August 2018 Briefing - HIV & AIDS
Here are what the editors at HealthDay consider to be the most important developments in HIV & AIDS for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that...
https://ift.tt/2oGs666
August 2018 Briefing - Urology
Here are what the editors at HealthDay consider to be the most important developments in Urology for August 2018. This roundup includes the latest research news from journal articles, as well as the FDA approvals and regulatory changes that are the...
https://ift.tt/2Cg3Lh2
miR-23b promotes cutaneous wound healing through inhibition of the inflammatory responses by targeting ASK1
Abstract
Wound healing is a complicated event that develops in three overlapping phases: inflammatory, proliferative, and remodeling. MicroRNAs (miRNAs) have been proved to play an important role in the healing process of skin trauma, and alteration of specific miRNA expression during different phases may be associated with abnormal wound healing. In this study, we determined the variation of miR-23b expression after trauma in normal mice and in cultured cells exposed to lipopolysaccharide. We further demonstrated that excessive miR-23b could significantly accelerate wound healing in vivo. Up-regulation of miR-23b decreases infiltration of inflammatory cells, as evidenced by pathologic staining. Meanwhile, miR-23b could significantly inhibit the expression of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and Ccl2, and significantly increase anti-inflammatory factor IL-10. Furthermore, miR-23b could also promote α-SMA expression in a fiber pattern and increase the expression of Col1a1 and Col3a1. Importantly, we also showed that miR-23b could inhibit inflammation to promote wound healing by targeting apoptotic signal-regulating kinase 1 (ASK1). Notably, knockdown of ASK1 could reduce inflammation factor expression in vitro. Together, our data reveal that miR-23b is a potent therapeutic agent for cutaneous wound healing that shortens the period of inflammatory responses and promotes keratinocyte migration for the re-epithelialization of wound sites.https://ift.tt/2oFKyvC
Inhibiting 6-phosphogluconate dehydrogenase enhances chemotherapy efficacy in cervical cancer via AMPK-independent inhibition of RhoA and Rac1
Abstract
Background
The oxidative pentose phosphate pathway (PPP) is essential for cancer metabolism and growth. However, the contribution of 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of PPP, to cervical cancer development remains largely unknown.
Methods
mRNA and protein levels of 6PGD were analyzed in cervical cancer cells and tissues derived from patients and compared to normal counterparts. Using cell culture system and xenograft mouse model, the functions of 6PGD in cervical cancer are determined and its molecular mechanism is analyzed. 6PGD inhibitor physcion and siRNA knockdown were used.
Results
In this work, we demonstrate that 6PGD is aberrantly upregulated and activated in cervical cancer cells and patient tissues compared to normal counterparts. Using different approaches and preclinical models, we show that 6PGD inhibition decreases growth and migration, and enhances chemosensitivity in cervical cancer. Mechanistically, inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and decreases RhoA and Rac1 activities. AMPK depletion significantly reduces the effects of 6PGD inhibition in decreasing RhoA and Rac1 activities, growth and migration in cervical cancer cells.
Conclusions
Our work is the first to demonstrate the aberrant expression of 6PGD and its predominant roles in cervical cancer cell growth and migration, via a AMPK-dependent activation. Our findings suggest 6PGD as a potential therapeutic target to enhance chemosensitivity in cervical cancer.
https://ift.tt/2wHzTnV
Retroperitoneal fibrosis secondary to non-urology carcinomas: a clinical and outcome analysis of 97 cases
Abstract
Purpose
Accumulated evidences have reminded us that since the prognosis of retroperitoneal fibrosis (RPF) secondary to non-urology carcinoma is poor it is essential to distinguish this condition from others. The objective of this study is to investigate the clinical features and outcomes of this infrequent but life-threatening disease.
Methods
A total of 97 patients diagnosed with RPF secondary to non-urology carcinoma were enrolled in this retrospective study. The baseline information, history of carcinoma, clinical presentation, laboratory results, diagnosis, treatment and prognosis of the patients were collected and analyzed.
Results
The mean age was 62.32 ± 11.22 years (range 31–85 years). It took 16.72 ± 7.11 days (range 3–34 days) for the patients with originally unexplained hydronephrosis to get a definite diagnosis of RPF secondary to non-urology carcinoma. Imaging-confirmed RPF [confirmed by computed tomography (CT) or magnetic resonance imaging (MRI)] was found in 91 patients. Fifty-seven patients were diagnosed with histological-confirmed malignant RPF. Sixty-six patients received surgical interventions. Cystoscopy and double J tube were performed in 68 cases (102 sides, 172 times) and was failed in 93 times (54.07%). Pyelostomy was performed in 72 patients (92 sides) without a single failure. Furthermore, eighty patients received chemotherapy and/or radiotherapy. The 6-month survival since RPF secondary to non-urology carcinoma was confirmed was 30%.
