What We're Reading: Article Recommendations from Our Deputy and Senior Editors

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A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice

Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2⁺ breast tumors. ADU S-100 induced HER-2–specific CD8⁺ T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice. In contrast, ADU S-100 did not sufficiently prime HER-2–specific CD8⁺ T cells in tolerant neu/N mice, resulting in only delayed tumor growth and tumor clearance in 10% of the mice. No differences in IFNβ production, DC priming, or HER-2–specific CD8⁺ T-cell trafficking were detected between FVB/N and neu/N mice. However, activation and expansion of HER-2–specific CD8⁺ T cells were defective in neu/N mice. Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8⁺ T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2–specific CD8⁺ T-cell activity, clearing tumors in 40% of neu/N mice. Thus, intratumoral STING agonists could potently prime tumor antigen–specific CD8⁺ T-cell responses, and adding PD-L1 blockade and OX40 receptor activation can overcome antigen-enforced immune tolerance to induce tumor regression. Cancer Immunol Res; 5(6); 468–79. ©2017 AACR.

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Novel "Elements" of Immune Suppression within the Tumor Microenvironment

Adaptive evolution has prompted immune cells to use a wide variety of inhibitory signals, many of which are usurped by tumor cells to evade immune surveillance. Although tumor immunologists often focus on genes and proteins as mediators of immune function, here we highlight two elements from the periodic table—oxygen and potassium—that suppress the immune system in previously unappreciated ways. While both are key to the maintenance of T-cell function and tissue homeostasis, they are exploited by tumors to suppress immuno-surveillance and promote metastatic spread. We discuss the temporal and spatial roles of these elements within the tumor microenvironment and explore possible therapeutic interventions for effective and promising anticancer therapies. Cancer Immunol Res; 5(6); 426–33. ©2017 AACR.

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Tumor-Derived {alpha}-Fetoprotein Directly Drives Human Natural Killer-Cell Activation and Subsequent Cell Death

Hepatocellular carcinoma (HCC) patients with reduced natural killer (NK)–cell numbers and function have been shown to have a poor disease outcome. Mechanisms underlying NK-cell deficiency and dysfunction in HCC patients remain largely unresolved. α-Fetoprotein (AFP) is an oncofetal antigen produced by HCC. Previous studies demonstrated that tumor-derived AFP (tAFP) can indirectly impair NK-cell activity by suppressing dendritic cell function. However, a direct tAFP effect on NK cells remains unexplored. The purpose of this study was to examine the ability of cord blood-derived AFP (nAFP) and that of tAFP to directly modulate human NK-cell activity and longevity in vitro. Short-term exposure to tAFP and, especially, nAFP proteins induced a unique proinflammatory, IL2-hyperresponsive phenotype in NK cells as measured by IL1β, IL6, and TNF secretion, CD69 upregulation, and enhanced tumor cell killing. In contrast, extended coculture with tAFP, but not nAFP, negatively affected long-term NK-cell viability. NK-cell activation was directly mediated by the AFP protein itself, whereas their viability was affected by hydrophilic components within the low molecular mass cargo that copurified with tAFP. Identification of the distinct impact of circulating tAFP on NK-cell function and viability may be crucial to developing a strategy to ameliorate HCC patient NK-cell functional deficits. Cancer Immunol Res; 5(6); 493–502. ©2017 AACR.

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Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology Keystone Symposia Meeting Summary

The Keystone Symposia conference on Cancer Immunology and Immunotherapy: Taking a Place in Mainstream Oncology was held at the Fairmont Chateau in Whistler, British Columbia, Canada, on March 19–23, 2017. The conference brought together a sold-out audience of 654 scientists, clinicians, and others from both academia and industry to discuss the latest developments in cancer immunology and immunotherapy. This meeting report summarizes the main themes that emerged during the four-day conference. Cancer Immunol Res; 5(6); 434–8. ©2017 AACR.

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RIG-I Resists Hypoxia-Induced Immunosuppression and Dedifferentiation

A hypoxic tumor microenvironment is linked to poor prognosis. It promotes tumor cell dedifferentiation and metastasis and desensitizes tumor cells to type-I IFN, chemotherapy, and irradiation. The cytoplasmic immunoreceptor retinoic acid-inducible gene-I (RIG-I) is ubiquitously expressed in tumor cells and upon activation by 5'-triphosphate RNA (3pRNA) drives the induction of type I IFN and immunogenic cell death. Here, we analyzed the impact of hypoxia on the expression of RIG-I in various human and murine tumor and nonmalignant cell types and further investigated its function in hypoxic murine melanoma. 3pRNA-inducible RIG-I–expression was reduced in hypoxic melanoma cells compared with normoxic controls, a phenomenon that depended on the hypoxia-associated transcription factor HIF1α. Still, RIG-I functionality was conserved in hypoxic melanoma cells, whereas responsiveness to recombinant type-I IFN was abolished, due to hypoxia-induced loss of type I IFN receptor expression. Likewise, RIG-I activation in hypoxic melanoma cells, but not exposure to recombinant IFNα, provoked melanocyte antigen-specific CD8⁺ T-cell and NK-cell attack. Scavenging of hypoxia-induced reactive oxygen species by vitamin C restored the inducible expression of RIG-I under hypoxia in vitro, boosted in vitro anti-melanoma NK- and CD8⁺ T-cell attack, and augmented 3pRNA antitumor efficacy in vivo. These results demonstrate that RIG-I remains operational under hypoxia and that RIG-I function is largely insensitive to lower cell surface expression of the IFNα receptor. RIG-I function could be fortified under hypoxia by the combined use of 3pRNA with antioxidants. Cancer Immunol Res; 5(6); 455–67. ©2017 AACR.

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4-1BB-Enhanced Expansion of CD8+ TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8+ T Cells

Triple-negative breast cancer (TNBC) highly infiltrated with CD8⁺ tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8⁺ TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8⁺ TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8⁺ T cells. This approach was first utilized in melanoma and, in this study, led to advantageous growth of TILs for the majority of TNBC tumors tested. The agonistic antibody was only added in the initial setting of the culture and yet favored the propagation of CD8⁺ TILs from TNBC tumors. These expanded CD8⁺ TILs were capable of cytotoxic functions and were successfully utilized to demonstrate the presence of immunogenic mutations in autologous TNBC tumor tissue without recognition of the wild-type counterpart. Our findings open the way for a successful adoptive immunotherapy for TNBC. Cancer Immunol Res; 5(6); 439–45. ©2017 AACR.

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Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade

Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480–92. ©2017 AACR.

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Combined Anti-VEGF and Anti-CTLA-4 Therapy Elicits Humoral Immunity to Galectin-1 Which Is Associated with Favorable Clinical Outcomes

The combination of anti-VEGF blockade (bevacizumab) with immune checkpoint anti–CTLA-4 blockade (ipilimumab) in a phase I study showed tumor endothelial activation and immune cell infiltration that were associated with favorable clinical outcomes in patients with metastatic melanoma. To identify potential immune targets responsible for these observations, posttreatment plasma from long-term responding patients were used to screen human protein arrays. We reported that ipilimumab plus bevacizumab therapy elicited humoral immune responses to galectin-1 (Gal-1), which exhibits protumor, proangiogenesis, and immunosuppressive activities in 37.2% of treated patients. Gal-1 antibodies purified from posttreatment plasma suppressed the binding of Gal-1 to CD45, a T-cell surface receptor that transduces apoptotic signals upon binding to extracellular Gal-1. Antibody responses to Gal-1 were found more frequently in the group of patients with therapeutic responses and correlated with improved overall survival. In contrast, another subgroup of treated patients had increased circulating Gal-1 protein instead, and they had reduced overall survival. Our findings suggest that humoral immunity to Gal-1 may contribute to the efficacy of anti-VEGF and anti–CTLA-4 combination therapy. Gal-1 may offer an additional therapeutic target linking anti-angiogenesis and immune checkpoint blockade. Cancer Immunol Res; 5(6); 446–54. ©2017 AACR.

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Combining DNA Vaccine and AIDA-1 in Attenuated Salmonella Activates Tumor-Specific CD4+ and CD8+ T-cell Responses

Stimulation of tumor-specific responses in both CD4⁺ and CD8⁺ T cells has been a challenge for effective tumor vaccines. We designed a vaccine vector containing the AIDA-1 autotransporter and DNA vaccine elements, generating a murine melanoma vaccine that was delivered by the attenuated Salmonella strain SL7207. Growth of murine subcutaneous melanoma was significantly inhibited by intranasal immunization with the Salmonella tumor vaccine. The vaccine activated tumor-specific CD4⁺ and CD8⁺ T-cell responses, with increased T-cell proliferation, tumor antigen–specific Th1 cytokine production, increased percentages of tetramer positive cells, and cytotoxicity. CD4⁺ or CD8⁺ T-cell depletion resulted in the loss of antitumor activity of the Salmonella tumor vaccine, suggesting that the efficacy of the vaccine was dependent on both CD4⁺ and CD8⁺ T cells. Lung metastasis of the tumor was also inhibited by vaccine treatment. Similarly, the percentages of tumor-specific Th1 cytokine production by CD4⁺ and CD8⁺ T cells in the spleen, tumor, and bronchoalveolar lavage were increased after vaccine treatment. Tumor-specific proliferation of CD4⁺ and CD8⁺ T cells was also promoted by the vaccine. Tetramer staining and cytotoxicity assay showed enhanced tumor-specific CD8⁺ T-cell response after vaccine treatment. Therefore, the Salmonella tumor vaccine could activate both tumor-specific CD4⁺ and CD8⁺ T-cell responses. This vaccine strategy may be widely applicable to the development of oral or nasal vaccines against tumors. Cancer Immunol Res; 5(6); 503–14. ©2017 AACR.

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Comparison of residual cancer burden, American Joint Committee on Cancer staging and pathologic complete response in breast cancer after neoadjuvant chemotherapy: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

Abstract

Purpose

Several pathologic staging systems characterize residual tumor in patients undergoing neoadjuvant chemotherapy for breast cancer. Pathologic complete response (pCR) is now accepted by the Food and Drug Administration as an endpoint for granting accelerated drug approval. Two other systems of post-neoadjuvant pathologic tumor staging—residual cancer burden (RCB) and the American Joint Committee on Cancer post-neoadjuvant therapy staging system (yAJCC)—have been developed to characterize residual tumors when patients do not achieve pCR. The optimal system and the ways in which these systems complement each other have not been fully determined.

