Recent Advances in Experimental Allergy

Atopic disorders are on the rise and pose a great burden on society. A better understanding of the underlying mechanisms is required for the development of improved or novel therapeutic strategies. Here we aim to highlight recent advances in experimental allergy, with a particular focus on proposed treatment alternatives for airway disorders, atopic dermatitis, and food allergy. Furthermore, we discuss recent work focusing on molecular and cellular mechanisms that might offer candidates for future preventive or therapeutic intervention.
Int Arch Allergy Immunol

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Local structural connectivity is associated with social cognition in autism spectrum disorder

Abstract

The current theory implying local, short-range overconnectivity in autism spectrum disorder, contrasting with long-range underconnectivity, is based on heterogeneous results, on limited data involving functional connectivity studies, on heterogeneous paediatric populations and non-specific methodologies. In this work, we studied short-distance structural connectivity in a homogeneous population of males with high-functioning autism spectrum disorder and used a novel methodology specifically suited for assessing U-shaped short-distance tracts, including a recently developed tractography-based atlas of the superficial white matter fibres. We acquired diffusion-weighted MRI for 58 males (27 subjects with high-functioning autism spectrum disorder and 31 control subjects) and extracted the mean generalized fractional anisotropy of 63 short-distance tracts. Neuropsychological evaluation included Wechsler Adult Intelligence Scale IV (WAIS-IV), Communication Checklist-Adult, Empathy Quotient, Social Responsiveness Scale and Behaviour Rating Inventory of Executive Function-Adult (BRIEF-A). In contradiction with the models of short-range over-connectivity in autism spectrum disorder, we found that patients with autism spectrum disorder had a significantly decreased anatomical connectivity in a component comprising 13 short tracts compared to controls. Specific short-tract atypicalities in temporal lobe and insula were significantly associated with clinical manifestations of autism spectrum disorder such as social awareness, language structure, pragmatic skills and empathy, emphasizing their importance in social dysfunction. Short-range decreased anatomical connectivity may thus be an important substrate of social deficits in autism spectrum disorder, in contrast with current models.

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A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms

Abstract

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na⁺/K⁺-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na⁺ and K⁺ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K⁺ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.

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Mini-Incision Open Appendectomy with Incision Skin Tissue Retractor vs. Laparoscopic Appendectomy: A Retrospective Study of the Management of Child Acute Appendicitis

Abstract

Introduction

This study aims to compare the clinical effects of an incision skin tissue retractor for mini-incision open appendectomy and laparoscopic surgery for pediatric appendicitis.

Methods

From January 2014 to July 2017, a total of 248 patients were included in the present study. Laparoscopic appendectomy was performed for 108 cases (LA group), and mini-incision open appendectomy with an incision skin tissue retractor was performed for 140 cases (MOA-ISTR group). Then, medical history, age, gender, operative duration, amount of bleeding during the operation, the determination of whether or not the appendix was perforated during the operation, hospitalization days, total cost of hospitalization, and complications after the operation (incision infection or intestinal obstruction) were compared. The SPSS 20.0 software package was used for the statistical analysis.

Results

There were no statistically significant differences in history, age, gender, perioperative perforation of the appendix, postoperative hospital stay and postoperative complications (incisional infection or intestinal obstruction, P  > 0.05). However, the values for duration of surgery, intraoperative blood loss and total hospitalization expense were smaller, when compared with the LA group (P  < 0.05).

Conclusion

Mini-incision open appendectomy with an incision skin tissue retractor has similar efficacy and incision appearance when compared with laparoscopic appendectomy. Furthermore, this approach leads to shorter operation time, less intraoperative blood loss and less hospitalization time, and is more convenient, especially for perforated appendicitis. Moreover, it can be widely used for pediatric appendicitis, and is more suitable for doctors who are not skilled in basic hospitals and laparoscopy.

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Annual Congress of the European Society for Medical Oncology (ESMO): Munich, Germany, 19–23 October 2018

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Acknowledgement to Referees

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Trends in stage at diagnosis for young breast cancer patients in the United States

Abstract

Purpose

Previous studies reported increasing rates of metastatic breast cancer among young US women. However, these studies were based on limited geographic areas and did not account for the sharp decline in unknown-stage disease. In this study, we examined trends in early-onset breast cancer incidence rates by stage at diagnosis in a national dataset, after correcting for temporal changes in unstaged disease.

Methods

Using data from 42 states, covering 82% of the US population, we examined trends in incidence rates by stage at diagnosis and race/ethnicity in women ages 20–39 years. Stage was imputed for non-Hispanic (NH) white and NH black cases with missing information by distributing cases proportionally according to survival statistics.

Results

During 2001–2015, incidence rates of early-onset metastatic breast cancer increased sharply among NH white, NH black, Hispanic, and Asian/Pacific Islander (API) women. Increasing trends were also observed for local-stage disease (all racial/ethnic groups) and regional-stage disease (NH white and API). In contrast, rates decreased sharply for unstaged disease among all groups. After imputing stage for cases with missing information, the increasing trends for regional- and distant-stage disease in NH whites and local-stage disease in NH blacks were no longer statistically significant, but the increase in distant-stage disease in NH blacks was unchanged.

Conclusions

After accounting for the sharp decline in unstaged cases, the increase in incidence rates for distant-stage disease became non-significant in NH whites but not in NH blacks. Future studies should consider accounting for temporal changes in unstaged disease when examining stage-specific incidence trends.

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Death by hanging: a retrospective case-control investigation of the intervertebral disc vacuum phenomenon on PMCT

Abstract

During hanging gravitational forces affect the spine. Intervertebral vacuum phenomenon (VP) implies that gas accumulations in the discs are caused by degeneration of the spine and trauma. It was hypothesized that VP detected on postmortem computed tomography (PMCT) has a higher incidence in hanging deaths, which can be correlated to age, degenerative spinal changes and type of hanging (complete-incomplete). Secondly, it was investigated whether the presence of Simon's bleedings is related to hanging type and VP on PMCT. A retrospective hanging case-control study of 72 cases was conducted. PMCT data were evaluated by two observers for the presence of VP and its localization within the thoracic and lumbar discs, and for any degenerative changes of the spine. Autopsy protocols were assessed for the presence of Simon's bleedings during autopsy. VP did not statistically differ among hanging and control cases but it was statistically correlated to complete hanging, increasing age and degenerative spinal changes. Centrally located VP within the discs was correlated to hanging, especially complete hanging, and younger ages, contrary to control cases that showed gas at the disc periphery. Simon's bleedings were correlated with complete hanging and centrally located VP. Centrally located VP within the discs increases the probability for complete hanging, while increasing age and degenerative changes reduce this probability. Intervertebral VP is multifactorial radiological entity. The presence of centrally located VP can indicate that hanging could be considered as an alternative mechanism of death and that great forces and loads may have affected the spine perimortem, especially with decreasing age and when Simon's bleedings are present.

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Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage, Published online: 12 November 2018; doi:10.1038/s41419-018-1180-y

Brain injury induces HIF-1α-dependent transcriptional activation of LRRK2 that exacerbates brain damage

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Prevention Strategies in Endometrial Carcinoma

Abstract

Purpose of the Review

To assess the most recent high-quality evidence for endometrial cancer prevention strategies.

Recent Findings

• Obesity is an established risk factor for endometrial cancer.

• Weight cycling and weight gain in middle age are risk factors for endometrial cancer.

• Bariatric surgery reduces the risk of endometrial cancer by up to 81% in obese women who attain and maintain a normal weight.

• Combined oral contraceptives provide durable protection against endometrial cancer for 30 years or more.

• Ever use of the levonorgestrel intrauterine system (LNG-IUS) and inert intrauterine devices reduce endometrial cancer risk.

• The first oestrogen-based non-progestin HRT for non-hysterectomised women that contains estradiol and bazedoxifene has an effective protective effect on endometrium.

• Bisphosphonates reduce endometrial cancer risk.

Summary

Weight loss and LNG-IUS would seem to be an effective strategy for preventing the development of obesity-driven endometrial cancer in the highest risk women. Future research may identify other safe and effective chemoprevention interventions, such as aspirin, bisphosphonates or metformin.

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Correction to: The Role of Oncolytic Viruses in the Treatment of Melanoma

A correction was made to a sentence in the original article to provide additional clarification in the "Other Oncolytic Viruses" section.

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Management of Locally Advanced and Metastatic Esophageal Cancer in the Older Population

Abstract

Purpose of Review

This review aims to synthesise the current literature on the management of early-stage and metastatic esophageal cancers, focusing on the older population. In particular, we aim to dissect out the elderly-specific data from the relevant trials and to discuss the issues unique to this population.

Recent Findings

While surgery is the curative modality in esophageal malignancies, the CROSS, MAGIC and FLOT trials demonstrate a clear advantage to neoadjuvant therapy (chemotherapy and chemoradiotherapy). These trials, however, included few elderly patients. There is a similar lack of elderly-specific data in the metastatic setting.

Summary

Esophageal malignancies remain highly lethal with increasing incidence with age. Despite the relative lack of elderly-specific data, the fit older population appear to similarly benefit from multimodal therapy in early-stage and palliative therapy in metastatic disease.

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The Gothenburg H70 Birth cohort study 2014–16: design, methods and study population

Abstract

To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014–16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n = 1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5 years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons.