Conclusions
All patients with newly diagnosed unexplained hydronephrosis should undergo an age-appropriate carcinoma screening. The prognosis of RPF secondary to non-urology carcinoma was dismal. When dealing with hydronephrosis affecting renal function, pyelostomy instead of double J tube catheterization should be performed ahead of time.
https://ift.tt/2NhNw7w
Treg Destabilization and Reprogramming: Implications for Cancer Immunotherapy
Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proinflammatory signals such as IL6 and IFNγ. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proinflammatory phenotype. In this review, we propose the hypothesis that this phenotypic modulation does not reflect infidelity to the Treg lineage, but rather represents a natural, physiologic response of Tregs during beneficial inflammation. In tumors, however, this inflammation-induced Treg destabilization is actively opposed by dominant stabilizing factors such as indoleamine 2,3-dioxygenase and the PTEN phosphatase pathway in Tregs. Under such conditions, tumor-associated Tregs remain highly suppressive and inhibit cross-presentation of tumor antigens released by dying tumor cells. Interrupting these Treg stabilizing pathways can render tumor-associated Tregs sensitive to rapid destabilization during immunotherapy, or during the wave of cell death following chemotherapy or radiation, thus enhancing antitumor immune responses. Understanding the emerging pathways of Treg stabilization and destabilization may reveal new molecular targets for therapy. Cancer Res; 78(18); 1–9. ©2018 AACR.
https://ift.tt/2wIgBzA
p63-dependent Dickkopf3 expression promotes esophageal cancer cell proliferation via CKAP4
Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family but exhibits structural divergence from other family members; and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promotes tumorigenesis remains to be clarified. We show here that DKK3 stimulates esophageal cancer cell proliferation via cytoskeleton-associated protein 4 (CKAP4), which acts as a receptor for DKK3. DKK3 was expressed in ~50% of tumor lesions of esophageal squamous cell carcinoma (ESCC) cases; simultaneous expression of DKK3 and CKAP4 was associated with poor prognosis. Anti-CKAP4 antibody inhibited both binding of DKK3 to CKAP4 and xenograft tumor formation induced by ESCC cells. p63, a p53-related transcriptional factor frequently amplified in ESCC, bound to the upstream region of the DKK3 gene. Knockdown of p63 decreased DKK3 expression in ESCC cells, and re-expression of DKK3 partially rescued cell proliferation in p63-depleted ESCC cells. Expression of ΔNp63α and DKK3 increased the size of tumor-like esophageal organoids, and anti-CKAP4 antibody inhibited growth of esophageal organoids. Taken together, these results suggest that the DKK3-CKAP4 axis might serve as a novel molecular target for ESCC.
https://ift.tt/2NNm4LZ
Astrocyte elevated gene-1 (AEG-1) regulates macrophage activation in hepatocellular carcinogenesis
Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 (AEG-1) regulates NF-kappaB activation, and germline knockout of AEG-1 in mice (AEG-1-/-) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell-specific AEG-1-/- mice (AEG-1deltaHEP and AEG-1deltaMAC, respectively) and induced HCC by treatment with N-nitrosodiethylamine and phenobarbital. AEG-1deltaHEP mice exhibited a significant reduction in disease severity compared to control littermates, while AEG-1deltaMAC mice were profoundly resistant. In vitro, AEG-1-/- hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1-/- macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis.
https://ift.tt/2oFBHu9
Elevated Stromal Inflammatory Mediators Promote Prostate Cancer Progression in African American Men
Progress in prostate cancer racial disparity (PCa-HD) research has been hampered by a lack of appropriate research tools and better understanding of the tumor biology. Recent gene expression studies suggest that the tumor microenvironment (TME) may contribute to racially disparate clinical outcomes in PCa. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African American (AA) compared to European American (EA) patients with PCa. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF-AA) and EA (PrF-EA) PCa tissues and studied their functional characteristics. PrF-AA showed increased growth response to androgens FGF2 and PDGF. Compared to PrF-EA, conditioned media from PrF-AA significantly enhanced the proliferation and motility of PCa cell lines. Expression of markers associated with myofibroblast activation (αSMA, vimentin, and tenascin-C) were elevated in PrF-AA. In vivo tumorigenicity of an AA patient-derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF-AA compared to PrF-EA. RNA-seq data and cytokine array analysis identified a panel of potential pro-inflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL18BP, IL6 and VEGF) to be enriched in PrF-AA. E006AA cell lines showed increased responsiveness to BDNF ligand compared to EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the pro-tumorigenic effects induced by PrF-AA compared to PrF-EA. These findings suggest that fibroblasts in the TME of AA patients may contribute to the health disparity observed in the incidence and progression of PCa tumors
https://ift.tt/2NSLZSk
Cancers, Vol. 10, Pages 310: Surgical Resection Versus Stereotactic Body Radiation Therapy for Stage I NSCLC: Can Randomized Trials Provide the Solution?
Cancers, Vol. 10, Pages 310: Surgical Resection Versus Stereotactic Body Radiation Therapy for Stage I NSCLC: Can Randomized Trials Provide the Solution?