Methods

Using data from the I-SPY 1 TRIAL, we compared pCR, RCB, and yAJCC as predictors of early recurrence-free survival (RFS) to identify ways to improve post-neoadjuvant pathologic evaluation.

Results

Among 162 patients assessed, pCR identified patients at lowest risk of recurrence, while RCB and yAJCC identified patients at highest risk. Hormone-receptor (HR) and HER2 subtypes further improved risk prediction. Recursive partitioning indicated that triple-negative or HER2+ patients with yAJCC III or RCB 3 have the highest recurrence risk, with an RFS of 27%. Our analysis also highlighted discrepancies between RCB and yAJCC stratification: 31% of patients had discrepant RCB and yAJCC scores. We identified differential treatment of lymph node involvement and tumor cellularity as drivers of these discrepancies.

Conclusions

These data indicate that there is benefit to reporting both RCB and yAJCC for patients in order to identify those at highest risk of relapse.

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Issue Information

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Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and sample size

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Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis; Methodological issues

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Epilepsy as a systemic condition: Link with somatic comorbidities

Background

People with epilepsy have more concomitant medical conditions than the general population; these comorbidities play an important role in premature mortality. We sought to generate explanatory hypotheses about the co-occurrence of somatic comorbidities and epilepsy, avoiding causal and treatment-resultant biases.

Methods

We collected clinical, demographic and somatic comorbidity data for 2016 consecutive adults with epilepsy undergoing assessment at a tertiary centre and in 1278 people with epilepsy in the community. Underlying causes of epilepsy were not classed as comorbidities.

Results

Somatic comorbidities were more frequent in the referral centre (49%) where people more frequently had active epilepsy than in the community (36%). Consistent risk factors for comorbidities were found in both cohorts. Using multivariable ordinal regression adjusted for age, longer epilepsy duration and an underlying brain lesion were independently associated with a smaller burden of somatic conditions. The treatment burden, measured by the number of drugs to which people were exposed, was not an independent predictor. Shorter epilepsy duration was a predictor for conditions that conceivably harbour significant mortality risks.

Conclusions

Somatic comorbidities do not occur randomly in relation to epilepsy; having more severe epilepsy seems to be a risk factor. Independently from age, the early period after epilepsy onset appears to be at particular risk, although it is not clear whether this relates to an early mortality or to a later decrease in the burden of comorbidities. These results suggest that, for some people, epilepsy should be considered a systemic condition not limited to the CNS.

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Temperature-dependent extraction kinetics of hydrolyzed collagen from scales of croaker fish using thermal extraction

Abstract

This study investigates the kinetics of hydrolyzed collagen extraction from the scales of the croaker fish (Pseudotolitus elongatus) at temperature ranging from 60°C to 90°C. Extraction was carried out using hydrothermal treatment over a period of 8 hr, during which the mass of hydrolyzed collagen extracted was obtained every hour. The rate order of extraction was temperature-dependent within the times investigated. At 60°C no measurable extraction was achieved, between 70°C and 80°C the extraction was a zero order while at 90°C and 100°C the extraction was a first order process. The rate constants for 70, 80, 90 and 100°C were 0.56 g s⁻¹, 1.03 g s⁻¹, 0.019 s⁻¹ and 0.04 s^-1, respectively. The overall yield increased as temperature is increased with the highest increase in yield occurring between 90 and 100°C. The yield increased from 6% at 70°C to 30% at 100°C, thus indicating that temperature has significant effect on the yield as well as kinetics. These findings are relevant in the predictive assessment as well as design and optimization of processes for extraction of hydrolyzed collagen from fish scales.

This study investigates the kinetics of hydrolyzed collagen extraction from the scales of the croaker fish (Pseudotolitus elongatus) at temperature ranging from 60°C to 90°C. Between 70°C and 80°C the extraction was a zero order while at 90°C and 100°C the extraction was a first order process. The rate constants for 70, 80, 90 and 100°C were 0.56 g s^-1, 1.03 g s^-1, 0.019 s^-1 and 0.04 s^-1, respectively.

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Combined Genetic Biomarkers and Betel Quid Chewing for Identifying High-Risk Group for Oral Cancer Occurrence

We integrated genetic risk scores (GRS) and environmental factors for identifying high-risk subjects for oral squamous cell carcinoma (OSCC) occurrence by using case–control study. A total of 447 patients diagnosed with OSCC and 580 unrelated subjects were recruited from two medical centers in Taiwan. A multinomial logistic regression model was conducted to access interaction between GRS and betel quid (BQ) chewing. We employed ROC curve to compare the accuracy of OSCC occurrence. Four tag SNPs were found in NOTCH1, BRCA1, COL9A1, and HSPA13 genes that were significantly associated with OSCC occurrence. GRS was calculated by the four tag SNP risk alleles. The higher GRS (scores = 4) remained independently associated with risk of OSCC after adjustment for age, the use of alcohol, BQ, and cigarette: adjusted OR = 4.42 [95% confidence interval (95% CI), 1.34–14.55]. The GRS and BQ chewing interaction showed an increased risk for OSCC occurrence with adjusting for other substance use and age (OR = 70.77; 95% CI, 8.70–575.73). The synergy index was 16.58 (95% CI, 2.27–70.56), suggesting a positive additive interaction between GRS and BQ chewing. The areas under the ROC curves (AUROC) were 0.91 for combined GRS and BQ chewing with sensitivity of 88.6% and specificity of 86.7%. The AUROC of GRS and BQ chewing is above 90%, which may be valuable in identifying high-risk subjects. Early screening can allow the clinician to provide the appropriate intervention and to reduce the OSCC occurrence. Cancer Prev Res; 10(6); 355–62. ©2017 AACR.

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Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small-bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention. Cancer Prev Res; 10(6); 345–54. ©2017 AACR.

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Sleep Duration across the Adult Lifecourse and Risk of Lung Cancer Mortality: A Cohort Study in Xuanwei, China

Sufficient sleep duration is crucial for maintaining normal physiological function and has been linked to cancer risk; however, its contribution to lung cancer mortality is unclear. Therefore, we evaluated the relationship between average sleep duration in various age-periods across the adult lifecourse, and risk of lung cancer mortality in Xuanwei, China. An ambidirectional cohort study was conducted in 42,422 farmers from Xuanwei, China. Participants or their surrogates were interviewed in 1992 to assess average sleep hours in the age periods of 21–30, 31–40, 41–50, 51–60, 61–70, and ≥71 years, which were categorized as ≤7, 8 (reference), 9, and ≥10 hours/day. Vital status was followed until 2011. Sex-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for lung cancer mortality in 1994–2011, adjusted for demographic, anthropometric, medical, and household characteristics. J-shaped relationships were found between average sleep duration and lung cancer mortality. The patterns were consistent across sex, age periods, and fuel usage. Compared with sleeping 8 hours/day on average, ≤7 hours/day was associated with significantly increased HRs ranging from 1.39 to 1.58 in ages ≥41 years in men, and 1.29 to 2.47 in ages ≥51 years in women. Furthermore, sleeping ≥10 hours/day was associated with significantly increased HRs ranging from 2.44 to 3.27 in ages ≥41 year in men, and 1.31 to 2.45 in ages ≤60 years in women. Greater and less than 8 hours/day of sleep in various age-periods may be associated with elevated risk of lung cancer mortality in Xuanwei, China. Cancer Prev Res; 10(6); 327–35. ©2017 AACR.

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Statin Use, Serum Lipids, and Prostate Inflammation in Men with a Negative Prostate Biopsy: Results from the REDUCE Trial

Statin use is associated with lower advanced prostate cancer risk. In addition to cholesterol lowering, statins have systemic anti-inflammatory properties. However, their effect on histologic prostate inflammation is not well understood, particularly among men at increased prostate cancer risk but with a negative prostate biopsy. We examined associations between serum lipid levels, statin use, and histologic prostate inflammation using data from 6,655 men with a negative baseline prostate biopsy in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial. Statin use and lipid levels [total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides] were assessed at baseline. Inflammation was assessed by central review. Logistic regression was used to examine the effects of lipids and statin use on presence and extent of chronic and acute prostate inflammation [none, moderate (<20%), severe (≥20% biopsy cores)]. Chronic and acute inflammation affected 77% and 15% of men, respectively. Men with high HDL (≥60 vs. <40 mg/dL) had reduced presence of acute inflammation [OR, 0.79; 95% confidence interval (CI), 0.63–0.99] and were less likely to have severe acute inflammation (OR, 0.66; 95% CI, 0.45–0.97), but there were no other associations between lipids and inflammation. Statin users had reduced presence of chronic inflammation (OR, 0.81; 95% CI, 0.69–0.95) and were less likely to have severe chronic (OR, 0.80; 95% CI, 0.68–0.95) and severe acute inflammation (OR, 0.73; 95% CI, 0.53–1.00), relative to non-users. Given the possible role for inflammation in prostate cancer, the inverse association between statins and prostate inflammation suggests a mechanism linking statins with lower advanced prostate cancer risk. Cancer Prev Res; 10(6); 319–26. ©2017 AACR.

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Bitter Melon Enhances Natural Killer-Mediated Toxicity against Head and Neck Cancer Cells

Natural killer (NK) cells are one of the major components of innate immunity, with the ability to mediate antitumor activity. Understanding the role of NK-cell–mediated tumor killing in controlling of solid tumor growth is still in the developmental stage. We have shown recently that bitter melon extract (BME) modulates the regulatory T cell (Treg) population in head and neck squamous cell carcinoma (HNSCC). However, the role of BME in NK-cell modulation against HNSCC remains unknown. In this study, we investigated whether BME can enhance the NK-cell killing activity against HNSCC cells. Our results indicated that treatment of human NK-cell line (NK3.3) with BME enhances ability to kill HNSCC cells. BME increases granzyme B accumulation and translocation/accumulation of CD107a/LAMP1 in NK3.3 cells exposed to BME. Furthermore, an increase in cell surface expression of CD16 and NKp30 in BME-treated NK3.3 cells was observed when cocultured with HNSCC cells. Collectively, our results demonstrated for the first time that BME augments NK-cell–mediated HNSCC killing activity, implicating an immunomodulatory role of BME. Cancer Prev Res; 10(6); 337–44. ©2017 AACR.