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Where Are We Going with Sentinel Lymph Node Mapping in Gynecologic Cancers?

Abstract

Purpose of Review

Sentinel lymph node (SLN) mapping is a standard of care for lymphatic assessment of many early-stage gynecologic malignancies. We review the current data, emphasizing the utility of SLN mapping in the management of gynecologic cancers.

Recent Findings

Endometrial cancer: recent studies have focused on confirming the safety and efficacy of SLN mapping for high-risk patients. Cervical cancer: the LACC Trial demonstrated reduced survival with minimally invasive surgery, calling into question the validity of prior studies evaluating SLN mapping with a minimally invasive approach. Vulvar cancer: the ongoing GROINS-V-II trial is investigating whether patients with SLN metastasis < 2 mm in diameter can safely undergo adjuvant radiation ± chemotherapy without completion inguinal lymphadenectomy.

Summary

NCCN guidelines have incorporated SLN mapping as a lymphatic assessment strategy for endometrial, cervical, and vulvar malignancies. SLN mapping appears to reduce morbidity while still maintaining an appropriate detection rate of lymphatic metastasis. Additional clinical trials will further our knowledge of these procedures.

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Palliative Care in Patients with Leukemia: When and How?

Abstract

Purpose of Review

Patients with hematologic malignancies get more aggressive treatment and the end-of-life, more ICU deaths, and prolonged hospital stays. In comparison to solid tumors, their access to palliative care and hospice is less.

Recent Findings

Multiple factors seem to play a role including curative goals, different treatment options, stronger relationship between patients and oncologist, symptom burden, and limitations of hospice care.

Summary

Improving the perception of palliative care in these patients, characterizing their needs, and more education can help to increase referrals and access to palliative care. Innovative ways to improve integration between hematology-oncology and palliative care are needed.

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Surgical Management of Lung Cancer: History, Evolution, and Modern Advances

Abstract

Purpose of Review

Although surgery for lung cancer was not common before the early twentieth century, it has enjoyed remarkable progress since then both in type of resection and technical approach. This has been coupled with significant technological advances. Here, we will review the history and evolution of this relatively new field of surgery.

Recent Findings

The gold standard of the extent of resection for lung cancer evolved from pneumonectomy to lobectomy to even sublobar resection for select situations. In addition, major advances have occurred in the technical aspect of the surgical procedure. The incisional approach has evolved from rib spreading thoracotomy to thoracoscopic surgery with the latter showing significant improvement in short-term outcomes over open thoracotomy. However, standard video-assisted thoracoscopic surgery or VATS is associated with visual and mechanical limitations, including lack of depth perception and rigid straight instruments. This makes it appropriate only for early-stage peripheral and small tumors. Most of the limitations of VATS can be overcome with the more recently introduced robotic-assisted thoracic surgery (RATS). RATS utilizes wristed instruments that are introduced in the chest through 8-mm ports and can mimic the movements of the human hand. In addition, magnified, three-dimensional and high definition imaging gives the surgeon an image of the lung unlike any other modality. This has allowed surgeons to perform advanced resections such as pneumonectomy or sleeve resection in a minimally invasive fashion. In addition, RATS has become a platform for the addition of other technical enhancements such as incorporating a near infra-red light source into the camera allowing identification of autoflourescent agents, such as indocyanin green. This has allowed localization of small nodules for resection and identification of tissue planes for sublobar resection. However, new technologies also require investments in time and money.

Summary

Thoracic surgery for lung cancer has evolved to include advanced minimally invasive techniques including video-assisted and robotic-assisted thoracoscopy. RATS in particular may enable surgeons to perform more advanced procedures in a minimally invasive fashion. It is hoped that the higher costs of new surgical technology may be offset by the potential for improved patient outcomes and resultant socioeconomic benefits.

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Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers

Abstract

Purpose of Review

Immune checkpoint blockade targeting PD-1 and PD-L1 improves immune recognition of tumor cells but had only modest success in gynecological cancers as monotherapy. Growing focus has been placed on combination immunotherapy strategies to overcome this resistance, and this review serves to discuss some of the most promising studies in gynecological cancers.

Recent Findings

PD-1- and PD-L1-targeting antibodies are being combined with many novel agents including anti-CTLA-4 antibodies, PARP inhibitors, targeted agents, and traditional chemotherapy in promising studies with the hopes of increasing the immune response and overcoming resistance by targeting other pathways. Novel immune techniques including vaccines and adoptive cell therapies are also being implemented in gynecological cancers.

Summary

Immune checkpoint combinations and novel immunotherapy strategies have demonstrated potential to overcome resistance to PD-1/PD-L1 blockade in gynecological cancers. Identification of biomarkers of response and resistance is a priority to tailor specific combination therapies to the appropriate patients.

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Practical Strategies for Optimizing and Integrating Palliative Care in Cancer

Abstract

Purpose of Review

Recent reforms in medical payment coupled with a rapidly evolving pharmacotherapeutic armamentarium is creating a transition in the field of oncology. This transition represents a key period for conceptual reevaluation, providing an opportunity for furthered strategic integration of palliative care within the realm of oncology.

Recent Findings

Historically, oncologists have relied upon prognostic assessments to gauge appropriateness for referrals to specialty palliative care. Recent literature has elucidated on the early palliative burdens of cancer, demonstrated the importance of complexity-based palliative referrals, and begun the conversation to define provider-specific roles.

Summary

Herein, we describe a model that overlaps complexity with oncology capacity, to target specialty services to those who could benefit most. This article will review the role of palliative care as a care philosophy, the enduring and important role of the oncologist in providing palliative care, and the important areas for integration of specialty services when needed.

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The Role of Hypnosis in Cancer Care

Abstract

Purpose of Review

This paper reviews the current evidence-base for the use of hypnosis as an adjunct treatment for common cancer-related symptoms and side effects, including those experienced during treatment, as well as long-term and late effects. First, a general description and history of medical hypnosis in cancer care is provided, followed by a review of the latest evidence across a range of common symptoms.

Recent Findings

The evidence suggests that hypnosis may help treat symptoms of nausea and vomiting in breast cancer patients, manage pain in a variety of contexts, and also reduce levels of anxiety and overall distress around surgical and medical procedures, both in children and adults. Emerging research shows promise for treating hot flashes in women with breast cancer.

Summary

The research in this area would benefit from assessing populations beyond women with breast cancer, including late-stage disease, using more rigorous study designs, following published reporting guidelines and better describing and standardizing interventions.

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CRISPR/Cas9 Methodology for the Generation of Knockout Deletions in Caenorhabditis elegans

The Caenorhabditis elegans Gene Knockout Consortium is tasked with obtaining null mutations in each of the more than 20,000 open reading frames (ORFs) of this organism. To date, approximately 15,000 ORFs have associated putative null alleles. As there has been substantial success in using CRISPR/Cas9 in C. elegans, this appears to be the most promising technique to complete the task. To enhance the efficiency of using CRISPR/Cas9 to generate gene deletions in C. elegans we provide a web-based interface to access our database of guide RNAs (https://ift.tt/2lH39WK). When coupled with previously developed selection vectors, optimization for homology arm length, and the use of purified Cas9 protein, we demonstrate a robust and effective protocol for generating deletions for this large-scale project. Debate and speculation in the larger scientific community concerning off-target effects due to non-specific Cas9 cutting has prompted us to investigate through whole genome sequencing the occurrence of single nucleotide variants and indels accompanying targeted deletions. We did not detect any off-site variants above the natural spontaneous mutation rate and therefore conclude that this modified protocol does not generate off-target events to any significant degree in C. elegans. We did, however, observe a number of non-specific alterations at the target site itself following the Cas9-induced double-strand break and offer a protocol for best practice quality control for such events.

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Altered function of the glutamate‐aspartate transporter GLAST, a potential therapeutic target in glioblastoma

In glioma patients, high levels of glutamate can cause brain edema and seizures. GLAST, a glutamate‐aspartate transporter expressed by astrocytes with a role in glutamate uptake, is highly expressed on the plasma membrane of glioblastoma (GBM) cells, and its expression significantly correlates with shortened patient survival. Here, it was demonstrated that inhibition of GLAST expression limited the progression and invasion of GBM xenografts. Magnetic resonance spectroscopy was used to measure glutamate in GLAST‐expressing gliomas showing that these tumors exhibit increased glutamate concentration compared to GLAST‐depleted glioma. Despite their GLAST expression, GBM stem‐like cells (GSCs) released rather than taking up glutamate due to their lack of Na+/K+‐ATPase. Overexpression of Na+/K+‐ATPase in these cells restored glutamate uptake and induced apoptosis. The therapeutic relevance of targeting GLAST in gliomas was assessed using the inhibitor UCPH‐101. In glioma‐bearing mice, a single intratumoral injection of UCPH‐101 significantly increased survival by decreasing GLAST expression and inducing apoptosis. Thus, GLAST has a novel role in GBM that appears to have crucial relevance in glutamate trafficking and may thus be a new therapeutic target.

This article is protected by copyright. All rights reserved.