Cancers doi: 10.3390/cancers10090310
Authors: Melanie P. Subramanian Bryan F. Meyers
Surgical resection has traditionally been considered the standard of care for patients with stage I non-small cell lung cancer (NSCLC). With the introduction of stereotactic radiation body therapy (SBRT), there is now a viable option for medically inoperable patients with stage I NSCLC. The effectiveness of SBRT in patients with stage I disease but at elevated surgical risk is unknown. Multiple randomized controlled trials (RCTs) have been attempted to compare surgical resection and SBRT in this population, but have been aborted due to poor patient enrollment. Despite these failures, there still remains a push for more RCTs. In this commentary, we review the challenges that RCTs face in their ability to appropriately compare these two therapies.
https://ift.tt/2wJPQKZ
Biochemical and kinetic properties of the complex Roco G-protein cycle
Journal Name: Biological Chemistry
Issue: Ahead of print
https://ift.tt/2PDTFbX
Aberrant expression of hsa_circ_0025036 in lung adenocarcinoma and its potential roles in regulating cell proliferation and apoptosis
Journal Name: Biological Chemistry
Issue: Ahead of print
https://ift.tt/2wGP8ya
A phase I clinical trial of hepatic arterial infusion of oxaliplatin and oral capecitabine, with or without intravenous bevacizumab, in patients with advanced cancer and predominant liver involvement
Abstract
Background
We investigated hepatic arterial infusion (HAI) oxaliplatin combined with capecitabine +/− bevacizumab in advanced cancer with predominant liver involvement.
Methods
Patients received HAI oxaliplatin (140 mg/m2) and escalating doses of capecitabine (500, 750, and 1000 mg/m2), with (Group 1) or without (Group 2) bevacizumab (10 mg/kg IV). A 3 + 3 dose design was used, followed by an expansion phase.
Results
From 9/2009 to 2/2014, 61 patients (34 men, 27 women) were enrolled (Group 1 = 44; Group 2 = 17). Patients were treated in Group 2 if they had contraindications to bevacizumab (n = 13) or if there was no opening in Group 1 (n = 4). The median age was 60 years (range, 20–88). The most common cancers were colorectal (22 patients), liver (12), pancreatic (7), breast (4), and biliary tract (4). The median number of prior therapies was 3 (range, 1–12); 32 (53%) patients had received oxaliplatin. The dose-limiting toxicity was Grade 3 diarrhea and occurred in 2 patients receiving 1000 mg/m2 capecitabine. The maximum tolerated dose was HAI oxaliplatin 140 mg/m2, capecitabine 750 mg/m2, and bevacizumab 10 mg/kg. The most common toxicities were nausea/vomiting, anemia, thrombocytopenia, neutropenia, and hypomagnesemia. The rates of partial response and stable disease ≥ 4 months were 22% and 39% (Group 1) and 9% and 0% (Group 2). The respective median time to treatment failure and overall survival were 3 and 6.9 months (Group 1) and 1.5 and 5.9 months (Group 2).
Conclusion
HAI oxaliplatin combined with capecitabine +/− bevacizumab was well-tolerated and was associated with favorable outcomes in selected patients.
https://ift.tt/2NRFJKY
EMS From a Distance: Responding to Emergency
Emphasizing the old-world values of Squad 51 in today's EMS
https://ift.tt/2NLZ1RO
Technical and dosimetric implications of respiratory induced density variations in a heterogeneous lung phantom
Abstract
Background
Stereotactic Body Radiotherapy (SBRT) is an ablative dose delivery technique which requires the highest levels of precision and accuracy. Modeling dose to a lung treatment volume has remained a complex and challenging endeavor due to target motion and the low density of the surrounding media. When coupled together, these factors give rise to pulmonary induced tissue heterogeneities which can lead to inaccuracies in dose computation. This investigation aims to determine which combination of imaging techniques and computational algorithms best compensates for time dependent lung target displacements.
Methods
A Quasar phantom was employed to simulate respiratory motion for target ranges up to 3 cm. 4DCT imaging was used to generate Average Intensity Projection (AIP), Free Breathing (FB), and Maximum Intensity Projection (MIP) image sets. In addition, we introduce and compare a fourth dataset for dose computation based on a novel phase weighted density (PWD) technique. All plans were created using Eclipse version 13.6 treatment planning system and calculated using the Analytical Anisotropic Algorithm and Acuros XB. Dose delivery was performed using Truebeam STx linear accelerator where radiochromic film measurements were accessed using gamma analysis to compare planned versus delivered dose.
Results
In the most extreme case scenario, the mean CT difference between FB and MIP datasets was found to be greater than 200 HU. The near maximum dose discrepancies between AAA and AXB algorithms were determined to be marginal (< 2.2%), with a greater variability occurring within the near minimum dose regime (< 7%). Radiochromatic film verification demonstrated all AIP and FB based computations exceeded 98% passing rates under conventional radiotherapy tolerances (gamma 3%, 3 mm). Under more stringent SBRT tolerances (gamma 3%, 1 mm), the AIP and FB based treatment plans exhibited higher pass rates (> 85%) when compared to MIP and PWD (< 85%) for AAA computations. For AXB, however, the delivery accuracy for all datasets were greater than 85% (gamma 3%,1 mm), with a corresponding reduction in overall lung irradiation.