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ROCK Inhibition Primes Tumor Tissue to Sensitize Cells to Chemotherapy [Pancreatic Cancer]

Short-term ROCK targeting improves cytotoxic drug efficacy in primary and metastatic pancreatic cancers.

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Medical Centers Sign On to Single IRB Model [News in Brief]

All 64 member institutions of the NIH's Clinical and Translational Science Awards program have agreed to a common framework for running multisite trials under the umbrella of just one Institutional Review Board. The NCI has long offered a centralized review board option. Come September, single Institutional Review Boards will be mandatory for all NIH-backed studies.

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LACTB May Be a Tumor Suppressor Gene in Breast Cancer [Tumor Suppressors]

LACTB promotes breast cancer cell differentiation and suppresses breast tumorigenesis in vivo.

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Correction: New Perspectives of Curcumin in Cancer Prevention

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A Presurgical Study of Lecithin Formulation of Green Tea Extract in Women with Early Breast Cancer

Epidemiologic data support an inverse association between green tea intake and breast cancer risk. Greenselect Phytosome (GSP) is a lecithin formulation of a caffeine-free green tea catechin extract. The purpose of the study was to determine the tissue distribution of epigallocatechin-3-O-gallate (EGCG) and its effect on cell proliferation and circulating biomarkers in breast cancer patients. Twelve early breast cancer patients received GSP 300 mg, equivalent to 44.9 mg of EGCG, daily for 4 weeks prior to surgery. The EGCG levels were measured before (free) and after (total) enzymatic hydrolysis by HPLC-MS/MS in plasma, urine, breast cancer tissue, and surrounding normal breast tissue. Fasting blood samples were taken at baseline, before the last administration, and 2 hours later. Repeated administration of GSP achieved levels of total EGCG ranging from 17 to 121 ng/mL in plasma. Despite a high between-subject variability, total EGCG was detectable in all tumor tissue samples collected up to 8 ng/g. Median total EGCG concentration was higher in the tumor as compared with the adjacent normal tissue (3.18 ng/g vs. 0 ng/g, P = 0.02). Free EGCG concentrations ranged from 8 to 65.8 ng/mL in plasma (P between last administration and 2 hours after <0.001). Free EGCG plasma levels showed a significant positive correlation with the Ki-67 decrease in tumor tissue (P = 0.02). No change in any other biomarkers was noted, except for a slight increase in testosterone levels after treatment. Oral GSP increases bioavailability of EGCG, which is detectable in breast tumor tissue and is associated with antiproliferative effects on breast cancer tissue. Cancer Prev Res; 10(6); 363–9. ©2017 AACR.

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LGR5+ Cancer Stem Cells Drive Primary and Metastatic Colorectal Cancer [Stem Cells]

LGR5⁺ colorectal cancer CSCs are dispensable for primary tumor growth due to plasticity.

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A FOXO4 Inhibitory Peptide Limits Chemotoxicity in Mice [Senescence]

The FOXO4 inhibitory peptide FOXO4-DRI promotes targeted apoptosis of senescent cells.

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Type 1 T Helper Cells Promote Tumor Vessel Normalization [Angiogenesis]

T_H1 cells promote tumor vessel pericyte coverage and vessel normalization to suppress metastasis.

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Study Suggests Treatment Approaches for Cholangiocarcinomas [News in Brief]

A comprehensive genome profile of cholangiocarcinoma reveals that the tumors fall into four molecular classes. The study suggests that patients with IDH1/2 mutations could benefit from drugs that inhibit oxidative phosphorylation or that target mutations in chromatin remodeling genes. The work also shows that some liver cancers are closely related to cholangiocarcinomas.

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Analysis Suggests Wider Use for PARP Inhibitors [News in Brief]

Researchers have developed a new tool, HRDetect, to pinpoint tumors that display BRCA deficiency but don't harbor BRCA1/2 mutations. Evaluating their method in breast, ovarian, and pancreatic cancers, they identified patients whose tumors were potentially vulnerable to PARP inhibition but who didn't carry these mutations.

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In This Issue [In This Issue]

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CAR T-cell Therapy: Defining Response Characteristics [News in Brief]

Findings from a phase I study suggest that the durability of patients' response to CAR T-cell therapy, and their long-term survival, are influenced by whether they have minimal residual or morphologic disease prior to treatment. The former fared better overall, and also experienced less-severe side effects from this form of immunotherapy.

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Chromosome Instability Drives Tumor Evolution [News in Depth]

A prospective study of patients with non–small cell lung cancer undergoing treatment reveals that chromosomal instability and tumor heterogeneity drive disease recurrence. Researchers involved in the TRACERx trial documented that genetic diversity by sequencing multiple regions of the primary tumor and then created bespoke ctDNA tests that allowed for early detection of relapse and metastasis.

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Coxsackievirus A21 Synergizes with Checkpoint Inhibitors [News in Brief]

Treatment with a combination of a proprietary formulation of coxsackievirus and either an anti–CTLA-4 or anti–PD-1 checkpoint inhibitor yielded a higher response rate in phase I testing for melanoma than any of these drugs given on their own. Because the viral therapy adds little toxicity, it might prove an effective part of a dual regimen, according to interim trial data presented at the American Association for Cancer Research Annual Meeting 2017.

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Adoptive T-cell Therapy Has Antitumor Activity in Uveal Melanoma [Clinical Trials]

Adoptive T-cell therapy achieved responses in 35% of patients with metastatic uveal melanoma.

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Atezolizumab Extends Survival for Breast Cancer [News in Brief]

The anti–PD-L1 drug atezolizumab produced durable responses among 10% of patients with triple-negative breast cancer in a large phase I trial presented at the American Association for Cancer Research Annual Meeting 2017. The therapy proved safe, with the highest response rates seen in women who received the drug as a first-line therapy and in those with elevated PD-L1 levels and other tumor biomarkers.

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Biden: Progress Made with Cancer Moonshot [News in Brief]

In an address to attendees at the American Association for Cancer Research Annual Meeting 2017, former Vice President Joe Biden urged optimism in the fight against cancer despite threats of funding cuts under the Trump administration. He also spoke about progress that has been made as part of the Beau Biden Cancer Moonshot.

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Immunotherapy Combo Offers Slight Survival Benefit in Melanoma [News in Brief]

Data on 2-year survival in the phase III CheckMate 067 trial testing nivolumab plus ipilimumab showed a slight survival benefit for the combination over nivolumab monotherapy—but the difference may not be dramatic enough to justify using the combination given the added side effects.

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Four Groups Win CRUK "Grand Challenge" [News in Brief]

Four research teams were each awarded Cancer Research UK's "Grand Challenge" prize of up to £20 million, or about $25 million, over 5 years. The winning teams bring together scientists and technologists from around the world to tackle some of the most pressing unsolved problems in cancer research.

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Profiling Differential Responses to Pan-HER Inhibition [News in Brief]

Findings from the phase II SUMMIT basket trial indicate that among patients with solid cancers harboring HER2/3 mutations, responses to the investigational pan-HER inhibitor neratinib vary by specific alteration and tumor type. Neratinib showed promising single-agent activity in breast, biliary tract, and cervical cancers, but was ineffective against bladder and colorectal cancers; among a small subset of patients with HER3 mutations, no responses were seen.

http://ift.tt/2ri7q6N

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype–phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype–genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

http://ift.tt/2qHDXnY

Auditory and otologic profile of Alström syndrome: Comprehensive single center data on 38 patients

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7–37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5–15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10–15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation.

http://ift.tt/2rrnG3B

Blood coagulation system in patients with chronic kidney disease: a prospective observational study

Objectives

Thromboembolic events are the major factor affecting the prognosis of patients with chronic kidney disease (CKD). Haemostatic alterations are possible causes of these complications, but their roles remain poorly characterised. In the prospective observational study, we investigated the entire coagulation process in patients with CKD to elucidate the mechanisms of their high thromboembolic risk.

Methods

A total of 95 patients with CKD and 20 healthy controls who met the inclusion criteria were consecutively recruited from September 2015 to March 2016. The platelet count, platelet aggregation, von Willebrand factor antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), fibrinogen, factor V (FV), FVII, FVIII, antithrombin III, protein C, protein S, D-dimer, standard coagulation tests and thromboelastography were measured in patients with CKD and controls. Associations between the estimated glomerular filtration rate (eGFR) and haemostatic biomarkers were tested using multivariable linear regression.

Results

The adjusted and unadjusted levels of vWF:Ag, vWF:RCo, fibrinogen, FVII, FVIII and D-dimer were significantly higher in patients with CKD than that in the healthy controls, and were elevated with CKD progression. However, after adjustment for baseline differences, platelet aggregation and thromboelastography parameters showed no significant differences between patients with CKD and healthy controls. In the correlation analysis, vWF:Ag, vWF:RCo and FVIII were inversely associated with eGFR (r=–0.359, p<0.001; r=–0.391, p<0.001; r=–0.327, p<0.001, respectively). During the 1-year of follow-up, one cardiovascular event occurred in patients with CKD 5 stage, whereas no thromboembolic event occurred in the CKD 3 and 4 and control groups.

Conclusions

Patients with CKD are characterised by endothelial dysfunction and increased coagulation, especially FVIII activity. The abnormal haemostatic profiles may contribute to the elevated risk of thrombotic events but further longer-term study with large samples is still required to more precisely determine the relationship between the elevation of procoagulant factors and clinical outcomes.

http://ift.tt/2rLu7BK

Barriers and facilitators to recruitment of South Asians to health research: a scoping review

Objectives

People of South Asian ethnicity are under-represented in health research studies. The objectives of this scoping review were to examine the barriers and facilitators to recruitment of South Asians to health research studies and to describe strategies for improving recruitment.

Design

Scoping review

Methods

Using the Arksey and O'Malley framework for scoping reviews, we comprehensively searched electronic databases (MEDLINE via PubMed, Cochrane Library, CINAHL and PsycINFO). Studies that identified barriers and facilitators to recruitment, or recruitment strategies for South Asian populations were included. Recruitment barriers, facilitators and strategies were grouped thematically and summarised narratively.