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Cancers, Vol. 10, Pages 434: Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers, Vol. 10, Pages 434: Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers doi: 10.3390/cancers10110434

Authors: Ming-Ju Tsai Jen-Yu Hung Mei-Hsuan Lee Chia-Yu Kuo Yu-Chen Tsai Ying-Ming Tsai Ta-Chih Liu Chih-Jen Yang Ming-Shyan Huang Inn-Wen Chong

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) &ldquo;a single sensitizing uncommon mutation&rdquo;, 7 (12%) &ldquo;multiple sensitizing mutations&rdquo;, 5 (9%) &ldquo;a sensitizing mutation and a resistant uncommon mutation&rdquo;, and 18 (32%) &ldquo;other resistant uncommon mutations&rdquo;. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

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Nanoemulsion Strategy for Ursolic and Oleanic Acids Isolates from Plumeria Obtusa Improves Antioxidant and Cytotoxic Activity in Melanoma Cells

Background: Triterpenoids are an important class of natural bioactive products present in many medicinal plants.

Objective: The aim of present study is to investigate the antioxidant and anticarcinogenic potential of Oleanolic Acid (OA) and Ursolic Acid (UA) on B16 murine melanoma cell line isolated from Plumeria obtusa, free and loaded in a nanoemulsion (NEm) system.

Methods: The nanoemulsion was characterized by dynamic light scattering, transmission electron microscopy. The viscosity was also evaluated. The antioxidant activity was determined by the reduction of 2,2-diphenyl-2- picrylhydrazyl (DPPH) free radical. In vitro proliferation studies were determined using the sulforhodamine-B method.

Results: OA/UA natural mixture exhibited high percentage of inhibition of DPPH (86.06% and 85.12%, with and without irradiation). Percentages of inhibition higher than 85% in samples with and without ultraviolet irradiation were recorded when loaded in the NEm system. The natural mixture incorporated into the NEm showed cytotoxic activity from 2.9 µM, whereas the free compounds from 17.4 µM.

Conclusion: We conclude that these pentacyclic triterpenes loaded in a NEm system could be considered as a new potential tool for further investigation as anticancer agents.

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Cold Atmospheric Plasma Activated Solution: A New Approach for Cancer Treatment

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Meet Our Associate Editor

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Edelfosine: An Antitumor Drug Prototype

Background: Lung cancer is the most prevalent cancer and a high fatality disease. Despite of all available therapeutic approaches, drug resistance of chemotherapy agents for patients remain as an obstacle. New drugs integrating immunotherapeutic and conventional cytotoxic effects is a powerful strategy for the treatment of cancer to overcome this limitation. Antineoplastic phospholipids combine both of these activities by affecting lipid metabolism and signaling through lipid rafts. Therefore, they emerge as interesting scaffolds for designing new drugs.

Objective: We aimed to evaluate antineoplastic phospholipids as scaffolds for designing new drugs for lung cancer treatment.

Methods: The initial screening in A549 cells was performed by MTT assay. Others cytotoxic effects were evaluated in A549 cells by clonogenic assay, Matrigel 3D culture and flow cytometry analyses of cell cycle, apoptosis, mitochondrial membrane electronic potential and superoxide production. Immunological effects of ED were accessed on dendritic cells (DCs) and the expression of some markers were evaluated by flow cytometry. In vivo lung colonization analysis was performed after intravenously injection of A549 cells and daily treatment with ED.

Results: Herein, ED showed to be the most efficient compound concerning cytotoxic, thereby, ED was selected for following tests. ED showed a cytotoxic profile in both monolayer and 3D culture and also in vivo models using A549 cells. This profile is due to G0/G1 phase cellular arrest and apoptosis drove by mitochondrial membrane depolarization and superoxide overproduction. Moreover, ED modulated DCs toward an activated pattern by the increased expression of CD83 and a remarkable decreased expression of PD-L1/CD274 on DCs membrane.

Conclusions: Thus, ED is an interesting antitumor drug prototype due to not only its direct cellular cytotoxicity but also given its immunological features.

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Effects of Plasma Activated Medium on Head and Neck FaDu Cancerous Cells: Comparison of 3D and 2D Response

Objective: The aim of this work is to investigate the inhibitory effect of Plasma Activated Medium (PAM) on Head and Neck cancerous cells (FaDu). The response of FaDu cells in monolayer cultures and Multi Cellular Tumor Spheroids (MCTS) after treatment with different PAMs will be compared.

Background: Head and Neck squamous cell carcinoma is a widespread cancer that responds poorly to anticancer treatments such as chemotherapy and radiotherapy. Nowadays there is a growing interest in cold plasmas and their applications in cancer therapy.

Methods: A homemade helium plasma jet is used to produce PAM. The effects of PAM and hydrogen peroxide H2O2 on FaDu 2D cells cultures and MCTS were characterized by evaluating the cell viability with PrestoBlue test and by measuring the size of MCTS.

Results: One treatment with PAM induce cell detachment from MCTS since the first day in a PAM exposure dependent manner. This is due to the presence of H2O2 in PAM. However, a rapid spheroids regrowth is observed attributed to a resistance of FaDu cells to H2O2. After multiple treatments of MCTS with PAM we obtained an inhibition of cell growth. MCTS are brought out when comparing PAM effect on 2D versus MCTS. Inversely, PAM induces cell death in the case of 2D cell culture.

Conclusion: PAM may be considered as a potentially efficient agent in the therapy of head and neck cancer. We also point out that MCTS is a more valuable model than 2D cell culture for the evaluation of the anti-cancer activity of PAM.

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2-Methoxy-6-Acetyl-7-Methyljuglone (MAM) Induces iNOS/NO-mediated DNA Damage Response through Activation of MAPKs Pathways

Background：There are inconsistent reports about the role of Nitric Oxide (NO) in cancer progression and prevention. Quinones demonstrate significant anti-cancer activities both in vitro and in vivo.

Objective： We investigated the effect of 2-methoxy-6-acetyl-7-methyljuglone (MAM), a natural naphthoquinone isolated from Polygonum cuspidatum Sieb. et Zucc, on NO generation and its role in DNA damage in cancer cells.

Methods: BEL-7402 and A549 cells were cultured and treated with MAM. The NO generation, DNA damage, and protein expression were determined.

Results: MAM induced inducible nitric oxide synthase (iNOS)/NO-mediated DNA damage response through activation of MAPKs pathways. MAM induced DNA damage by activating ATM/Chk2. MAM increased iNOS expression, NO production, and MAPKs (JNK1/2, ERK1/2, and p38MAPK) phosphorylation in concentrationand time- dependent manners. Furthermore, iNOS inhibitor 1400W, iNOS siRNA, and NO scavenger hemoglobin (Hb) could significantly reverse MAM-induced DNA damage, ATM/Chk2 activation, NO production, and cell death. In addition, MAPKs inhibitors (SP600125, U0126, and SB203580) reversed MAM-induced cell death and ATM/Chk2 activation. MAM-induced cell death was partially reversed by 1400W and Hb but enhanced by L-arginine.

Conclusion: These results suggested that MAM induced iNOS/NO activation and generation mediated by MAPKs pathways, which resulted in DNA damage.

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Targeting Protective Catalase of Tumor Cells with Cold Atmospheric Plasma- Activated Medium (PAM)

Background: Application of cold atmospheric plasma to medium generates "plasma-activated medium" that induces apoptosis selectively in tumor cells and that has an antitumor effect in vivo. The underlying mechanisms are not well understood.

Objective: Elucidation of potential chemical interactions within plasma-activated medium and of reactions of medium components with specific target structures of tumor cells should allow to define the active principle in plasma activated medium.

Methods: Established knowledge of intercellular apoptosis-inducing reactive oxygen/nitrogen species-dependent signaling and its control by membrane-associated catalase and SOD was reviewed. Model experiments using extracellular singlet oxygen were analyzed with respect to catalase inactivation and their relevance for the antitumor action of cold atmospheric plasma. Potential interactions of this tumor cell-specific control system with components of plasma-activated medium or its reaction products were discussed within the scope of the reviewed signaling principles.

Results: None of the long-lived species found in plasma-activated medium, such as nitrite and H2O2, nor OCl- or .NO seemed to have the potential to interfere with catalase-dependent control of apoptosis-inducing signaling of tumor cells when acting alone. However, the combination of H2O2 and nitrite might generate peroxynitrite. The protonation of peroxnitrite to peroxynitrous acid allows for the generation of hydroxyl radicals that react with H2O2, leading to the formation of hydroperoxide radicals. These allow for singlet oxygen generation and inactivation of membrane-associated catalase through an autoamplificatory mechanism, followed by intercellular apoptosis-inducing signaling.

Conclusion: Nitrite and H2O2 in plasma-activated medium establish singlet oxygen-dependent interference selectively with the control system of tumor cells.

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The Effect of Flubendazole on Adhesion and Migration in SW480 and SW620 Colon Cancer Cells

Background: Colon cancer is the most common type of gastrointestinal cancer. Despite advances during the last two decades, the efficacy of colorectal cancer treatment is still insufficient and new anticancer agents are necessary.

Methods: In our study, colon cancer cells derived from a primary tumor (SW480) and lymph node metastasis (SW620) from the same patient were used and compared. The effect of flubendazole (FLU) on cell adhesion and migration was monitored using the x-CELLigence Real-Time Cell Analysis system. Expressions of molecules involved in adhesion and migration were analyzed using RT-PCR and western blot. Furthermore, RNA silencing of nuclear factor-κB in SW620 cells was used to determine the involvement of the NF-κB p65 regulation pathway in FLU action.