Conclusions
Despite the substantial density variations between computational datasets over an extensive range of target movement, the dose difference between CT datasets is small and could not be quantified with ion chamber. Radiochromatic film analysis suggests the optimal CT dataset is dependent on the dose algorithm used for evaluation. With AAA, AIP and FB resulted in the best conformance between measured versus calculated dose for target motion ranging up to 3 cm under both conventional and SBRT tolerance criteria. With AXB, pass rates improved for all datasets with the PWD technique demonstrating slightly better conformity over AIP and FB based computations (gamma 3%, 1 mm). As verified in previous studies, our results confirm a clear advantage in delivery accuracy along with a relative decrease in calculated dose to the lung when using Acuros XB over AAA.
https://ift.tt/2NLPXfI
Atypical presentation of acute aortic dissection in a young competitive rower
A 27-year-old man (who is also the lead author) presented with dull pain deep to the suprasternal notch, following a period of intense exercise (rowing). He was initially sent home with no diagnosis, but 24 hours later returned to a different Accident & Emergency (A&E), due to continued discomfort and an increasingly altered mental state, and was diagnosed with an extensive type A aortic dissection extending from the aortic root to the iliac bifurcation of the aorta, with an ~8 cm aneurysm on the ascending aorta and a diseased aortic valve. Following emergency surgery to replace the aortic valve and the aorta from the aortic root to the middle of the aortic arch (hemiarch), the patient recovered well.
https://ift.tt/2NdbDnX
First report of concomitant pheochromocytoma and duodenal neuroendocrine tumour in a sporadic multiple endocrine neoplasia type 1
A 77-year-old woman was diagnosed with pheochromocytoma followed by adrenalectomy at age 57. Hyperparathyroidism without osteoprosis was diagnosed at age 58. At age 75, Dual Energy X-ray Absoptiometry (DEXA) revealed osteoporosis and sestamibi scan showed a left parathyroid adenoma. Criteria for parathyroidectomy were met, and she underwent parathyroidectomy. Furthermore, she presented with haematochezia at age 75. An abdominal CT demonstrated a mass in the second portion of the duodenum. Additionally, octreoscan revealed somatostatin receptor positive tissue in the duodenum and Gallium 68 dotatate scan also showed a well-differentiated duodenal neuroendocrine tumour (NET). Genetic testing for MEN1, MEN2 and MEN4 was negative. Diagnosis of sporadic MEN1 syndrome was made. The patient underwent resection of the duodenal NET at age 76. She is in good health 21 years after her first presentation of MEN1. In summary, we present the first sporadic case of MEN1 with concomitant pheochromocytoma and duodenal NET which occurred 20 years apart.
https://ift.tt/2MKw10d
Incidentally detected adrenocortical carcinoma in familial adenomatous polyposis: an unusual presentation of a hereditary cancer syndrome
Description
A 30-year-old woman presented to us with complaints of intermittent bleeding per rectum, vague abdominal pain and altered bowel habits for last 3 months. There was no history of headache, palpitations, diarrhoea, weight loss, skin lesions, haematuria and hypertension. Her grandmother had history of colostomy for acute intestinal obstruction and died of unexplained cause at age of 55 years. Her laboratory investigations were normal. On digital rectal examination, multiple polypoidal firm masses were felt approximately 1–5 cm from anal verge. On colonoscopy, number of polyps were seen in the colon around 40–50 in number, ranging from few millimetres to largest measuring around 3 cm. These polyps spread over ascending to sigmoid colon and rectum in increasing number. The biopsy from these polyps was suggestive of tubular adenomas. A definitive diagnosis of familial adenomatous polyposis (FAP) was made. FAP is associated with a myriad of presentations, and hence, a thorough work...
https://ift.tt/2LZucXY
Ultrasonographic assessment of the lens
Description
B scan ultrasonography is the most commonly used modality for the assessment of posterior segment pathologies.1–3 On placing the probe along the lateral longitudinal axis, the nasal aspect of the retina, ciliary body, the lens in its entirety, iris, angle and peripheral cornea can be appreciated easily. Using this technique, the anatomy of the lens can be studied in terms of its width along the horizontal and anteroposterior extent; similarly, by placing the probe along the inferior longitudinal axis, the vertical width of the lens can be defined, along with the anteroposterior thickness. This technique helps in the assessment of lens in its entirety, from the anterior capsule to the posterior capsule. Herein few pathologies of the lens and its capsule are illustrated using B scan ultrasound (Sonomed, New York, USA).