Synthesis

Of 1846 potentially relevant articles, 15 met the inclusion criteria and were included in the thematic synthesis. Multiple facilitators and barriers to enrolment of South Asians in health research studies were identified; these most commonly related to logistical challenges, language and cultural barriers, concerns about adverse consequences of participating and mistrust of research. Several actionable strategies were discussed, the most common being engagement of South Asian communities, demonstration of cultural competency, provision of incentives and benefits, language sensitivity through the use of translators and translated materials and the development of trust and personal relationships.

Conclusion

There is a growing awareness of the barriers and facilitators to recruitment of South Asian participants to health research studies. Knowledge of effective recruitment strategies and implementation during the grant funding stages may reduce the risk of poor recruitment and representation of South Asians.

http://ift.tt/2rLaV6Y

Sex differences in auditory verbal hallucinations in early, middle and late adolescence: results from a survey of 17 451 Japanese students aged 12-18 years

Objectives

Women have higher rates of auditory verbal hallucinations (AVH) than men; however, less is known about sex differences in the prevalence of AVH in early, middle and late adolescence. We sought to elucidate the differences in the prevalence of AVH and to examine the degree to which these differences could be explained by differences in levels of depressive symptoms.

Design

We used a cross-sectional design and a self-reported questionnaire.

Setting

Participants were recruited from public junior and senior high schools in Tsu, Mie Prefecture and Kochi Prefecture, Japan.

Participants

In total, 19 436 students were contacted and 18 250 participated. Responses from 17 451 students with no missing data were analysed (aged 12–18 years, M_age=15.2 years (SD=1.7), 50.6% girls).

Measures

AVH were assessed through one of four items adopted from the schizophrenia section of the Japanese version of the Diagnostic Interview Schedule for Children. Depressive symptoms were assessed using the 12-item General Health Questionnaire.

Results

The prevalence of AVH was 7.0% among early adolescents (aged 12–13 years), 6.2% among middle adolescents (aged 14–15 years) and 4.8% among late adolescents (aged 16–18 years). Being female was significantly associated with a higher prevalence of AVH through adolescence (OR=1.71, 95% CI 1.31 to 2.23 in early adolescence; OR=1.42, 95% CI 1.14 to 1.76 in middle adolescence; OR=1.52, 95% CI 1.23 to 1.87 in late adolescence); however, these differences became non-significant after adjusting for depressive symptoms (OR=1.21, 95% CI 0.92 to 1.60; OR=1.00, 95% CI 0.80 to 1.25; OR=1.16, 95% CI 0.93 to 1.44, respectively).

Conclusions

Sex differences in auditory hallucinations are seen in both adult and youth populations. The higher rates of auditory verbal hallucinations seen in girls may be secondary to the differences in the rate of depressive symptoms.

http://ift.tt/2skmoYr

The Taking Charge After Stroke (TaCAS) study protocol: a multicentre, investigator-blinded, randomised controlled trial comparing the effect of a single Take Charge session, two Take Charge sessions and control intervention on health-related quality of life 12 months after stroke for non-Maori, non-Pacific adult New Zealanders discharged to community living

Introduction

Stroke is one of the leading causes of disability worldwide. Recent data support the possibility that person-centred, self-management interventions can reduce dependence after stroke. However, there is limited information on the generalisability and optimum dose of these interventions.

Methods

The Taking Charge After Stroke (TaCAS) study is a multicentre, investigator-blinded, randomised controlled trial recruiting 400 participants following acute stroke from seven hospitals in New Zealand. All patients discharged to community living who have ongoing symptoms at time of discharge (modified Rankin scale>0) will be eligible. Participants will be randomly assigned to one Take Charge session, two Take Charge sessions 6 weeks apart or control.

Outcomes

The primary outcome will be the Physical Component Summary score of the Short-Form 36 at 12 months post stroke. Secondary outcomes will include dependence (modified Rankin scale), performance in activities of daily living (Barthel Index) and carer strain (Caregiver Strain Index), at 6 and 12 months post stroke. All analyses will be conducted on an intention-to-treat basis.

Ethics and dissemination

The TaCAS study is funded by a Health Research Council of New Zealand grant. It has been approved by the Central Health and Disability Ethics Committee (15/CEN/115). Results will be published and presented at relevant stroke meetings within New Zealand and internationally, informing the use of a self-management intervention after stroke.

Trial registration

Australia and New Zealand Clinical Trials Registry ACTRN12615001163594. Date registered 02-11-2015. Medical Research Institute of New Zealand Registry TCS01. Universal trial number U1111-1171-4127.

http://ift.tt/2skQaML

Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition

Abstract

Tumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long-term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA-binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the mRNA-processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal BRAF inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low-doses vemurafenib treatment. We then use single-cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster-proliferating vemurafenib-sensitive or -resistant subpopulations showed higher death tendency and reduced size, and slower-proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies.

Tumor heterogeneous response of melanoma cells to targeted therapies is limiting their efficacy. In this study, using single-cell mass cytometry, we were able to track within the heterogeneous response of a melanoma BRAFV600-sensitive cell line, the paradoxically proliferating subsets of cells that emerge as an immediate response to suboptimal BRAF inhibition. Moreover, we were able to show that the overexpression of the human antigen R overcomes such immediate heterogeneous response. This study initiates a new avenue to prevent the occurrence of adaptive resistance to targeted therapies.

http://ift.tt/2qHvAc2

Ten-year survival after endoscopic stenting as a bridge to surgery in obstructing colon cancer

Self-expandable metallic stents are increasingly used in the treatment of obstructing colorectal cancer (CRC). Although endoscopic colonic stenting is widely accepted in palliation, disagreement exists about its role in a curative setting. This study aims to describe long-term survival data in a large patient group, treated with colonic stenting as a bridge to surgery (BTS) for CRC.

http://ift.tt/2qHTyUv

Electromagnetic-guided placement of nasoduodenal feeding tubes versus endoscopic placement: a randomized, multicenter trial

Electromagnetic-guided placement (EMP) of a nasoduodenal feeding tube by trained nurses is an attractive alternative to esophagogastroduodenoscopy guided placement (EGDP). We aimed to compare EMP and EGDP in outpatients, ward patients, and critically ill patients with normal upper GI anatomy.

http://ift.tt/2rqUCJJ

The 150 most important questions in cancer research and clinical oncology series: questions 31–39

To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 9 more questi...

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Palonosetron compared with ondansetron in pediatric cancer patients: multicycle analysis of a randomized Phase III study

Future Oncology Ahead of Print.


http://ift.tt/2skh0od

Lymphocyte Nadir and Esophageal Cancer Survival Outcomes Following Chemoradiotherapy

We evaluated whether decreased host immunity, as seen by lymphopenia, during chemoradiation for esophageal cancer affect survival and if so, are there factors that may predict for lymphopenia. In this retrospective study that included 504 patients, lymphopenia was significantly associated with poor patient outcomes. Chemo regimen, radiation modality, tumor location, and mean body dose predicted for lymphopenia.

http://ift.tt/2qMgFbK

Inverse-planned Respiratory Phase Gating in Lung Conformal Radiotherapy

The standard method of using a fixed respiratory phase, typically end-of-exhale, for respiratory gating does not necessarily result in the best OAR sparing. We use an inverse planning optimization approach and identify the patient-specific optimal gating phase for each beam considering (i) the state of the anatomy at each respiratory phase and (ii) the time spent in each phase.

http://ift.tt/2qMecOx

Capecitabine Extends Survival for Biliary Tract Cancer [News in Brief]

Findings could lead to new standard of care for patients with the uncommon disease.

http://ift.tt/2sklJ96

AACR Project GENIE: Powering Precision Medicine Through An International Consortium [Research Articles]

The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI MATCH Trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine.

SIGNIFICANCE: The AACR Project GENIE aims to catalyze sharing of integrated genomic and clinical datasets across multiple institutions worldwide, and thereby enable precision cancer medicine research, including the identification of novel therapeutic targets, design of biomarker-driven clinical trials, and identification of genomic determinants of response to therapy. Cancer Discov; 7(8); 1–14. ©2017 AACR.

http://ift.tt/2rL1gxt

Readability Assessment of Online Patient Education Material on Congestive Heart Failure

Background. Online health information is being used more ubiquitously by the general population. However, this information typically favors only a small percentage of readers, which can result in suboptimal medical outcomes for patients. Objective. The readability of online patient education materials regarding the topic of congestive heart failure was assessed through six readability assessment tools. Methods. The search phrase "congestive heart failure" was employed into the search engine Google. Out of the first 100 websites, only 70 were included attending to compliance with selection and exclusion criteria. These were then assessed through six readability assessment tools. Results. Only 5 out of 70 websites were within the limits of the recommended sixth-grade readability level. The mean readability scores were as follows: the Flesch-Kincaid Grade Level (9.79), Gunning-Fog Score (11.95), Coleman-Liau Index (15.17), Simple Measure of Gobbledygook (SMOG) index (11.39), and the Flesch Reading Ease (48.87). Conclusion. Most of the analyzed websites were found to be above the sixth-grade readability level recommendations. Efforts need to be made to better tailor online patient education materials to the general population.

http://ift.tt/2rnHO6C

Estrogen Replacement Reduces Risk and Increases Survival Times of Women With Hepatocellular Carcinoma

Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. We investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC.

http://ift.tt/2skn4gj

Confluence of Epidemics of Hepatitis C, Diabetes, Obesity, and Chronic Kidney Disease in the United States Population

Obesity, kidney disease, and diabetes are common conditions that can affect outcomes of patients with chronic hepatitis C. We aimed to quantify the burden of these comorbid conditions among adults with chronic hepatitis C in the United States and to estimate the risk of death among people with chronic hepatitis C and comorbidities.

http://ift.tt/2rKK237

Acute Pancreatitis has Long-term Deleterious Effect on Physical Quality of Life

It is not clear how acute pancreatitis (AP) affects quality of life (QOL). We aimed to determine the long-term independent effect of AP on physical and mental QOL.

http://ift.tt/2skE2en

The elderly and direct antiviral agents: constraint or challenge?

direct antiviral agents (DAAs) for chronic hepatitis C showed great effectiveness and good safety profile. So far, few data are available about their use in elderly subjects.

http://ift.tt/2rKTCmw

Comparative proteomic profiling of the serum differentiates pancreatic cancer from chronic pancreatitis

Abstract

Finland ranks sixth among the countries having highest incidence rate of pancreatic cancer with mortality roughly equaling incidence. The average age of diagnosis for pancreatic cancer is 69 years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis is 40–50 years, however, many cases overlap in age. By radiology, the evaluation of a pancreatic mass, that is, the differential diagnosis between chronic pancreatitis and pancreatic cancer is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for pancreatic cancer, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry analysis (High Definition MS^E) of serum samples from patients with chronic pancreatitis (13) and pancreatic cancer (22). We have quantified 291 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis. The proteomic signature of chronic pancreatitis versus pancreatic cancer samples was able to separate the two groups by multiple statistical techniques. Some of the enriched pathways in the proteomic dataset were LXR/RXR activation, complement and coagulation systems and inflammatory response. We propose that multiple high-confidence biomarker candidates in our pilot study including Inter-alpha-trypsin inhibitor heavy chain H2 (Area under the curve, AUC: 0.947), protein AMBP (AUC: 0.951) and prothrombin (AUC: 0.917), which should be further evaluated in larger patient series as potential new biomarkers for differential diagnosis.