Results: FLU significantly suppressed the adhesion of SW480 cells and reduced the expression of adhesion markers (ICAM-1, αE-catenin; β-catenin; integrin α5 and β1). Moreover, a significant anti-migratory potential of FLU was manifested in the SW620 cells. In addition, FLU suppressed the phosphorylation of NF-κB p65 and potentiated the suppression of several metastatic markers (ICAM-1, EpCAM, integrin α5, β1, α-tubulin) caused by NF-κB p65 silencing.

Conclusion: FLU has a significant anti-migratory effect in intestinal cancer cell SW480 and its lymph node metastatic cells SW620. FLU decreases the expression of some proteins involved in metastatic processes and inhibits activation of NF-κB p65.

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How Does Plasma Activated Media Treatment Differ From Direct Cold Plasma Treatment?

Objective: The aim of the paper is to investigate the optimum condition for generation of Plasma Activated Media (PAM), where it can deactivate the cancer cells while minimum damage for normal cells.

Background: Over past few years, cold atmospheric Plasma-Activated Media (PAM) have shown its promising application in plasma medicine for treatment of cancer. PAM has a tremendous ability for selective anti-cancer capacity in vitro and in vivo.

Methods: We have analyzed the radicals in air using the optical emission spectroscopy and in culture media using chemical analysis. Further, we have tested the toxicity of PAM using MTT assay.

Results: We observed that more cancer cell death is for the Ar plasma followed by the Ar-N2 plasma, and the least cell death was observed for the Ar-O2 plasma at all treatment times both by direct treatment and through PAM treatment. The concentration of the RNS species is high for Ar-N2 plasma in gas as well as inside the culture media compared to that for pure Ar plasma. However, the difference is significantly less between the Ar plasma treatments and the Ar-N2 plasma treatments, showing that ROS is the main factor contributing to cell death.

Conclusion: Among all three feeding gas plasmas the best system is Ar-O2 plasma for direct treatments towards the cancer cells. In addition, the best system for PAM preparation is Ar-N2 at low time treatments (1 min and 2 min) because it has no effect on normal cells, but kills the cancer cells.

https://ift.tt/2FkSNbU

Hydrogen Peroxide and Beyond-the Potential of High-voltage Plasma-activated Liquids Against Cancerous Cells

Background: The use of plasma-activated liquids such as PBS, medium or simply plasma-activated water (PAW) has been receiving increasing attention for applications in cancer treatments. Amongst the reactive species contained in these solutions, hydrogen peroxide appears to play a pivotal role in causing cytotoxic effects. H2O2 concentrations can be correlated with reduced cell viability and growth and used as an indicator of the potential efficacy of a plasma-activated liquid.

Objective: To investigate the cytotoxic mediators generated in water specific to high-voltage DBD-ACP.

Method: Using a high-voltage dielectric barrier atmospheric cold plasma (DBD-ACP) system, we examined PAW-mediated cytotoxic effects on different mammalian cell lines employing a set-up where short-lived reactive species can be discounted and activated liquids with long-term stability are generated.

Results: The PAW potency could be modulated using voltage level, treatment time and post-treatment storage time and target-related characteristics such as surface to volume ratio. All of these parameters effected cell viability in a hydrogen peroxide concentration correlated manner. The susceptibility of two cancer cell lines to PAW was similar to that observed for two non-cancer cell lines and the toxicity of plasma-activated water exceeded that of the corresponding hydrogen peroxide concentrations.

Conclusion: In cytotoxic plasma activated water an essential role for H2O2 has been demonstrated multi-fold, yet further contributing factors are apparent and remain to be identified.

https://ift.tt/2FishzN

Polyphyllin I Induces Cell Cycle Arrest and Cell Apoptosis in Human Retinoblastoma Y-79 Cells through Targeting p53

Background: Retinoblastoma is the most common intraocular malignant tumor in childhood. Although external beam radiation and enucleation are effective to control retinoblastoma, eye salvage and vision preservation are still significant challenges. Polyphyllin I (PPI), a natural compound extracted from Paris polyphylla rhizomes, has a wide range of activities against many types of cancers. However, the potential effect of this herbal compound on retinoblastoma has not yet been investigated.

Method: In the present study, we evaluated the cytotoxic effect of PPI on human retinoblastoma Y-79 cells as well as its underlying molecular mechanism. Our results indicated that PPI treatment significantly inhibited cell proliferation, arrested the cell cycle at G2/M phase and induced cell apoptosis of Y79 cells through the mitochondrial- dependent intrinsic pathway. Moreover, p53 is involved in PPI-induced cytotoxicity in human retinoblastoma Y-79 cells. Exposure to 10 μM PPI for 48 h dramatically induced the expression levels of p53, phosphorylated- p53 and acetylated-p53. Furthermore, blockade of p53 expression effectively attenuated PPI-induced cell cycle arrest and cell apoptosis in Y-79 cells.

Result: These results demonstrated that PPI exhibits anti-proliferation effect on human retinoblastoma Y-79 cells through modulating p53 expression, stabilization and activation. This information shed light on the potential application of PPI in retinoblastoma therapy.

https://ift.tt/2qHALq7

Cold Physical Plasma-Treated Buffered Saline Solution as Effective Agent Against Pancreatic Cancer Cells

Background: Cold physical plasma has been suggested as a new anticancer tool recently. However, direct use of plasma is limited to visible tumors and in some clinical situations, is not feasible. This includes repetitive treatment of peritoneal metastases, which commonly occur in advanced gastrointestinal cancer and in pancreatic cancer in particular. In case of diffuse intraperitoneal metastatic spread, Hyperthermic Intraperitoneal Intraoperative Chemotherapy (HIPEC) is used as a therapeutic approach. Plasma-treated solutions may combine non-toxic characteristics with the anticancer effects of HIPEC. Previous work has provided evidence for an anticancer efficacy of plasma-treated cell culture medium but the clinical relevance of such an approach is low due to its complex formulation and lack of medical accreditation.

Objective: Plasma-treated Phosphate-Buffered Saline (PBS), which closely resembles medically certified solutions, was investigated for its cytotoxic effect on 2D monolayer murine pancreatic cancer cells in vitro.

Methods: Toxicity studies of primary murine fibroblasts, PDA6606 murine pancreatic cancer cells, and COLO 357 human pancreatic cancer cells exposed to plasma-treated PBS were performed.

Results: Plasma-treated PBS significantly decreased cancer cell metabolisms and proliferation whereas plasma-treated Dulbecco's Modified Eagle Medium had no effect. Moreover, tumor cell growth attenuation was significantly higher when compared to syngeneic primary murine fibroblasts. Both results were confirmed in a human pancreatic cancer cell line. Finally, plasma-treated PBS also decreased the size of pancreatic tumors in a three-dimensional manner, and induction of apoptosis was found to be responsible for all anticancer effects identified.

Conclusion: Plasma-treated PBS inhibited cell growth in 2D and 3D models of cancer. These results may help facilitate the development of new plasma-derived anticancer agent with clinical relevance in the future.

https://ift.tt/2FkSI86

Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors

Background: Phosphatidylinositol-3-kinase α (PI3Kα) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer.

Methods: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3Kα enzyme.

Results: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 µM and 4.25 µM, respectively. Further, the same compound also exhibited potent PI3Kα inhibitory activity with IC50 value of 1.26 µM.

Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.

https://ift.tt/2qGTK3Y

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors "omics", including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research.

It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

https://ift.tt/2FkSDRQ

Synthesis and Biological Evaluation of New 1,3,4-Oxadiazoles as Potential Anticancer Agents and Enzyme Inhibitors

Background: 1,3,4-Oxadiazoles have been known with a wide variety of pharmacological activities including anticancer activity.

Objective: In this study, novel 2,5-disubstituted 1,3,4-oxadiazole derivatives were synthesized and evaluated for determining their anticancer, anticholinesterase and lipoxygenase (LOX) inhibitory activity.

Methods: All compounds were tested against C6 rat glioma, A549 human lung carcinoma and NIH/3T3 mouse embryo fibroblast cell lines to define cytotoxic concentrations and apoptosis induction levels which they cause.

Results: Many of the compounds exhibited remarkable potency that compounds 2a, 2b, 2e, 2h and 2j against C6 cells and compounds 2a, 2b, 2d, 2g, 2i, 2j against A549 cells were found more active than cisplatin. Compound 2d namely, 2-[(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-chlorophenyl)ethan-1-one induced apoptosis of A549 cells with 74.9% whereas cisplatin caused 70.9% percentage.

Conclusion: Among them, compounds 2d and 2j against A549 cell line, compounds 2b and 2e against both tumor cell lines showed selective cytotoxicity evaluating the inhibition concentration against NIH/3T3 cell line. None of the compounds showed significant acetylcholinesterase (AChE) and lipoxygenase inhibitory activities.

https://ift.tt/2qHEljV

Diagnostic role of cytology in serous effusions of patients with hematologic malignancies

Background

We investigated serous effusions occurring during the course of an already known hematologic neoplasia or as a first manifestation of it. We correlated cytology results with flow cytometry results, when available. In the absence of flow cytometry, our correlation was based on clinical follow up information obtained retrospectively. We evaluated our results in relation to the data of the literature and we considered some new suggestions for the improvement of cytology service.