After making the patient lie down in a comfortable supine...
https://ift.tt/2wH52YH
Mumps presenting with unilateral, synchronous parotid and submandibular gland swelling
A previously healthy 22-year-old woman presented with acute, unilateral facial and neck swelling, associated with fever and malaise. She was initially treated with intravenous antibiotics; however, CT imaging showed unilateral, synchronous swelling and inflammation of the parotid and submandibular glands, and a PCR swab from the parotid duct was positive for mumps. She was fully immunised and had no contact in the preceding period with anyone diagnosed with mumps. She responded to supportive management and her symptoms resolved over the course of her admission. Unilateral, synchronous swelling and severe inflammation of both the parotid and submandibular glands in mumps is a very unusual presentation, and not one previously reported in the literature.
https://ift.tt/2LWjaTe
Management of a giant uterine leiomyoma
Uterine leiomyomas are the most common tumours arising from the female reproductive tract. However, giant myomas, which are greater than 11.4 kg in weight, are exceedingly rare. They may cause a pressure effect on surrounding organs, heart and lungs, which can be potentially life threatening. We present a case of a 53-year-old woman with a massive uterine mass complicated by restrictive lung disease. She underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy with frozen section and reconstruction of the abdominal wall by the gynaecologists and plastic surgeons. The excised specimen weighed 27.8 kg, which included a benign subserosal leiomyoma measuring 64 by 50.5 by 15 cm. Intraoperative blood loss was 7 L and her postoperative recovery was complicated by coagulopathy and haemorrhagic shock. This case illustrates the pivotal role of multidisciplinary care in the management of complicated surgical patients and the need for careful perioperative care.
https://ift.tt/2NhP7u2
Vacuum-assisted right atrial infected clot extraction due to persistent bacteraemia: a percutaneous approach for the management of right-sided endocarditis
A 56-year-old woman with non-ischaemic cardiomyopathy with implantable cardioverter defibrillator (ICD) presented to the hospital with progressive dyspnoea of 4 weeks' duration. She soon spiralled down to develop septic shock with methicillin-sensitive Staphylococcus aureus bacteraemia. A transoesophageal echocardiogram revealed a 2.4x2.1 cm large mobile echodensity in the right atrium likely attached to the ICD lead and to the interatrial septum. Although the ICD along with its leads was extracted, bacteraemia persisted despite appropriate antibiotic therapy. Because of her worsening condition, she underwent a right atrial infected clot extraction by the AngioVac system. Her clinical condition noticeably improved soon after evacuation of the infected clot.
https://ift.tt/2LWja5G
Laryngopyocoele with contralateral laryngocoele: a rare cause of respiratory distress
We present the case of a 76-year-old patient who attended our emergency department with signs of sepsis and severe respiratory distress. She had stridor, type 1 respiratory failure and a left-sided neck swelling. On CT, it was initially misdiagnosed as parapharyngeal abscess. When the imaging was reviewed, it was found to be a left-sided mixed laryngopyocoele obstructing the larynx with an asymptomatic contralateral laryngocoele. The internal component of the left laryngopyocoele was excised through a microlaryngoscopy approach while the external component was approached through a transcervical incision. The patient recovered well despite a postoperative myocardial infarction. Both laryngocoeles and laryngopyocoeles are rare, with the latter being the rarer of the two, however, extensive literature review could not identify any previous cases where both have coexisted in the same patient.
https://ift.tt/2NhOVuO
Hereditary sensory and autonomic neuropathy in a male child: 'The other side of not feeling pain
Description
A 1-year-old boy was brought to our outpatient department with complaints of whitish opacity in both eyes noticed 3 months ago. The mother also gave a history of self-mutilating behaviour in the child. There was a history of absence of crying during vaccination. There was no history of consanguinity and a similar disease in the family. The child was following light binocularly. On anterior segment examination, bilateral corneal scarring secondary to keratitis was seen (figure 1A). Corneal sensations were absent. An ocular ultrasonography was done for posterior segment evaluation, which revealed no abnormalities. There were signs of self-mutilation in the perioral area in form of damage to both upper and lower lips that caused as a result of repeated insults in form of tooth bite (figure 1B). Apart from this, similar injuries were present in fingers of hands (figure 1C) as...
https://ift.tt/2wEfbFv
Missed ureteral injury in a young man with stab injury
Description
An 18-year-old man was referred to us from the department of emergency surgery for management of his ureteric injury. The patient underwent exploratory laparotomy for bowel injury that he had sustained due to a stab wound to his left flank 1 month ago. At that time his ureteric injury was missed. Two weeks after being discharged he developed fever and his ultrasonogram was suggestive of a large left retroperitoneal collection with mild left hydronephrosis. A contrast-enhanced CT (CECT) scan was done that demonstrated leak of contrast from left ureter into the collection (figure 1A). The patient then underwent insertion of a percutaneous nephrostomy tube into the left kidney along with placement of a drain into the retroperitoneal collection. The drain placed into the collection had purulent output suggesting an infected urinoma. Two weeks later another CECT scan was done, which showed persistent retroperitoneal urinoma, and ureter...
https://ift.tt/2LTMR7v
Typhoid fever with isolated left lateral rectus palsy
A 17-year-old young woman presented to Patan Hospital, Kathmandu, Nepal, with high-grade fever and headache for 4 days and non-projectile vomiting for 1 day. She also had blurred vision with dizziness on and off. There was no abnormal physical finding. Enteric fever was suspected, and she was empirically started on azithromycin (20 mg/kg) for 7 days. She became afebrile after 2 days and was followed up in 7 days with diplopia since 5 days. At this time, the blood culture was positive for Salmonella serovar typhi. On examination, there was isolated left lateral rectus palsy which accounted for her diplopia. Methylprednisolone (1 mg/kg) was prescribed which was tapered over 1 month and gradually her diplopia subsided. We hypothesise that vasculitic change in the blood vessel supplying the left abducens nerve could be causing the diplopia.