Serum proteomics has the potential to find the candidate biomarkers for various types of cancers enabling differential diagnosis. We have performed HDMSE of serum samples from chronic pancreatitis and pancreatic cancer patients and quantified hundreds of proteins. Exhaustive statistical analyses such as OPLS-DA, PCA, ROC curve analyses and multiple pathway analyses were performed which provided dysregulated pathways in these diseases and high-confidence potential biomarker candidates were proposed.

http://ift.tt/2s02JQ7

Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States

To evaluate the incidence, trends, seasonality, and age at the time of hepatoportoenterostomy (Kasai procedure) for biliary atresia in the US.

http://ift.tt/2suuTPB

Early Mortality and Morbidity in Infants with Birth Weight of 500 Grams or Less in Japan

To assess the short-term prognosis of Japanese infants with a birth weight (BW) of ≤500 g.

http://ift.tt/2rwGiBc

Cognitive reserve is a resilience factor for cognitive dysfunction in hepatic encephalopathy

Abstract

Cognitive Reserve (CR) modulates symptoms of brain disease. The aim of this study was: to evaluate the effect of CR on cognition in cirrhosis and on the mismatch between cognitive and neurophysiologic assessment of hepatic encephalopathy (HE). Eighty-two outpatient patients with cirrhosis without overt HE were studied [73% males; age: 62 (54–68) (median, interq. range) yrs.; education: 8 (6–13) yrs.]. The Psychometric Hepatic Encephalopathy Score (PHES) was used as cognitive measure of HE. The spectral analysis of the electroencephalogram (EEG) was used as neurophysiologic measure of HE. The CR was assessed by the CR Index (CRI), which was measured by the CRI questionnaire (CRIq) (http://cri.psy.unipd.it). The PHES was altered in 28% of patients and the EEG in 41%. Altered PHES was related to the severity of cirrhosis as assessed by Child-Pugh classification (R = 0.31, p < 0.005). Patients with maintained PHES had higher CRI than those with altered PHES (CRI = 100 ± 20 vs. 88 ± 12 vs., p < 0.01), but not the ones with normal EEG compared to those with abnormal EEG (CRI = 96 ± 17 vs. 98 ± 17 vs. p: n.s.).The PHES, but not the EEG, was found to be related to the CRI (r = 0.35, p < 0.01). The mismatch between cognitive and neurophysiologic evaluation of non-overt HE (the ratio between PHES and the mean dominant frequency -MDF- of the EEG i.e., cognitive performance normalized by EEG speed) was found to be correlated to the CRI (r = 0.36, p < 0.005). CR is a resilience factor for cognitive dysfunction in cirrhosis, and is easily measurable by CRIq.

http://ift.tt/2rwNa1L

Gallic acid and p -coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats

Abstract

The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

http://ift.tt/2suAl5o

The role of oxidative stress in EBV lytic reactivation, radioresistance and the potential preventive and therapeutic implications

Abstract

Epstein-Barr virus (EBV) is an important cancer causing virus. Cancer associated with EBV account for approximately 1.5% of all cancers, and represent 1.8% of all cancer deaths worldwide. EBV reactivation plays an important role in the development of EBV-related diseases and is closely related with patients' survival and clinical stages of EBV-related cancers. The therapy regarding to EBV-related cancers is very urgent, especially in endemic areas. Generating oxidative stress is a critical mechanism by which host cells defend against infection by virus. In addition, ROS-mediated oxidative stress plays a significant but paradoxical role acting as a "double-edged sword" to regulate cellular response to radiation, which is the main therapy strategy for EBV-related cancers, especially nasopharyngeal carcinoma. Therefore, in this review we primarily discuss the possible interplay among the oxidative stress, EBV lytic reactivation and radioresistance. Understanding the role of oxidative stress in EBV lytic reactivation and radioresistance will assist in the development of effective strategies for prevention and treatment of EBV-related cancers. This article is protected by copyright. All rights reserved.

http://ift.tt/2rhb4xA

Occupational solvent exposure and adult chronic lymphocytic leukemia: No risk in a population-based case-control study in four Nordic countries

Abstract

The aim of this study was to assess the effect of occupational solvent exposure on the risk of adult chronic lymphocytic leukemia (CLL). The current case-control study was nested in the Nordic Occupational Cancer Study (NOCCA) cohort. 20,615 CLL cases diagnosed in 1961-2005 in Finland, Iceland, Norway and Sweden, and 103,075 population-based controls matched by year of birth, sex, and country were included. Occupational histories for cases and controls were obtained from census records in 1960, 1970, 1980/81 and 1990. Exposure to selected solvents were estimated by using the NOCCA job-exposure matrix (NOCCA-JEM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by using conditional logistic regression models. Overall, non-significant CLL risk elevations were observed for methylene chloride, perchloroethylene, and 1,1,1-trichloroethane. Compared to unexposed, significantly increased risks were observed for cumulative perchloroethylene exposure ≤ 13.3 ppm-years (OR=1.85, 95% CI 1.16-2.96) and average life-time perchloroethylene exposure ≤ 2.5 ppm (1.61, 95% CI 1.01-2.56) among women, and cumulative methylene chloride exposure ≤ 12.5 ppm-years (OR=1.19, 95% CI 1.01-1.41) and 12.5-74.8 ppm-years (OR=1.23, 95% CI 1.01-1.51) among men in an analysis with 5 years lag-time, though without dose-response pattern. Decreased CLL risk was observed for aliphatic and alicyclic hydrocarbon solvents and toluene. This study did not support associations for solvent exposure and CLL. Observed weak associations for methylene chloride, perchloroethylene, 1,1,1-trichloroethane exposures, aliphatic and alicyclic hydrocarbons, and toluene were not consistent across sexes, and showed no gradient with amount of exposure. This article is protected by copyright. All rights reserved.

http://ift.tt/2qLWqLh

Plasma microRNA signature is associated with risk stratification in prostate cancer patients

Abstract

The aim of the current study was to establish a unique expression profile of circulating cell-free microRNAs (miRNAs) capable of differentiating between prostate cancer (PCa) patients with high risk and intermediate risk Gleason scores. MiRNA expression profiles were determined in plasma samples from 79 treatment-naïve PCa patients, 1-2 follow-up samples after radical prostatectomy (RP) from 51 out of the 79 PCa patients, and 33 healthy men, using a quantitative real time PCR based array containing 48 selected miRNAs. We identified 27 up- and 2 downregulated plasma miRNAs in PCa patients compared with healthy men. Most of the upregulated miRNAs levels were also associated with increasing PSA levels and Gleason scores. Particularly, the levels of miR-16 (p=0.002), miR-148a (p=0.006) and miR-195 (p=0.006) significantly correlated with high-risk Gleason scores, whereby miR-148a (p=0.003) was also significantly associated with increasing PSA values. The high miRNA levels before RP remained increased in the postsurgical plasma samples. Our findings show a network of deregulated plasma miRNAs. In particular, miR-16, miR-148a and miR-195 are involved in the regulation of the PI3K/Akt signaling pathway. These miRNAs may be promising therapeutic targets for high-risk PCa stratification. This article is protected by copyright. All rights reserved.

http://ift.tt/2rhkrxm

A New Teaching Model for Demonstrating the Movement of the Extraocular Muscles

Abstract

The extraocular muscles consist of the superior, inferior, lateral, and medial rectus muscles and the superior and inferior oblique muscles. This study aimed to create a new teaching model for demonstrating the function of the extraocular muscles. A coronal section of the head was prepared and sutures attached to the levator palpebral superioris muscle and six extraocular muscles Tension was placed on each muscle from a posterior approach and movement of the eye documented from an anterior view. All movements were clearly seen less that of the inferior rectus muscle. To our knowledge, this is the first cadaveric teaching model for demonstrating the movements of the extraocular muscles. This article is protected by copyright. All rights reserved.

http://ift.tt/2rKDilZ

Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the possibility of cure for sickle cell disease (SCD) patients. Unfortunately, the probability of finding an HLA-matched donor for SCD patients is low. HSCT from HLA-haploidentical donors using reduced intensity conditioning, unmanipulated bone marrow and post-transplantation cyclophosphamide (ptCy) has resulted in negligible toxicity but high rates of graft rejection. We hypothesized that combining ptCy with a myeloablative reduced toxicity conditioning including serotherapy to increase immune ablation would allow for better engraftment. In a pilot approach, we treated three patients with SCD (5, 8, and 20 years old) lacking a matched donor. All patients had severe disease-related complications despite standard treatment. They received unmanipulated bone marrow from parental HLA-haploidentical donors. Conditioning consisted of alemtuzumab 0.2 mg/kg/day on days −9 and −8, fludarabine 30 mg/m²/day on days −7 to −3, treosulfan 14 g/m²/day on days −7 to −5, thiotepa 2 × 5 mg/kg/day on day −4, and cyclophosphamide 14.5 mg/kg/day on days −3 and −2. GVHD prophylaxis was performed using cyclophosphamide 2 × 50 mg/kg on days +3 and +4 and mycophenolate mofetil, tacrolimus from day +5. After a follow-up of 11, 14, and 30 months, all three patients are alive and well, off immunosuppression, and without symptoms of SCD. One patient experienced mild skin GVHD grade I, none showed chronic GVHD. Asymptomatic CMV reactivation was seen in two patients. HLA-haploidentical HSCT can extend the donor pool for patients with SCD. Whether intensification of the conditioning regimen and intensive immunosuppression leads to improvement in engraftment rates while still allowing a favorable toxicity profile deserves further investigation.