Methods

Serous effusions in hematologic patients were retrieved from the files of the Department of Cytology, Laiko Hospital, for a period of 2 years. All patients had enrolled either a previous hematologic history, or a suspicious clinical and imaging status. Seventy‐three serous effusions were included. Cytology reports consisting of morphology and immunocytochemistry assessment were correlated to flow cytometry results and, occasionally, to clinical follow‐up.

Results

In the group of patients with previous history, sensitivity was 82.76%, positive predictive value was 100%, specificity 100%, and negative predictive value was 58.33%. In the group of patients without previous history, sensitivity and positive predictive value were both 91%, whereas specificity and negative predictive value could not be estimated.

Conclusion

We provide evidence that the diagnostic accuracy of cytology with the adjunct of immunocytochemistry is high compared to flow cytometry for detecting hematologic malignancies. In order to improve clinical performance, it is suggested that a cytology triage of serous effusions in all patients with hematologic malignancy must be implemented.

https://ift.tt/2FeAzIS

A critical appraisal of the Milan system for reporting salivary gland cytology (MSRSGC) with histological correlation over a 3‐year period: Indian scenario

Background

Fine needle aspiration cytology (FNAC) is the first line investigation for pre‐operative diagnosis of salivary gland lesions, but due to its inherent limitations remains a challenge for the cytopathologists. The recently proposed international risk stratification scheme, the Milan System for Reporting Salivary Gland Cytology (MSRSGC) aims to promote and standardise the communication between cytopathologist and clinician thereby improving patient care.

Methods

A retrospective study of all salivary gland cytology cases was performed over a 3‐year period, reviewed by pathologists and categorised into 1 of the 6 diagnostic categories according to MSRSGC, namely, non‐diagnostic, non‐neoplastic, atypia of undetermined significance (AUS), benign neoplasm, and salivary gland neoplasm of undetermined significance (SUMP), suspicious for malignancy (SFM), and malignant neoplasm. Cyto‐ histological correlation was done wherever possible. Risk of malignancy (ROM) was calculated for each diagnostic category.

Results

Out of a total of 150 salivary FNAC cases, histopathology was available for 64 cases. The sensitivity of FNAC was 81.8%, specificity was 100% while the diagnostic accuracy was 96.9%. The positive and negative predictive values were 100% and 96.4% respectively. The ROM for non‐diagnostic, non‐neoplastic, AUS, benign neoplasm, SUMP, SFM, and malignant categories were 0%, 10%, 50%, 2.5%, 50%, 100%, and 100% respectively.

Conclusion

MSRSGC fulfils the critical need for a uniform, internationally acceptable reporting system with ROM specified for each category. However, large scale multi centre studies need to be conducted before its reliability and validity is proven.

https://ift.tt/2qHDdgb

Comparison of urinary cytology and fluorescence in situ hybridization in the detection of urothelial neoplasia: An analysis of discordant results

Background

We examine the performance of cytology and FISH in the detection of urothelial carcinoma (UC), and explore the reasons for discrepant results, and potential clinical implications.

Methods

Urine samples from 89 patients were prospectively collected for simultaneous cytology and UroVysion FISH, and results correlated with concurrent biopsies and/or clinical or histologic follow‐up data. Corresponding tissue biopsies, where available, were also evaluated by FISH.

Results

Sensitivity and specificity of cytology and FISH for the detection of UC was 54.8% and 92% and 50% and 88%, respectively. Only one of seven false‐positive urinary FISH results proved to be an "anticipatory positive" on extended follow‐up. Five of eight (62.5%) high grade (HG) carcinomas with false‐negative urinary FISH, were negative due to the absence/paucity of FISH‐detectable changes in the tumor cells. In atypical cytology cases, the FISH result did not assist in identifying UC. There was no significant difference between an atypical cytology result and a positive FISH result, with respect to the identification of patients with UC.

Conclusions

We found urinary cytology to be more sensitivity and specific than FISH in the detection of UC, though the difference was not statistically significant. Up to 24% of HG UCs are FISH negative due to an absence of FISH‐detectable abnormalities in the tumor cells. Paucity of neoplastic cells in the urine also contributes to false‐negative FISH results in both HG and low grade tumors. Negative urinary FISH cannot be taken alone as indicating the absence of significant disease in patients with atypical cytology.

https://ift.tt/2FiN3iF

Monitoring of fluconazole and caspofungin activity against in vivo Candida glabrata biofilms by bioluminescence imaging. [Experimental Therapeutics]

Candida glabrata can attach to various medical implants and forms thick biofilms despite its inability to switch from-yeast-to hyphae. Current in vivo C. glabrata biofilm models only provide limited information about colonization and infection and usually require animal sacrifice. To gain real-time information from individual BALB/c mice we developed a non-invasive imaging technique to visualize C. glabrata biofilms in catheter fragments that were subcutaneously implanted on the back of mice. Bioluminescent C. glabrata reporter strains (luc_OPT 7/2/4 and luc_OPT 8/1/4), free of auxotrophic markers, expressing a codon-optimized firefly luciferase were generated. A murine subcutaneous model was used to follow real-time in vivo biofilm formation in the presence and absence of fluconazole and caspofungin. Fungal load in biofilms was quantified by colony forming unit counts and by bioluminescence imaging (BLI). C. glabrata biofilms formed within the first 24 h, as documented by the increased number of device-associated cells and elevated bioluminescent signal compared to adhesion at the time of implant. The in vivo model allowed monitoring of the anti-biofilm activity of caspofungin against C. glabrata biofilms through bioluminescent imaging from day four after initiation of treatment. Contrarily, signals emitted from biofilms implanted in fluconazole-treated mice was similar to the light emitted from control-treated mice.

This study gives insights into real-time development of C. glabrata biofilms under in vivo conditions. BLI proved to be a dynamic, non-invasive and sensitive tool to monitor continuous biofilm formation and activity of antifungal agents against C. glabrata biofilms formed on abiotic surfaces in vivo.

https://ift.tt/2T8ooQX

Development of a broad-spectrum antimicrobial combination for the treatment of Staphylococcus aureus and Pseudomonas aeruginosa corneal infections [Experimental Therapeutics]

Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common causes of bacterial keratitis and corresponding corneal blindness. Accordingly, such infections are predominantly treated with broad spectrum fourth generation fluoroquinolones, such as moxifloxacin. Yet rising fluoroquinolone resistance has necessitated the development of alternative therapeutic options. Herein we describe development of a polymyxin B/trimethoprim (PT) ophthalmic formulation containing the antibiotic rifampicin, which exhibits synergistic antimicrobial activity toward a panel of contemporary ocular clinical S. aureus and P. aeruginosa isolates, low spontaneous resistance frequency, and displays in vitro bactericidal kinetics and antibiofilm activities equaling or exceeding the antimicrobial properties of moxifloxacin. The PT + rifampicin combination also demonstrated increased efficacy in comparison to either commercial PT or moxifloxacin in a murine keratitis model of infection, resulting in bacterial clearance of 70% in animals treated. These results suggest that the combination PT and rifampicin may represent a novel antimicrobial agent in the treatment of bacterial keratitis.

https://ift.tt/2zPrf8v

Antibiotic Resistance of Campylobacter spp. in a Pediatric Cohort Study [Epidemiology and Surveillance]

Objectives

To determine phenotypic patterns of antibiotic resistance and epidemiology of drug-resistant Campylobacter spp. from a low-resource setting.

Methods

A birth cohort of 303 was followed until 5 years of age. Stool from asymptomatic (n= 10,008) and diarrhea samples (n=3175) were cultured for Campylobacter. Disk diffusion to CIP, NAL, ERY, AZM, TET, GM, AMP, AMC, CRO, C and TMS were determined. Antibiotic resistance between C. jejuni and non-C. jejuni isolates, and surveillance and diarrhea samples were compared and the association between personal macrolide exposure and subsequent occurrence of a macrolide resistant Campylobacter spp. was assessed.

Results

Of 917 Campylobacter isolates, 77.4% of C. jejuni isolates and 79.8% non-C. jejuni isolates were resistant to ciprofloxacin while 4.9% of C. jejuni isolates and 24.8% of non-C. jejuni isolates were not susceptible to azithromycin. Of the 303 children, 33.1% were ever diagnosed with a Campylobacter strain non-susceptible to both azithromycin and ciprofloxacin. Personal macrolide exposure did not affect the risk of macrolide resistant Campylobacter. Amoxicillin and clavulanic acid (94.0%) was one of the antibiotics with the highest rates of susceptibility.