https://ift.tt/2MMVB4U
Clear cell chondrosarcoma of the larynx
Chondrosarcomas represent a group of malignant tumours composed of cells producing cartilage, and clear cell chondrosarcomas (CCC) represent a variant of these. A rare case of a laryngeal CCC is presented. The patient was a 70-year-old man who presented with a 6-week history of throat pain, worsening dysphonia and a lump in the neck. Examination revealed a level 3 neck mass and positron emission tomography imaging revealed a metabolically active right laryngeal mass. Biopsies revealed a cartilaginous neoplasm. The patient underwent total laryngectomy, and the pathology confirmed CCC of the larynx. Chondrosarcomas are the most common type of sarcoma in the larynx but the CCC variant is rare. CCC are usually low-grade tumours affecting long bones, with a male predominance. Less than six cases have been described in the literature affecting the larynx. Management of these malignancies is complete surgical excision given the high risk of local recurrence.
https://ift.tt/2wKOgbg
Double pylorus
Description
A 69-year-old man with a past medical history of asthma, chronic back pain and hypertension presented with symptoms of light headedness, epigastric pain and blood-mixed bowel movement of 2 days duration. Since the past 9 months the patient had been taking two to three pills of ibuprofen almost on a daily basis for his back pain. He had also received short courses of prednisone tablets frequently in the last 6 months for his poorly controlled asthma. On arrival in the emergency room, his blood pressure was 84/48 mm Hg, heart rate 121/min, respiratory rate 18/min, temperature 36°C and oxygen saturation was 94% on room air. His haemoglobin (Hb) was 7.2 mg/dL. The patient was given proton pump inhibitor (PPI) therapy, volume resuscitated and was admitted to the intensive care unit. After 2 units of packed red blood cell transfusion his Hb was 9.1 mg/dL. He underwent upper gastrointestinal (GI) endoscopy which showed two openings into...
https://ift.tt/2MLf85r
Atypical giant prolactinoma with frontal lobe manifestations
Description
Prolactinomas having the diameter above 4 cm are termed 'giant prolactinomas'.1 2 Their incidence is approximately 2%–3% of all prolactinomas1. These are associated with very high prolactin concentration and numerous neurological sequelae, arising from their extension into surrounding structures. However, frontal lobe symptoms have not been reported frequently in the literature.3 These are more common in males with the male-to-female ratio of 9:1.1 We report an atypical case of a giant prolactinoma that presented with frontal lobe symptoms but responded remarkably well to dopamine agonist treatment.
We present a case of a 65-year-old woman who presented with progressively worsening short-term memory loss, confusion, mild intermittent headaches, increased somnolence, difficulty in walking due to unsteadiness and urine incontinence of 2 months' duration. There was a major change in behaviour and personality. On examination, she was confused with Montreal Cognitive Assessment...
https://ift.tt/2MLeXqN
Bronchobiliary fistula: a rare complication after pancreaticoduodenectomy
Biliary anatomic pathologies are rare disease occurrences that can result from a number of causes, most commonly iatrogenic, infectious and malignant aetiologies. Communications between the biliary and bronchial systems are even rarer and few cases have been documented in the literature. The present study describes a case of a 70-year-old man who underwent a pancreaticoduodenectomy (Whipple Procedure) as a curative procedure for an early stage neuroendocrine tumour. He presented nearly a decade after surgery with a communication between the biliary and bronchial tree initially manifesting as bilioptysis. His underlying medical conditions and poor clinical picture made treatment options limited. Therefore, he was treated conservatively with percutaneous biliary balloon dilation of the anastomotic stricture followed by temporary percutaneous internal/external drain and made a full recovery.
https://ift.tt/2LWj3qM
Yes-associated protein (YAP) binds to HIF-1α and sustains HIF-1α protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress
Abstract
Background
Hypoxia-inducible factor 1α (HIF-1α) is essential in hepatocellular carcinoma (HCC) glycolysis and progression. Yes-associated protein (YAP) is a powerful regulator and is overexpressed in many cancers, including HCC. The regulatory mechanism of YAP and HIF-1α in HCC glycolysis is unknown.
Methods
We detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. The relationship between YAP mRNA expression and that of HIF-1α was analyzed using The Cancer Genome Atlas HCC tissue data. We cultured HepG2 and Huh7 HCC cells under normoxic (20% O2) and hypoxic (1% O2) conditions, and measured the lactate and glucose levels, migration and invasive capability, and the molecular mechanism of HCC cell glycolysis and progression.
Results
In this study, we detected YAP expression in 54 matched HCC tissues and the adjacent noncancerous tissues. We observed that hypoxia-induced YAP activation is crucial for accelerating HCC cell glycolysis. Hypoxia inhibited the Hippo signaling pathway and promoted YAP nuclear localization, and decreased phosphorylated YAP expression in HCC cells. YAP knockdown inhibited HCC cell glycolysis under hypoxic. Mechanistically, hypoxic stress in the HCC cells promoted YAP binding to HIF-1α in the nucleus and sustained HIF-1α protein stability to bind to PKM2 gene and directly activates PKM2 transcription to accelerate glycolysis.