http://ift.tt/2qG1qlz

Low-dose nivolumab-induced responses in acute lymphoblastic leukaemia relapse after allogeneic haematopoietic stem cell transplantation

http://ift.tt/2rYr3lk

Issue Information

http://ift.tt/2rh0oyT

Prognostic impact of HER-2 Subclonal Amplification in breast cancer

Abstract

The presence of a limited number of cells with HER-2 amplification (Subclonal Amplification) in breast carcinomas is occasionally encountered, but its prognostic impact is poorly known. The purpose of this study is to evaluate the prognostic impact of HER-2 Subclonal Amplification in a retrospective series of breast cancers. Accordingly, 81 consecutive breast carcinomas showing HER-2 Subclonal Amplification were obtained from the histology files (case series). These cases were subdivided into two groups: (a) those cases in which the HER-2 Subclonal Amplification was consonant to the accepted criteria for amplification, showing clusters of amplified cells, and (b) those cases with rare HER-2 Subclonal Amplification that did not reflect the accepted criteria for amplification, showing scattered amplified cells only. The incidence of metastases and late recurrences of the case series was compared with a series composed of 109 consecutive cases, being HER-2 homogeneous (comprising 14 Amplified and 95 Non-Amplified cases), matched for grade and stage (control series). It appeared that cases showing Subclonal Amplification had an incidence of metastases intermediate between the cases Amplified and Non-Amplified. Specifically, Subclonal Amplification with clustered cells had a lower incidence of metastases than Amplified cases (12.9 versus 21.4%). On the contrary, Subclonal Amplification with scattered cells showed an incidence of metastases higher than Non-Amplified cases (14 versus 9.47%). In addition, patients Subclonal Amplification with clustered cells, who were treated with the specific monoclonal antibody, had a lower incidence of metastases than patients showing Subclonal Amplification with scattered cells, who did not receive target therapy. These data, together with those recently published, indicate that Subclonal Amplification has an impact on prognosis and should be taken into consideration to correctly plan the treatment of breast cancer patients.

http://ift.tt/2rKIZAg

Early detection: the impact of genomics

Abstract

The field of genomics has shifted our view on disease development by providing insights in the molecular and functional processes encoded in the genome. In the case of cancer, many alterations in the DNA accumulate that enable tumor growth or even metastatic dissemination. Identification of molecular signatures that define different stages of progression towards cancer can enable early tumor detection. In this review, the impact of genomics will be addressed using early detection of colorectal cancer (CRC) as an example. Increased understanding of the adenoma-to-carcinoma progression has led to the discovery of several diagnostic biomarkers. This combined with technical advancements, has facilitated the development of molecular tests for non-invasive early CRC detection in stool and blood samples. Even though several tests have already made it to clinical practice, sensitivity and specificity for the detection of precancerous lesions still need improvement. Besides the diagnostic qualities, also the accuracy of the intermediate endpoint is an important issue on how the effectiveness of a novel test is perceived. Here, progression biomarkers may provide a more precise measure than the currently used morphologically based features. Similar developments in biomarker use for early detection have taken place in other cancer types.

http://ift.tt/2sk4THK

Systemic Embolization from an Unusual Intracardiac Mass in the Left Ventricular Outflow Tract

Endocarditis can affect any endocardial surface; in the vast majority of cases, the cardiac valves are involved. It is exceedingly rare to develop infective endocarditis on the endocardium of the left ventricular outflow tract due to the high velocity of blood that traverses this area. Herein, we present a rare case of left ventricular outflow tract endocarditis that likely occurred secondary to damage to the aortic valve leaflets (from healed prior aortic valve endocarditis) causing a high velocity aortic valve regurgitant jet that impinged upon the interventricular septum which damaged the endocardium and resulted in a fibrotic "jet lesion." This fibrous jet lesion served as a nidus for bacterial proliferation and vegetation formation. The high shear stress (due to high blood flow velocity through the left ventricular outflow tract) likely promoted the multiple embolic events observed in this case. Our patient was successfully treated with aortic valve replacement, vegetation resection, and antibiotics.

http://ift.tt/2rgBjUV

MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1

http://ift.tt/2rKTl2W

MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells

http://ift.tt/2sjPNli

CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells

http://ift.tt/2rKTkMq

Inside EMS Podcast: Does EMS need voice-activated technology?

Our co-hosts are joined by EMS1 Editor-in-Chief Greg Friese to discuss emerging technologies and their application in EMS

http://ift.tt/2qLDbBy

E2F1 induces TINCR transcriptional activity and accelerates gastric cancer progression via activation of TINCR/STAU1/CDKN2B signaling axis

E2F1 induces TINCR transcriptional activity and accelerates gastric cancer progression via activation of TINCR/STAU1/CDKN2B signaling axis

Cell Death and Disease 8, e2837 (June 2017). doi:10.1038/cddis.2017.205

Authors: Tong-Peng Xu, Yan-Fen Wang, Wei-Liang Xiong, Pei Ma, Wen-Yu Wang, Wen-Ming Chen, Ming-De Huang, Rui Xia, Rong Wang, Er-Bao Zhang, Yan-Wen Liu, Wei De & Yong-Qian Shu

http://ift.tt/2stZIEe

Disease-linked connexin26 S17F promotes volar skin abnormalities and mild wound healing defects in mice

Disease-linked connexin26 S17F promotes volar skin abnormalities and mild wound healing defects in mice

Cell Death and Disease 8, e2845 (June 2017). doi:10.1038/cddis.2017.234

Authors: Eric Press, Katanya C Alaga, Kevin Barr, Qing Shao, Felicitas Bosen, Klaus Willecke & Dale W Laird

http://ift.tt/2rw27B8

P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo

P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo

Cell Death and Disease 8, e2858 (June 2017). doi:10.1038/cddis.2017.250

Authors: Chao Gu, Yan Zhang, Qingsong Hu, Jiayuan Wu, Haigang Ren, Chun-Feng Liu & Guanghui Wang

http://ift.tt/2rKx1X8

Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia–reperfusion injury

Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia–reperfusion injury

Cell Death and Disease 8, e2841 (June 2017). doi:10.1038/cddis.2017.236

Authors: Mian Ge, Weifeng Yao, Dongdong Yuan, Shaoli Zhou, Xi Chen, Yihan Zhang, Haobo Li, Zhengyuan Xia & Ziqing Hei

http://ift.tt/2sjJdv1

Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression

Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression

Cell Death and Disease 8, e2857 (June 2017). doi:10.1038/cddis.2017.249

Authors: Shin Kasai, Yoshiyuki Furuichi, Norie Ando, Keiko Kagami, Masako Abe, Takaya Nakane, Kumiko Goi, Takeshi Inukai, Sei Saitoh, Shinichi Ohno, Shogo Okazaki, Osamu Nagano, Hideyuki Saya & Kanji Sugita

http://ift.tt/2rKz79J

The putative tumor suppressor microRNA-30a-5p modulates clear cell renal cell carcinoma aggressiveness through repression of ZEB2

The putative tumor suppressor microRNA-30a-5p modulates clear cell renal cell carcinoma aggressiveness through repression of ZEB2

Cell Death and Disease 8, e2859 (June 2017). doi:10.1038/cddis.2017.252

Authors: Zhenhua Chen, Jiaxing Zhang, Zhiling Zhang, Zihao Feng, Jinhuan Wei, Jun Lu, Yong Fang, Yanping Liang, Junjie Cen, Yihui Pan, Yong Huang, Fangjian Zhou, Wei Chen & Junhang Luo

http://ift.tt/2sjALw2

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition

Cell Death and Disease 8, e2856 (June 2017). doi:10.1038/cddis.2016.457

Authors: Yuyao Yin, Mingming Zhang, Robert Gregory Dorfman, Yang Li, Zhenguo Zhao, Yida Pan, Qian Zhou, Shan Huang, Shimin Zhao, Yuling Yao & Xiaoping Zou

http://ift.tt/2rKoCDq

Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling

Cytoprotective effect of neuropeptides on cancer stem cells: vasoactive intestinal peptide-induced antiapoptotic signaling

Cell Death and Disease 8, e2844 (June 2017). doi:10.1038/cddis.2017.226

Authors: Konduru S Sastry, Aouatef Ismail Chouchane, Ena Wang, George Kulik, Francesco M Marincola & Lotfi Chouchane

http://ift.tt/2sjLWF6

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth

The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth

Cell Death and Disease 8, e2843 (June 2017). doi:10.1038/cddis.2017.235

Authors: Hyun Seung Ban, Bo-Kyung Kim, Hongsub Lee, Hwan Mook Kim, Dipesh Harmalkar, Miso Nam, Song-Kyu Park, Kiho Lee, Joon-Tae Park, Inhyub Kim, Kyeong Lee, Geum-Sook Hwang & Misun Won

http://ift.tt/2sjwRmG

MiR-125b regulates proliferation and apoptosis of nasopharyngeal carcinoma by targeting A20/NF-κB signaling pathway

MiR-125b regulates proliferation and apoptosis of nasopharyngeal carcinoma by targeting A20/NF-κB signaling pathway

Cell Death and Disease 8, e2855 (June 2017). doi:10.1038/cddis.2017.211

Authors: Zhen Zheng, Jia-Quan Qu, Hong-Mei Yi, Xu Ye, Wei Huang, Ta Xiao, Jiao-Yang Li, Yuan-Yuan Wang, Juan Feng, Jin-Feng Zhu, Shan-Shan Lu, Hong Yi & Zhi-Qiang Xiao

http://ift.tt/2rK2iJO

Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer

Long noncoding RNA UCA1 induced by SP1 promotes cell proliferation via recruiting EZH2 and activating AKT pathway in gastric cancer