Conclusion

There is a high incidence of quinolone and macrolide resistant Campylobacter infections in infants under 24 months of age. Given the lack of association between personal exposure to macrolides and a subsequent Campylobacter infection resistant to macrolides, there is a need to evaluate the source of MDR Campylobacter. This study provides compelling evidence to propose amoxicillin/clavulanic acid as a treatment for Campylobacteriosis.

https://ift.tt/2T8oiZB

The inhibition of protein secretion in Escherichia coli and sub-MIC effects of arylomycin antibiotics [Mechanisms of Action]

At sufficient concentrations, antibiotics effectively eradicate many bacterial infections. However, during therapy bacteria are unavoidably exposed to lower antibiotic concentrations, and sub-minimum inhibitory concentration (MIC) exposure can result in a wide variety of other effects, including the induction of virulence, which can complicate therapy, or horizontal gene transfer (HGT), which can accelerate the spread of resistance genes. Bacterial type I signal peptidase (SPase) is an essential protein that acts at the final step of the general secretory pathway. This pathway is required for the secretion of many proteins, including many required for virulence, and the arylomycins are a class of natural product antibiotics that target SPase. Here, we investigated the consequences of exposing Escherichia coli to sub-MIC levels of an arylomycin. Using multidimensional protein identification technology mass spectrometry, we find that arylomycin treatment inhibits the proper extracytoplasmic localization of many proteins, both those that appear to be SPase substrates as well as several that do not. The identified proteins are involved in a broad range of extracytoplasmic processes and include a number of virulence factors. The effects of arylomycin on several processes required for virulence were then individually examined, and we found that even at sub-MIC levels, the arylomycins potently inhibit flagellation, motility, biofilm formation, and the dissemination of antibiotic resistance via HGT. Thus, we conclude that the arylomycins represent promising novel therapeutics with the potential to eradicate infections while simultaneously reducing virulence and the dissemination of resistance.

https://ift.tt/2zPr5hp

A protein complex from human milk enhances the activity of antibiotics and drugs against Mycobacterium tuberculosis [Experimental Therapeutics]

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug resistant strains has become a major challenge for health care systems and, in some cases, rendered TB untreatable. However, developing new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make Mtb more susceptible to existing TB drugs. In this study, we show that HAMLET, an alpha-lactalbumin - oleic acid complex derived from human milk, has bactericidal activity against Mtb. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured alpha-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sub-lethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against Mtb. For example, the minimal inhibitory concentrations of rifampicin, bedaquiline, delamanid and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed Mtb and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of Mtb. Previous studies showed that HAMLET is stable after oral delivery in mice and non-toxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed.

https://ift.tt/2T35UB8

Target (MexB) and efflux based mechanisms decreasing the effectiveness of the efflux pump inhibitor D13-9001 in P. aeruginosa PAO1: uncovering a new role for MexMN-OprM in efflux of {beta}-lactams and a novel regulatory circuit (MmnRS) controlling MexMN expression [Mechanisms of Resistance]

Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in P. aeruginosa. Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified and these fell into two categories; those having alterations in the target MexB (F628L and V177) and those with mutations in PA1438 (L172P substitution) which encoded a putative sensor kinase of unknown function. The alterations in MexB were consistent with reported structural studies of D13-9001 interaction with MexB. The PA1438_L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and >50-fold upregulation of PA1438 and the neighboring response regulator gene PA1437. We propose that these be renamed as mmnR/mmnS for MexMN Regulator and Sensor. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several β-lactams, monobactams and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnS_L172P also mediated a decrease in susceptibility to imipenem / biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds was downregulated, suggesting that this channel is also part of the MmnSR regulon. RNA-seq of cells encoding MmnS_L172P revealed among other things an interrelationships between regulation of mexMN and genes involved in heavy metal resistance.

https://ift.tt/2zNaLh3

High-dosage cefazolin achieves sufficient cerebrospinal diffusion to treat an external ventricular drainage-related Staphylococcus aureus ventriculitis. [Pharmacology]

A patient received continuous infusion of cefazolin 10 g then 8 g daily for an external ventricular drainage-related methicillin susceptible Staphylococcus aureus (MSSA) ventriculitis.

Median free concentrations in the cerebrospinal fluid were 11.9 mg/L and 6.1 mg/L after a 10-g and an 8-g dosage respectively. Free concentrations in the cerebrospinal fluid were always above MIC usually displayed by MSSA.

These results support the use of high dose cefazolin to achieve sufficient meningeal concentrations.

https://ift.tt/2T35MSa

DRUG INTERACTIONS BETWEEN DOLUTEGRAVIR AND ARTEMETHER-LUMEFANTRINE OR ARTESUNATE-AMODIAQUINE [Antiviral Agents]

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need co-treatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine or artesunate-amodiaquine given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether, dihydroartemisinin, lumefantrine, desbutyl-lumefantrine over 264 hours. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, desethylamodiaquine over 624 hours. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine nor significantly alter AUC for artesunate, dihydroartemisinin, amodiaquine and desethylamodiaquine. Co-administration of dolutegravir with artmether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with artesunate-amodiaquine resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above dolutegravir target concentrations of 300ng/mL. Study drugs were well-tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir.

https://ift.tt/2zPAFRv

Population Pharmacodynamics of Amphotericin B Deoxycholate for Disseminated Infection Caused by Talaromyces marneffei [Pharmacology]

Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them 55 patients had serial fungal colony forming units counts in blood also available for analysis. A population pharmacokinetics-pharmacodynamics model was fitted to the data. The relationships between area under the concentration time curve (AUC):MIC, and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC with a mean (standard deviation) of 11.51 (3.39) mg*h/L. The maximal rate of drug induced kill was 0.133 log₁₀CFU/mL/h, and the plasma concentration of the DAmB that induced half-maximal rate of kill was 0.02 mg/L. Fifty percent of patients sterilized their bloodstream by 83.16 hours (range 13-264 hours). A higher initial fungal burden was associated with longer time to sterilization (hazard ratio (HR): 0.51, 95% confidence interval (CI): 0.36-0.70, p<0.001). There was no relationship between AUC:MIC and the time to sterilization (HR: 1.03, 95% CI: 1.00-1.06, p=0.091). Furthermore, there was no relationship between the AUC:MIC and time to death (HR: 0.97, 95% CI: 0.88-1.08, p=0.607); or early fungicidal activity (slope= log(0.501-0.003*AUC:MIC), p=0.319) adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream is a useful pharmacodynamic endpoint for future studies.

https://ift.tt/2TbJ2jd

Efficacy of Humanized Cefiderocol Exposures Over 72 hours Against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model [Pharmacology]

Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72h against pathogens with cefiderocol MICs of 0.5–16 μg/mL in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs 0.5–8 (n=11), sustained kill was observed at 72h among 9 isolates. Post-exposure MICs revealed a single 2 dilution increase compared with control in one animal (1/54 samples, 1.8%) at 72h. Adaptive resistance during therapy was not observed.

https://ift.tt/2zKdJTw

Targeting Purinergic Receptor P2Y2 prevents the growth of pancreatic ductal adenocarcinoma by inhibiting cancer cell glycolysis

Purpose: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. Experimental Design: Expression of P2RY2 was determined in 264 human PDAC samples, and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. Results: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevating expression of c-Myc and HIF1a, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacological inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. Additionally, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. Conclusions: These findings revealed the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

https://ift.tt/2FkSUnC

Distinct biological types of ocular adnexal sebaceous carcinoma: HPV-driven and virus-negative tumors arise through non-overlapping molecular-genetic alterations

Purpose: Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy of the eyelid and ocular adnexa that frequently recurs and metastasizes, and effective therapies beyond surgical excision are lacking. There remains a critical need to define the molecular-genetic drivers of the disease to understand carcinomagenesis and progression and to devise novel treatment strategies. Experimental Design: We present next generation sequencing of a targeted panel of cancer-associated genes in 42 and whole transcriptome RNA sequencing from 8 OA sebaceous carcinomas from 29 patients. Results: We delineate two potentially distinct molecular-genetic subtypes of OA sebaceous carcinoma. The first is defined by somatic mutations impacting TP53 and/or RB1 (20/29 [70%] patients, including 10 patients whose primary tumors contained co-existing TP53 and RB1 mutations) with frequent concomitant mutations affecting NOTCH genes. These tumors arise in older patients and show frequent local recurrence. The second subtype (9/29 [31%] patients) lacks mutations affecting TP53, RB1, or NOTCH family members, but in 44% (4/9) of these tumors, RNA sequencing and in situ hybridization studies confirm transcriptionally active high-risk human papillomavirus (HPV). These tumors arise in younger patients and have not shown local recurrence. Conclusions: Together, our findings establish a potential molecular-genetic framework by which to understand the development and progression of OA sebaceous carcinoma and provide key molecular-genetic insights to direct the design of novel therapeutic interventions.

https://ift.tt/2qQQR0N

E3611- A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High Dose Interferon-{alpha}2b in Advanced Melanoma

Purpose: Interferon-α favors a Th1 shift in immunity and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy supporting this hypothesis. Experimental Design: E3611 followed a 2 by 2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipi doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. Results: For eligible and treated patients (N=81) at a median follow-up time of 29.8 months, median PFS was 4.4 months (95%CI: 2.7-8.2) when ipilimumab was used alone and 7.5 months (95%CI: 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95%CI: 2.6-7.5) with 3mg/kg ipilimumab and 6.5 months (95%CI: 5.1-13.5) with 10mg/kg. By study arm, median PFS was 8.0 months (95%CI: 2.8-20.2) in arm A, 6.2 months (95%CI: 2.7-25.7) in B, 5.7 months (95%CI: 1.5-11.1) in C and 2.8 months (95%CI: 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. Conclusions: While PFS was increased, the differences resulting from adding interferon-α or higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

https://ift.tt/2Fknf5J

Whole-body imaging of cell death provides a systemic, minimally invasive, dynamic and near-real time indicator for chemotherapeutic drug toxicity