Conclusions
Our findings describe a new regulatory mechanism of hypoxia-mediated HCC metabolism, and YAP might be a promising therapeutic target in HCC.
https://ift.tt/2oE2SW1
Relapse patterns in patients with local and regional cutaneous melanoma
Abstract
Background
The differences in features and risk factors for recurrence after definitive surgical excision are yet to be determined. The aim of this study was to understand these factors influencing recurrence patterns with local and regional disease in these patients.
Methods
A total of 365 relapsed patients, of whom 196 presented with local disease (stage I–II) and 169 with regional disease (stage III), were investigated in this retrospective study.
Results
The median time to initial recurrence for stage I–II and stage III patients was 22.3 and 13.4 months, respectively. Stage III patients were found to have higher Clark levels (p = 0.0001) and thicker lesions (p = 0.0001), and they were more significantly associated with the absence of tumor-infiltrating lymphocytes (p = 0.02) than stage I–II patients. Stage III patients were more significantly associated with recurrences compared to the stage I–II patients (p = 0.0001). Locoregional relapses were significantly associated with stage I–II melanomas, whereas majority of the distant metastases occurred in stage III patients (p = 0.01). Pulmonary metastasis was most frequently observed and the distribution of the sites for distant metastases was similar in both groups of the patients. On univariate analysis, male sex, increased tumor depth, presence of ulceration, nodular histopathology, higher Clark level, higher mitotic rate, and presence of lymphovascular invasions were found to predict shorter time to relapse for stage I–II patients; whereas only nodular pathology, presence of ulceration, and high mitotic rate were found to be associated with poor relapse-free survival in stage III patients. However, on multivariate analysis, only mitotic rate maintained its significance for both clinical staging groups.
Conclusion
Potential differences among early-stage melanoma patients, who developed recurrence, were noted and mitotic rate was found as the single significant prognostic factor for recurrence in both stage I–II and III patients.
https://ift.tt/2NMaT6k
Beyond first-line systemic treatment for metastatic urothelial carcinoma of the bladder
Abstract
Metastatic urothelial carcinoma of the bladder is a rarely curable disease. Patients receive systemic therapy with limited response rates and survival benefits. The rescue regimens of these patients who have failed first-line treatment had remained problematic until the recent advances. Several trials with novel regimens, including immune checkpoint inhibitors and targeted therapy, to salvage relapsed urothelial carcinoma of the bladder have recently been published. However, the choice of an optimal treatment regimen remains challenging in the absence of randomized trials comparing regimen sequences. Daily clinical cases provoke the question of whether there is a preferred second-line regimen. This paper provides an overview of recent trials and proposes a management algorithm based on subgroup analyses and prognostic features.
https://ift.tt/2oHc5g9
Impact of diabetes comorbidity on the efficacy and safety of FOLFOX first-line chemotherapy among patients with metastatic colorectal cancer: a pooled analysis of two phase-III studies
Abstract
Background
The current analysis aims to provide an evaluation of the impact of diabetes mellitus (DM) on the efficacy and safety of first-line FOLFOX chemotherapy for patients with metastatic colorectal cancer (mCRC).
Methods
This is a pooled analysis of the comparator arms of two clinical trials (NCT00272051; NCT00305188) which evaluated first-line FOLFOX chemotherapy for patients with mCRC. The overall survival and progression-free survival according to patient subsets (non-diabetic and diabetic patients) were assessed through Kaplan–Meier analysis and log-rank testing. Propensity score matching was additionally conducted to account for heterogeneity in baseline characteristics of different subsets of patients.
Results
A total of 756 patients were enrolled in the current analysis; of which 64 patients have pre-existing DM while 692 patients were non-diabetic. Through Kaplan–Meier analysis, no evidence for overall or progression-free survival difference was found among the two patient subsets (P = 0.501; P = 0.960, respectively). Moreover, metformin treatment does not affect overall or progression-free survival among diabetic patients (P = 0.598; P = 0.748, respectively). Repetition of overall and progression-free survival assessment following propensity score matching does not reveal any differences. Comparing diabetic to non-diabetic patients, there were no differences between the two groups in terms of acute oxaliplatin-induced neurological symptoms including cold-induced dysthesia (P = 0.600), laryngeal dysthesia (P = 0.707), jaw pain (P = 0.743) or muscle pain (P = 0.506). Moreover, no difference was seen between the two groups in terms of the incidence of long-term oxaliplatin-induced paresthesia (P = 0.107), highest grade of paresthesia (P = 0.498) or rates of recovery from paresthesia (P = 0.268). Diabetic patients have, however, a shorter time to develop oxaliplatin-induced paresthesia (P = 0.024).