Cell Death and Disease 8, e2839 (June 2017). doi:10.1038/cddis.2017.143

Authors: Zhen-Qiang Wang, Qiang Cai, Lei Hu, Chang-Yu He, Jian-Fang Li, Zhi-Wei Quan, Bing-Ya Liu, Chen Li & Zheng-Gang Zhu

http://ift.tt/2sjoEPF

Cystatin C as a potential therapeutic mediator against Parkinson’s disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units

Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units

Cell Death and Disease 8, e2854 (June 2017). doi:10.1038/cddis.2017.240

Authors: Jing Zou, Zhaoyu Chen, Xiaobo Wei, Zhigang Chen, Yongmei Fu, Xiaoyan Yang, Dan Chen, Rui Wang, Peter Jenner, Jia-Hong Lu, Min Li, Zhuohua Zhang, Beisha Tang, Kunlin Jin & Qing Wang

http://ift.tt/2rKfiPX

RGD-modified oncolytic adenovirus-harboring shPKM2 exhibits a potent cytotoxic effect in pancreatic cancer via autophagy inhibition and apoptosis promotion

RGD-modified oncolytic adenovirus-harboring shPKM2 exhibits a potent cytotoxic effect in pancreatic cancer via autophagy inhibition and apoptosis promotion

Cell Death and Disease 8, e2835 (June 2017). doi:10.1038/cddis.2017.230

Authors: Yanni Xu, Liang Chu, Sujing Yuan, Yuanqin Yang, Yu Yang, Bin Xu, Kangjian Zhang, Xin-Yuan Liu, Ruwei Wang, Ling Fang, Zhinan Chen & Zongsuo Liang

http://ift.tt/2sjWS5l

Single-cell time-lapse imaging of intracellular O2 in response to metabolic inhibition and mitochondrial cytochrome-c release

Single-cell time-lapse imaging of intracellular O2 in response to metabolic inhibition and mitochondrial cytochrome-c release

Cell Death and Disease 8, e2853 (June 2017). doi:10.1038/cddis.2017.247

Authors: Heiko Düssmann, Sergio Perez-Alvarez, Ujval Anilkumar, Dmitri B Papkovsky & Jochen HM Prehn

http://ift.tt/2rKib3b

Oocyte-specific deletion of furin leads to female infertility by causing early secondary follicle arrest in mice

Oocyte-specific deletion of furin leads to female infertility by causing early secondary follicle arrest in mice

Cell Death and Disease 8, e2846 (June 2017). doi:10.1038/cddis.2017.231

Authors: Tie-Gang Meng, Meng-Wen Hu, Xue-Shan Ma, Lin Huang, Qiu-Xia Liang, Yue Yuan, Yi Hou, Hongmei Wang, Heide Schatten, Zhen-Bo Wang & Qing-Yuan Sun

http://ift.tt/2sjUqMu

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

Cell Death and Disease 8, e2852 (June 2017). doi:10.1038/cddis.2017.237

Authors: Mayilaadumveettil Nishana, Namrata M Nilavar, Rupa Kumari, Monica Pandey & Sathees C Raghavan

http://ift.tt/2rKp3xs

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

Cell Death and Disease 8, e2851 (June 2017). doi:10.1038/cddis.2017.215

Authors: Tongmeng Jiang, Guojie Xu, Qiuyan Wang, Lihui Yang, Li Zheng, Jinmin Zhao & Xingdong Zhang

http://ift.tt/2rKjFKx

Mitochondrial AKAP1 supports mTOR pathway and tumor growth

Mitochondrial AKAP1 supports mTOR pathway and tumor growth

Cell Death and Disease 8, e2842 (June 2017). doi:10.1038/cddis.2017.241

Authors: Laura Rinaldi, Maria Sepe, Rossella Delle Donne, Kristel Conte, Antonietta Arcella, Domenica Borzacchiello, Stefano Amente, Fernanda De Vita, Monia Porpora, Corrado Garbi, Maria A Oliva, Claudio Procaccini, Deriggio Faicchia, Giuseppe Matarese, Federica Zito Marino, Gaetano Rocco, Sara Pignatiello, Renato Franco, Luigi Insabato, Barbara Majello & Antonio Feliciello

http://ift.tt/2sjCSzK

MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion

MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion

Cell Death and Disease 8, e2850 (June 2017). doi:10.1038/cddis.2017.243

Authors: Xin Chen, Xue-Mei Jiang, Lin-Jing Zhao, Lin-Lin Sun, Mei-Ling Yan, You Tian, Shuai Zhang, Ming-Jing Duan, Hong-Mei Zhao, Wen-Rui Li, Yang-Yang Hao, Li-Bo Wang, Qiao-Jie Xiong & Jing Ai

http://ift.tt/2rKq4FV

Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype

Loss of epidermal AP1 transcription factor function reduces filaggrin level, alters chemokine expression and produces an ichthyosis-related phenotype

Cell Death and Disease 8, e2840 (June 2017). doi:10.1038/cddis.2017.238

Authors: Christina A Young, Ellen A Rorke, Gautam Adhikary, Wen Xu & Richard L Eckert

http://ift.tt/2sjRdwr

4 things EMS providers need to know about pulmonary embolism

Careful diagnosis of respiratory and circulatory compromise will help you choose the most appropriate treatment and destination for patients with suspected pulmonary embolism

http://ift.tt/2stAzJZ

Exposure to specific toxins and nutrients during late pregnancy and early life correlate with autism risk

A new study uses a unique source -- baby teeth -- to reveal that both the timing and amount of exposure can affect diagnosis.

http://ift.tt/2rgeMr8

Sequential Bronchoscopic Cryobiopsy and Cryotherapy

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 1036-1040, June 2017.


http://ift.tt/2qLc0Xm

A Phase II Clinical Trial of an Aromatase Inhibitor for Postmenopausal Women with Lymphangioleiomyomatosis

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 919-928, June 2017.


http://ift.tt/2qL4LPy

Acute Respiratory Distress Syndrome and Diffuse Alveolar Damage. New Insights on a Complex Relationship

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 844-850, June 2017.


http://ift.tt/2rgpeiC

Canon in Intensive Care Unit Utilization: The Importance of a Fine-Tuned Instrument

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 836-838, June 2017.


http://ift.tt/2rglqxS

Relationship of Antibiotic Treatment to Recovery after Acute FEV1 Decline in Children with Cystic Fibrosis

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 937-942, June 2017.


http://ift.tt/2rgHmsD

Preserving Lung Function: The Holy Grail in Managing Cystic Fibrosis

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 833-835, June 2017.


http://ift.tt/2qLc1uF

High Complication Rate after Introduction of Transbronchial Cryobiopsy into Clinical Practice at an Academic Medical Center

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 851-857, June 2017.


http://ift.tt/2qLjqKB

Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 903-911, June 2017.


http://ift.tt/2qKRJBw

Assessing the Usefulness and Validity of Frailty Markers in Critically Ill Adults

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 952-959, June 2017.


http://ift.tt/2rgxOxW

Inhaled Corticosteroids and Systemic or Topical Antifungal Therapy: A Symmetry Analysis

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 1045-1047, June 2017.


http://ift.tt/2qL4yvw

Refining the Burden of Idiopathic Pulmonary Fibrosis: The Cocktail Party Effect

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 829-830, June 2017.


http://ift.tt/2qLlwd9

Supplemental Oxygen for Patients with Interstitial Lung Disease: Managing Expectations

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 831-832, June 2017.


http://ift.tt/2qLoFtv

Cryobiopsy: A Work in Progress

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 827-828, June 2017.


http://ift.tt/2qLaOn9

Indwelling Pleural Catheters for Patients with Hematologic Malignancies. A 14-Year, Single-Center Experience

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 976-985, June 2017.


http://ift.tt/2qL7xEh

Code-based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis. Case Validation and Improvement

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 880-887, June 2017.


http://ift.tt/2rgE8p3

Clinical Equipoise and Shared Decision-making in Pulmonary Nodule Management. A Survey of American Thoracic Society Clinicians

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 968-975, June 2017.


http://ift.tt/2qL2F26

Near-Fatal Lung Injury with Rapid-Onset Bronchiectasis Caused by Traditional Fumigation Therapy on the French Island of Mayotte

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 1041-1044, June 2017.


http://ift.tt/2rglnSI

End-Tidal Carbon Dioxide as a Prognostic Feature in Pulmonary Arterial Hypertension

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 896-902, June 2017.


http://ift.tt/2rgp8Yd

Dose De-escalation of Intrapleural Tissue Plasminogen Activator Therapy for Pleural Infection. The Alteplase Dose Assessment for Pleural Infection Therapy Project

Annals of the American Thoracic Society, Volume 14, Issue 6, Page 929-936, June 2017.


http://ift.tt/2qLhpxR

FTOs, is your trainee 'in the zone'?

By Sean Hulsman It's a typical day as a field training officer. Your probie, James, arrives for his third day of training. You're in the middle of inspecting the rig when the radio crackles, summoning you to an unresponsive person. James is a brand new EMT with no previous experience, but he drove hot to two calls the previous shift and had no difficulties. He gets you to the call safely ...

http://ift.tt/2rpKaSJ

Midostaurin Approved by FDA for Acute Myeloid Leukemia

The FDA has approved midostaurin for patients with newly diagnosed acute myeloid leukemia (AML) with mutations in the FLT3 gene. The approval also several other conditions.

http://ift.tt/2qFx0zO

On the Importance of Retaining Stresses and Strains in Repositioning Computational Biomechanical Models of the Cervical Spine

Abstract

Human body models are created in a specific posture and often repositioned and analyzed without retaining stresses that result from repositioning. For example, repositioning a human neck model within the physiological range of motion to a head-turned posture prior to an impact results in initial stresses within the tissues distracted from their neutral position. The aim of this study was to investigate the effect of repositioning on the subsequent kinetics, kinematics and failure modes of a lower cervical spine motion segment, to support future research at the full neck level.