Purpose: Response to toxicity in chemotherapies vary considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug-induced toxicity on an individual-basis. Experimental Design: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate or cisplatin. In vivo whole-body imaging data were acquired using ^99mTc-duramycin which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared to standard blood and serum panels for toxicology. Results: The in vivo whole-body imaging data detected widespread changes, where spatially-heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared to conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. Conclusions: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis.

https://ift.tt/2qJk25z

Inhibition of mTOR Signaling and Clinical Activity of Rapamycin in Head and Neck Cancer in a Window of Opportunity Trial

Purpose: We studied the impact of mTOR signaling inhibition with rapamycin in head and neck squamous cell carcinoma (HNSCC) in the neoadjuvant setting. The goals were to evaluate the mTOR pathway as a therapeutic target for advanced HNSCC patients, and the clinical safety, anti-tumor, and molecular activity of rapamycin administration on HNSCC. Experimental Design: Patients with untreated stage II-IVA HNSCC received rapamycin for 21 days (day 1, 15mg; days 2-12, 5mg) prior to definitive treatment with surgery or chemoradiation. Treatment responses were assessed clinically and radiographically with CT and FDG-PET. Pre- and post-treatment biopsies and blood were obtained for toxicity, immune monitoring and immunohistochemical assessment of mTOR signaling, as well as exome sequencing. Results: Sixteen patients (8 oral cavity, 8 oropharyngeal) completed rapamycin and definitive treatment. Half of patients were p16 positive. One patient had a pathological complete response and 4 (25%) patients met RECIST criteria for response (1 CR, 3 PR, 12 SD). Treatment was well tolerated with no grade 4 or unexpected toxicities. No significant immune suppression was observed. Downstream mTOR signaling was downregulated in tumor tissues as measured by phosphorylation of S6 (p<0.0001), AKT (p<0.0001), and 4EBP (p=0.0361), with a significant compensatory increase in phosphorylated ERK in most patients (p<0.001). Ki67 was reduced in tumor biopsies in all patients (p=0.013). Conclusions: Rapamycin treatment was well tolerated, reduced mTOR signaling and tumor growth, and resulted in significant clinical responses despite the brief treatment duration, thus supporting the potential role of mTOR inhibitors in treatment regimens for HNSCC.

https://ift.tt/2FknduD

Searching for the value of accountable care organizations in cancer care

https://ift.tt/2qHU8PT

Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014

Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014

Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014, Published online: 13 November 2018; doi:10.1038/s41416-018-0292-6

Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014

https://ift.tt/2DiA9ys

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint, Published online: 13 November 2018; doi:10.1038/s41416-018-0302-8

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint

https://ift.tt/2PPdUqT

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer, Published online: 13 November 2018; doi:10.1038/s41416-018-0289-1

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

https://ift.tt/2DgjfRg

Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma, Published online: 13 November 2018; doi:10.1038/s41416-018-0334-0

Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

https://ift.tt/2PQVYw1

SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance, Published online: 13 November 2018; doi:10.1038/s41416-018-0338-9

SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

https://ift.tt/2DhBohu

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study, Published online: 13 November 2018; doi:10.1038/s41416-018-0225-4

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study

https://ift.tt/2PYrKqI

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer, Published online: 13 November 2018; doi:10.1038/s41416-018-0319-z

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer

https://ift.tt/2DgOmw6

Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival

Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival

Binding of <i>eEF1A2</i> to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival, Published online: 13 November 2018; doi:10.1038/s41416-018-0336-y

Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival

https://ift.tt/2PSVsxj

Pediatric ependymoma: current treatment and newer therapeutic insights

Future Oncology, Ahead of Print.


https://ift.tt/2zK6VoW

NFIX downregulation independently predicts poor prognosis in lung adenocarcinoma, but not in squamous cell carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2T93RvE

A New Physiologic Mouse Model of One Anastomosis Gastric Bypass

Background: One anastomosis gastric bypass (OAGB) is a modern metabolic operation that has been demonstrated to be a rapid, safe, and effective procedure. As for other bariatric operations, the mechanisms and long-term effects of this procedure remain largely unknown and are difficult to address in human studies. Here, we present a new physiologic mouse model for mechanistic and long-term investigations. Methods: Six-week-old C57Bl/6 mice were fed a high-fat diet for 12 weeks and scheduled for OAGB or sham operation. Mice were observed for 2 weeks after the operation, and weight and metabolic condition were monitored. Results: Six mice were used to adapt the surgical technique. Afterwards, another 7 mice were scheduled for OAGB without further complications. The newly established OAGB procedure resulted in significant weight loss and improvement of glucose metabolism 2 weeks after the operation. Conclusions: The operation presented here is an easy-to-learn and physiologic mouse model of OAGB that can be used for further studies in mice.
Eur Surg Res 2018;59:320–328

https://ift.tt/2PZ8JEy

Isoform-Dependent Changes in Cytochrome P450-Mediated Drug Metabolism after Portal Vein Ligation in the Rat

Background: Surgical removal of complicated liver tumors may be realized in two stages via selective portal vein ligation, inducing the atrophy of portally ligated lobes and the compensatory hypertrophy of nonligated liver lobes. Unlike morphological changes, functional aspects such as hepatic cytochrome P450 (CYP)-mediated drug metabolism remain vaguely understood, despite its critical role in both drug biotransformation and hepatic functional analysis. Our goal was the multilevel characterization of hepatic CYP-mediated drug metabolism after portal vein ligation in the rat. Methods: Male Wistar rats (n = 24, 210–230 g) were analyzed either untreated (controls; n = 4) or 24/48/72/168/336 h (n = 4 each) following portal vein ligation affecting approximately 80% of the liver parenchyma. Besides the weights of ligated and nonligated lobes, pentobarbital (30 mg/kg)-induced sleeping time, CYP1A(2), CYP 2B(1/2), CYP2C(6/11/13), CYP3A(1) enzyme activities, and corresponding isoform mRNA expressions, as well as CYP3A1 protein expression were determined by in vivo sleeping test, CYP isoform-selective assays, polymerase chain reaction, and immunohistochemistry, respectively. Results: Portal vein ligation triggered atrophy in ligated lobes and hypertrophy nonligated lobes. Sleeping time was transiently elevated (p = 0.0451). After an initial rise, CYP1A, CYP2B, and CYP3A enzyme activities dropped until 72 h, followed by a potent increase only in the nonligated lobes, paralleled by an early (24–48 h) transcriptional activation only in nonligated lobes. CYP2C enzyme activities and mRNA levels were bilaterally rapidly decreased, showing a late reconvergence only in nonligated lobes. CYP3A1 immunohistochemistry indicated substantial differences in positivity in the early period. Conclusions: Beyond the atrophy-hypertrophy complex, portal vein ligation generated a transient suppression of global and regional drug metabolism, re-established by an adaptive, CYP isoform-dependent transcriptional response of the nonligated lobes.
Eur Surg Res 2018;59:301–319

https://ift.tt/2DfKPxQ

Mitochondrial DNA D-Loop Diversity of the Helmeted Guinea Fowls in Kenya and Its Implications on HSP70 Gene Functional Polymorphism

We analyzed variations in 90 mitochondrial DNA (mtDNA) D-loop and heat shock protein 70 (HSP70) gene sequences from four populations of domesticated helmeted Guinea fowls (70 individuals) and 1 population of wild helmeted Guinea fowls (20 individuals) in Kenya in order to get information about their origin, genetic diversity, and traits associated with heat stress. 90 sequences were assigned to 25 distinct mtDNA and 4 HSP70 haplotypes. Most mtDNA haplotypes of the domesticated helmeted Guinea fowls were grouped into two main haplogroups, HgA and HgB. The wild population grouped into distinct mtDNA haplogroups. Two mtDNA haplotypes dominated across all populations of domesticated helmeted Guinea fowls: Hap2 and Hap4, while the dominant HSP70 haplotype found in all populations was CGC. Higher haplotype diversities were generally observed. The HSP70 haplotype diversities were low across all populations. The nucleotide diversity values for both mtDNA and HSP70 were generally low. Most mtDNA genetic variations occurred among populations for the three hierarchical categories considered while most variations in the HSP70 gene occurred among individuals within population. The lack of population structure among the domestic populations could suggest intensive genetic intermixing. The differentiation of the wild population may be due to a clearly distinct demographic history that shaped its genetic profile. Analysis of the Kenyan Guinea fowl population structure and history based on mtDNA D-loop variations and HSP70 gene functional polymorphisms complimented by archaeological and linguistic insight supports the hypothesis that most domesticated helmeted Guinea fowls in Kenya are related to the West African domesticated helmeted Guinea fowls. We recommend more molecular studies on this emerging poultry species with potential for poverty alleviation and food security against a backdrop of climate change in Africa.

https://ift.tt/2FjNp8V

Innovative Techniques to Enhance Musculoskeletal Surgery Outcomes

https://ift.tt/2qKgbFi

Expression optimization of recombinant cholesterol oxidase in Escherichia coli and its purification and characterization