Conclusion
DM does not seem to affect overall or progression-free survival of mCRC patients treated with first-line FOLFOX chemotherapy. Moreover, DM does not influence the incidence or severity of oxaliplatin-induced paresthesia in those patients while it might lead to a shorter time to develop oxaliplatin-induced paresthesia compared to non-diabetic patients.
https://ift.tt/2CoRjvs
Mitral Valve Endocarditis due to Lactobacillus
Lactobacillus species are Gram-positive, facultative anaerobic, rod-shaped bacteria. They belong to the lactic acid bacteria group and are also known as a usual part of the normal flora of the gastrointestinal tract as well as of the urinary and genital tracts. They are an infrequent human pathogen but can induce several infections such as bacteremia and infectious endocarditis. We report the case of an 81-year-old woman with Lactobacillus bacteremia and mitral valve endocarditis as well as splenic abscesses.
https://ift.tt/2NLHUzA
Cancers, Vol. 10, Pages 309: A Dietary Intervention to Lower Serum Levels of IGF-I in BRCA Mutation Carriers
Cancers, Vol. 10, Pages 309: A Dietary Intervention to Lower Serum Levels of IGF-I in BRCA Mutation Carriers
Cancers doi: 10.3390/cancers10090309
Authors: Patrizia Pasanisi Eleonora Bruno Elisabetta Venturelli Daniele Morelli Andreina Oliverio Ivan Baldassari Francesca Rovera Giovanna Iula Monica Taborelli Bernard Peissel Jacopo Azzolini Siranoush Manoukian
Background: Insulin-like growth factor I (IGF-I) and other markers of insulin resistance (IRm) might influence the penetrance of BRCA gene mutation. In a demonstration project on BRCA mutation carriers we tested the effect of the 'Mediterranean diet', with moderate protein restriction, on serum levels of IGF-I and IRm. Methods: BRCA mutation carriers, with or without breast cancer, aged 18–70 years and without metastases were eligible. After the baseline examinations, women were randomized to an active dietary intervention or to a control group. The intervention group attended six full days of life-style intervention activities (cookery classes followed by lunch, sessions of walking for 45 min and nutritional conferences) over the next six months. Results: 213 BRCA mutation carriers completed the six-month study. Women in the intervention group (110) showed major changes in all the parameters under study. They significantly lost weight (p < 0.001), fat mass (p = 0.002), with reduced hip circumference (p = 0.01), triglycerides (p = 0.02) and IGF-I (p = 0.02) compared with controls. They also had a significantly higher levels of insulin-like growth factor-binding protein 3 (IGFI-BP3) (p = 0.03) and a lower IGF-I/IGFI-BP3 ratio (p = 0.04). The reduction of serum levels of IGF-I was significantly associated with the reduction in the consumption of animal products (p = 0.04). Conclusions: Women in the intervention group showed significant improvements in IGF-I and in other IRm that might influence the penetrance of BRCA mutations.
https://ift.tt/2MMHGvE
CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway
Human innate lymphoid cells (ILCs) develop from tissue-resident ILC precursors (ILCPs) in secondary lymphoid tissues. Here, Chen et al. describe a model of human ILC development in tonsils in which NK cells and group 3 ILCs derive from a CD56+ subset of ILCPs that cannot differentiate into group 2 ILCs.
https://ift.tt/2Q1zq8Z
Antibodies Set Boundaries Limiting Microbial Metabolite Penetration and the Resultant Mammalian Host Response
Bacteria-derived metabolites pervade the mammalian host, shaping immunity and metabolism. Using stable isotope tracing, Uchimura and colleagues profile the scope and depth of host tissue penetration by bacterial metabolites. Extensive host immune and metabolic responses to microbial metabolite penetration are constrained by secretory antibodies that limit microbial small-intestinal dwell time.
https://ift.tt/2wG9dUt
The Zinc-Finger Protein ZCCHC3 Binds RNA and Facilitates Viral RNA Sensing and Activation of the RIG-I-like Receptors
Recognition of viral RNA by RIG-I-like receptors (RLRs) initiates innate antiviral response. Lian et al. demonstrate that ZCCHC3 is a co-receptor for RLRs, thereby acting as an important modulator of innate antiviral response.
https://ift.tt/2wHSpML
Cinobufacini Injection Improves the Efficacy of Chemotherapy on Advanced Stage Gastric Cancer: A Systemic Review and Meta-Analysis
Gastric cancer has a high morbidity and mortality. Chemotherapy regimens are routine advanced stage gastric cancer (AGC) treatment protocols, but most of these drugs have side-effects such as myelosuppression and gastrointestinal disorders. Cinobufacini, an extractive from TCM, could suppress cell proliferation and inhibit gastric cancer. In this study, we comprehensively reviewed the literature on the efficacy comparison between Cinobufacini injection combined with chemotherapy and chemotherapy solely used in AGC treatment. We extracted data for from six electronic databases to evaluate the efficacy of Cinobufacini injection on AGC patients. Twelve studies with a total of 853 patients were finally included in our study. The results indicated that Cinobufacini injection could increase response rate and disease control rate of chemotherapy on AGC, improve the life quality of AGC patients, increase leukocytes, improve anemia, improve hand-foot syndrome induced by chemotherapy, and relieve cancer pain. This study has its own limitations that prevented us from drawing a definite conclusion and more well-designed clinical trials of TCM are needed.
https://ift.tt/2NIZBj5
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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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