Repositioning was investigated for three modes (tension, flexion, extension) and three load cases. The model was repositioned and loaded to failure in one continuous load history (Case 1), or repositioned then restarted with retained stresses and loaded to failure (Case 2). In Case 3, the model was repositioned and then restarted in a stress-free state, representing current repositioning methods. It was found that not retaining the repositioning stresses and strains resulted in different kinetics, kinematics or failure modes, depending on the mode of loading. For the motion segment model, the differences were associated with the intervertebral disc fiber reorientation and load distribution, since the disc underwent the largest deformation during repositioning.

This study demonstrated that repositioning led to altered response and tissue failure, which is critical for computational models intended to predict injury at the tissue level. It is recommended that stresses and strains be included and retained for subsequent analysis when repositioning a human computational neck model.

http://ift.tt/2rvmWwm

Real-time Tracking of DNA Fragment Separation by Smartphone

Traditional slab gel electrophoresis (SGE) experiments require a complicated apparatus and high chemical consumption. This work presents a protocol that describes a low-cost method to separate DNA fragments within a short timeframe.

http://ift.tt/2rpIjNI

Sudden cardiac death and Ethical issues of CRISPR technology

http://ift.tt/2qGp4SV

Targeted therapy and maintenance in myeloma

Abstract

Introduction

Maintenance therapy aims to extend progression-free survival (PFS) and overall survival (OS), but the convenience of administration, tolerability and toxicity are essentials.

Source of data

A search was conducted to identify published literature and clinical studies about maintenance for multiple myeloma using PubMed and ClinicalTrials.gov.

Areas of agreement

There are different drug classes able to ensure durable responses previously achieved after induction followed or not by transplant, translating into a significant benefit in PFS and OS.

Areas of controversy

It is not well established the optimal maintenance approach, what the ideal duration of maintenance is, and whether all patients have to receive maintenance therapy.

Growing points

To define the role of risk factors and minimal residual disease monitoring for tailored maintenance.

Areas timely for developing research

The development of new therapies and monitoring strategies able to individualize the maintenance to prevent both under and overtreatment.

http://ift.tt/2rpzK5B

Physiotherapy management of lower limb osteoarthritis

Abstract

Background

Osteoarthritis (OA) of the lower limb affects millions of people worldwide, and results in pain and reduced function. We reviewed guidelines and Cochrane reviews for physical therapy interventions to manage the condition.

Sources of data

Evidence from meta-analyses and systematic reviews was included. We also identified the recommendations from guidelines relevant to practice in the UK.

Areas of agreement

There is strongest evidence to support the use of exercise to improve pain, function and quality of life.

Areas of controversy

There is limited evidence to support the use of some commonly utilized physiotherapy interventions. National Institute for Health and Clinical Excellence do not recommend the use of acupuncture.

Growing points

Programmes that include single exercise type may be more beneficial than combined strengthening and aerobic interventions.

Areas timely for developing research

Further research is required to determine how to facilitate long-term engagement with exercise to sustain the beneficial effects on pain, function and quality of life. Studies that investigate packages of care, combining interventions require further investigation.

http://ift.tt/2qGp6dv

Return to sport following stress fractures of the great toe sesamoids: a systematic review

Abstract

Introduction

This review aims to provide information on return rates and times to sport following stress fractures of the great toe sesamoids (SFGTSs).

Sources of data

A systematic search of CINAHAL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Scopus, SPORTDiscus and Web of Science was performed using the keywords 'stress', 'fractures', 'great', 'toe', 'sesamoid', 'athletes', 'sports', 'non-operative', 'conservative', 'operative' and 'return to sport'.

Areas of agreement

Fourteen studies were included: three studies reported on the outcome of conservatively-managed SFGTSs; thirteen studies reported on the outcome of surgically-managed SFGTSs. The management principles were to attempt conservative management for 2–6 months using activity modification, analgesia, orthotics and physiotherapy; if symptoms persisted following this, surgical management was to be recommended, either with internal fixation or sesamoidectomy.

Areas of controversy

The optimal treatment modalities for SFGTSs remain to be defined.

Growing points

Internal fixation shows the best return to full-level sport rates with low rates of complications.

Areas timely for developing research

Future prospective studies should aim to establish the optimal treatment modalities for SFGTSs.

http://ift.tt/2rpCG1S

Sudden cardiac death

Abstract

Introduction

Sudden cardiac arrest continues to be the leading cause of death in the industrialized world.

Sources of data

Original papers, reviews and guidelines.

Areas of agreement

Community programs for lay bystander cardiopulmonary resuscitation (CPR) and automatic external defibrillation improve outcomes. Post-arrest care, including targeted temperature management (TTM) combined with early coronary angiography and percutaneous coronary intervention, is helpful for those suffering cardiac arrest during an ST-segment elevation myocardial infarction.

Areas of controversy

(1) The optimal approach to encourage lay bystanders to assist with resuscitation efforts. (2) Whether TTM combined with early coronary angiography is cost effective for those without ST elevation on their post-arrest ECG is unknown.

Growing points

Increasing data show that chest compression-only CPR is preferred by lay rescuers and improves local survival rates.

Areas timely for developing research

Randomized clinical trials are underway to examine the utility of early coronary angiography in the treatment of post-arrest patients without ST-segment elevation.

http://ift.tt/2qGoNj1

Expect the unexpected: screening for secondary findings in clinical genomics research

Abstract

Background

Due to decreasing cost, and increasing speed and precision, genomic sequencing in research is resulting in the generation of vast amounts of genetic data. The question of how to manage that information has been an area of significant debate. In particular, there has been much discussion around the issue of 'secondary findings' (SF)—findings unrelated to the research that have diagnostic significance.

Sources of data

The following includes ethical commentaries, guidelines and policies in respect to large-scale clinical genomics studies.

Areas of agreement

Research participant autonomy and their informed consent are paramount—policies around SF must be made clear and participants must have the choice as to which results they wish to receive, if any.

Areas of controversy

While many agree that clinically 'actionable' findings should be returned, some question whether they should be actively sought within a research protocol.

Growing points

SF present challenges to a growing field; diverse policies around their management have the potential to hinder collaboration and future research.

Areas timely for developing research

The impact of returning SF and accurate estimates of their clinical utility are needed to inform future protocol design.

http://ift.tt/2rpG8tz

Apoptosis and rotator cuff tears: scientific evidence from basic science to clinical findings

Abstract

Introduction

Excessive apoptosis has been hypothesized as possible cause of tendinopathy and tear in the tendons of the rotator cuff (RC). Different mechanisms and molecules play a key role in cell regulation. Biological interventions can affect the process of apoptosis to control the tendinopathy process, and may be useful to design new treatments.

Source of data

We identified basic science, in vitro and in vivo preclinical and clinical studies listed in the Pubmed Google Scholar, CINAHL, Cochrane Central and Embase Biomedical databases in English, Spanish, Italian and French concerning the effects of apoptosis on RC tendons.

Areas of agreement

The homeostasis between the apoptotic and inflammatory processes is dynamic and controlled by pro- and anti-apoptotic mechanisms and signals, with variable balance in different areas of the RC tendons in human specimens.

Areas of controversy

Apoptosis can be identified along the whole tendon, not only in the area of the lesion. Therefore, it is not necessary to undertake wide debridement of the torn edges of the tendon when undertaking a repair.

Growing points

The identification of the various factors that control apoptosis and its mechanisms can help to design new treatments and exert positive effects in the recovery from tendon tears.

Areas timely for developing research

Further studies are needed to produce clear guidelines to determine how to balance the apoptosis process to reduce the failed healing response found in non-traumatic RC tears.

http://ift.tt/2qGo5Ck

Colour vision requirements in visually demanding occupations

Abstract

Normal trichromatic colour vision (CV) is often required as a condition for employment in visually demanding occupations. If this requirement could be enforced using current, colour assessment tests, a significant percentage of subjects with anomalous, congenital trichromacy who can perform the suprathreshold, colour-related tasks encountered in many occupations with the same accuracy as normal trichromats would fail. These applicants would therefore be discriminated against unfairly. One solution to this problem is to produce minimum, justifiable CV requirements that are specific to each occupation. This has been done successfully for commercial aviation (i.e. the flight crew) and for Transport for London train drivers. An alternative approach is to make use of new findings and the statistical outcomes of past practices to produce graded, justifiable CV categories that can be enforced. To achieve this aim, we analysed colour assessment outcomes and quantified severity of CV loss in 1363 subjects. The severity of CV loss was measured in each subject and statistical, pass/fail outcomes established for each of the most commonly used, conventional colour assessment tests and protocols. This evidence and new findings that relate severity of loss to the effective use of colour signals in a number of tasks provide the basis for a new colour grading system based on six categories. A single colour assessment test is needed to establish the applicant's CV category which can range from 'supernormal', for the most stringent, colour-demanding tasks, to 'severe colour deficiency', when red/green CV is either absent or extremely weak.

http://ift.tt/2rpstTe

Effect of vitamin D deficiency in developed countries

Abstract

Introduction

Vitamin D deficiency is common worldwide with adverse effects on skeletal health. In recent years, there has been great interest in non-classical actions of vitamin D. Basic research has uncovered actions in a range of non-skeletal tissues, and observational studies have identified inverse relationships with risk of a number of disease states including sarcopenia, obesity, the metabolic syndrome, cardiovascular disease, cancer and autoimmune diseases.

Sources of data

PubMed, Medline and Cochrane Systematic Reviews.

Areas of agreement

Current evidence supports the use of vitamin D supplementation in deficiency to improve skeletal outcomes such as falls/fracture risk and bone mineral density.

Areas of controversy

There is debate reflected in guidelines on optimal thresholds for circulating levels of vitamin D. Further studies are required to refine dosing regimens and treatment target levels of vitamin D.

Growing points

A number of studies have investigated the extra-skeletal effects of vitamin D deficiency but causality in humans has yet to be confirmed.

Areas timely for developing research

Large-scale randomized controlled trials incorporating data on vitamin D status at baseline and follow up, adverse events, and comparison of dosing regimens are required. It is imperative that studies are carried out with a diverse range of participants (age, gender and ethnicity), and settings to allow for a more individualized approach. In addition, we would advocate incorporating cutting-edge research tools into human studies to advance our understanding of the mechanisms of vitamin D action in extra-skeletal disease. This may involve multi-metabolite analysis of vitamin D metabolites, or unbiased approaches to assess regulation of gene/protein expression in tissues of interest.

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