Cholesterol oxidase is a bacterial flavoenzyme which catalyzes oxidation and isomerization of cholesterol. This enzyme has a great commercial value because of its wide applications in cholesterol analysis of c...

https://ift.tt/2QDynMj

Preferences for in‐person disclosure: Patients declining telephone disclosure characteristics and outcomes in the multi‐center COGENT Study

Telephone disclosure of cancer genetic test results is non‐inferior to in‐person disclosure. However, how patients who prefer in‐person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multi‐center, randomized, non‐inferiority trial (NCT01736345) comparing telephone to in‐person disclosure of genetic test results. We evaluated preferences for in‐person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in‐person disclosure. These patients were more likely to be older (p=0.007) and to have had multi‐gene panel testing (p<0.001). General anxiety (p=0.007), state anxiety (p=0.008), depression (p=0.011), cancer‐specific distress (p=0.021) and uncertainty (p=0.03) were higher after pre‐test counseling. After disclosure of results, they also had higher general anxiety (p=0.003), depression (p=0.002) and cancer‐specific distress (p=0.043). While telephone disclosure is a reasonable alternative to in‐person disclosure in most patients, some patients have a strong preference for in‐person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in‐person disclosure should be honored when possible.

https://ift.tt/2OIlheS

Phenotero: annotate as you write

In clinical genetics, the Human Phenotype Ontology as well as disease ontologies are often used for deep phenotyping of patients and coding of clinical diagnoses. However, assigning ontology classes to patient descriptions is often disconnected from writing patient reports or manuscripts in word processing software. This additional workload and the requirement to install dedicated software may discourage usage of ontologies for parts of the target audience.

Here we present Phenotero, a freely available and simple solution to annotate patient phenotypes and diseases at the time of writing clinical reports or manuscripts. We adopt Zotero, a citation management software to create a tool which allows to reference classes from ontologies within text at the time of writing. We expect this approach to decrease the additional workload to a minimum while ensuring high quality associations with ontology classes. Standardised collection of phenotypic information at the time of describing the patient allows for streamlining the clinic workflow and efficient data entry. It will subsequently promote clinical and molecular diagnosis with the ultimate goal of better understanding genetic diseases. Thus, we hope that Phenotero eases the usage of ontologies and controlled vocabularies in the field of clinical genetics.

https://ift.tt/2z3YOUv

Recurrent Cholangiocarcinoma in Pregnancy: A Case Report

AJP Rep 2018; 08: e261-e263
DOI: 10.1055/s-0038-1675376

Hepatobiliary malignancies during pregnancy are extremely rare and portend a poor prognosis. There are only seven published cases of cholangiocarcinoma in an obstetrical patient, all are cases of primary cholangiocarcinoma (1–7). Herein, we describe the first case of recurrent cholangiocarcinoma during pregnancy. The patient did not receive chemotherapy during pregnancy and required prolonged hospitalizations for nutritional and intensive medical support. She delivered preterm, at 30 2/7 weeks gestation, after developing pre-eclampsia with severe features. The infant was healthy, with no malformations, and currently exhibits no neurological or behavioral sequelae at 8months of age. We discuss themanagement considerations inherent to this complex clinical scenario including metastatic disease severity, ethical considerations, and palliative care treatment options.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

https://ift.tt/2DBJwu2

Pre‐treatment wait time for head and neck cancer patients in Western Australia: description of a new metric and examination of predictive factors

Background

Prolonged pre‐treatment wait times in head and neck cancer are associated with increased morbidity and reduced survival. Traditional metrics exclude delays prior to biopsy, which represents an important and measurable period of time. This study aims to describe total wait time for head and neck cancer patients in our institution, to define a more accurate representation of the clinically relevant pre‐treatment wait time, and to evaluate predictive factors for prolonged wait times.

Methods

A retrospective review of head and neck cancer patients treated over 2 years in a tertiary referral centre was conducted. Patient demographics, referral symptoms, tumour details, treatment plan and key dates were analysed to identify total wait time and factors predictive of increased wait time.

Results

Two hundred and ninety‐four patients were included. Mean total wait time from initial referral to treatment initiation was 71.6 (median 61) days. The period from referral to biopsy represented 29% of mean total wait time. Factors predictive of increased wait time included presenting symptom of hoarseness, laryngeal cancer and treatment with definitive radiotherapy.

Conclusions

This study demonstrates that time from referral to biopsy represents a significant portion of total wait time, and we suggest that this be incorporated into future wait time metrics for improved clinical relevance. Furthermore, we have identified factors predicting increased wait time which can be targeted for future service improvement.

https://ift.tt/2RPU1gx

Spotlight: Cradlepoint’s 4G LTE cloud-managed solution creates a secure and reliable network for first responders

Cradlepoint is committed to making sure first responders can rely on them to keep them connected and protected.

https://ift.tt/2QD2DH0

Visualization of the electrical activity of the cauda equina using a magnetospinography system in healthy subjects

In lumbar spinal diseases such as lumbar spinal canal stenosis, compression lesions in multiple vertebrae are often found in imaging examinations. However, it is often difficult to evaluate the true lesion sites responsible for symptoms by imaging techniques alone (Kent et al., 1992; Mamisch et al., 2012). In addition, it is often necessary to evaluate the locations of the spinal nerve compression, such as intra-canal, intra-foraminal, or extra-foraminal, to choose the appropriate surgical technique (Macnab, 1971; Wiltse et al., 1984; Kunogi and Hasue, 1991; Olsewski et al., 1991).

https://ift.tt/2DhijMq

Smoking cessation sharply reduced lung cancer mortality in a historical cohort of 3185 Chinese silicotic workers from 1981 to 2014

https://ift.tt/2PtNVG8

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint

https://ift.tt/2QyeUfP

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

https://ift.tt/2PsgPq3

Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma

https://ift.tt/2QEliT4

SOX9 expression decreases survival of patients with intrahepatic cholangiocarcinoma by conferring chemoresistance

https://ift.tt/2Pq0fqz

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study

https://ift.tt/2QEH8G6

SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer

https://ift.tt/2Po5mrA

Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival

https://ift.tt/2QD9118

Internal mammary node irradiation (IMNI) improves survival outcome for patients with clinical stage II-III breast cancer after preoperative systemic therapy

This study is designed to evaluate the effect of internal mammary node irradiation (IMNI) in breast cancer patients after preoperative systemic therapy and surgery. We reviewed patients with clinical stage II-III breast cancer who underwent NAC and postoperative radiotherapy with or without IMNI. Patients in IMNI group showed improved survival outcomes, especially those with residual disease of the primary lesion and pathologically positive nodes.

https://ift.tt/2zfeW63

Medical Malpractice Analysis in Radiation Oncology: a Decade of Results from a National Comparative Benchmarking System

Medical errors in radiation oncology practice have received significant national attention over the last decade. We extracted all closed RO cases from years 2005 to 2014 in the REMOVED FOR BLINDING Comparative Benchmarking System; cases were then characterized and association with indemnity payment was tested within categories.

https://ift.tt/2ODqhl1

Premature Mortality From Drug Overdoses: A Comparative Analysis of 13 Organisation for Economic Co-operation and Development Member Countries With High-Quality Death Certificate Data, 2001 to 2015

https://ift.tt/2QDs7Ee

Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism A Controlled Pragmatic Trial

Background:

Many low-risk patients with acute pulmonary embolism (PE) in the emergency department (ED) are eligible for outpatient care but are hospitalized nonetheless. One impediment to home discharge is the difficulty of identifying which patients can safely forgo hospitalization.

Objective:

To evaluate the effect of an integrated electronic clinical decision support system (CDSS) to facilitate risk stratification and decision making at the site of care for patients with acute PE.

Design:

Controlled pragmatic trial. (ClinicalTrials.gov: NCT03601676)

Setting:

All 21 community EDs of an integrated health care delivery system (Kaiser Permanente Northern California).

Patients:

Adult ED patients with acute PE.

Intervention:

Ten intervention sites selected by convenience received a multidimensional technology and education intervention at month 9 of a 16-month study period (January 2014 to April 2015); the remaining 11 sites served as concurrent controls.

Measurements:

The primary outcome was discharge to home from either the ED or a short-term (<24-hour) outpatient observation unit based in the ED. Adverse outcomes included return visits for PE-related symptoms within 5 days and recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within 30 days. A difference-in-differences approach was used to compare pre–post changes at intervention versus control sites, with adjustment for demographic and clinical characteristics.

Results:

Among 881 eligible patients diagnosed with PE at intervention sites and 822 at control sites, adjusted home discharge increased at intervention sites (17.4% pre- to 28.0% postintervention) without a concurrent increase at control sites (15.1% pre- and 14.5% postintervention). The difference-in-differences comparison was 11.3 percentage points (95% CI, 3.0 to 19.5 percentage points; P = 0.007). No increases were seen in 5-day return visits related to PE or in 30-day major adverse outcomes associated with CDSS implementation.

Limitation:

Lack of random allocation.

Conclusion:

Implementation and structured promotion of a CDSS to aid physicians in site-of-care decision making for ED patients with acute PE safely increased outpatient management.

Primary Funding Source:

Garfield Memorial National Research Fund and The Permanente Medical Group Delivery Science and Physician Researcher Programs.

https://ift.tt/2ProCnM