Prognostic Stratification of Patients With Advanced Oral Cavity Squamous Cell Carcinoma

Abstract

Purpose of Review

Prognosis of advanced oral squamous cell carcinoma remains a challenge for clinicians despite progress in its diagnosis and treatment over the past decades. In this review, we assessed clinicopathological factors and potential biomarkers along with their prognostic relevance in an attempt to develop optimal treatment strategies for these patients.

Recent Findings

In addition to several pathologic factors that have been proposed to improve prognostic stratification and treatment planning in the eighth edition of the American Joint Committee staging manual on cancer, we reviewed some other imaging and clinicopathological parameters demonstrated to be closely associated with patient prognosis, along with the biomarkers related to novel target or immune therapy.

Summary

Evaluation of current literature regarding the prognostic stratification used in contemporary clinicopathological studies and progress in the development of targeted or immune therapy may help these patients benefit from tailored and personalized treatment and obtain better oncological results.

http://ift.tt/2urlH42

Immunotherapy in Breast Cancer: the Emerging Role of PD-1 and PD-L1

Abstract

Purpose of Review

The purpose of the review is to summarize the data regarding PD-L1 expression in breast cancer and the results of first clinical trials with PD-1 or PD-L1 inhibitors in patients with metastatic breast cancer.

Recent Findings

PD-L1 expression is heterogeneous across primary breast cancers, and is generally associated with the presence of tumor-infiltrating lymphocytes and the presence of poor-prognosis features such as high grade, and aggressive molecular subtypes (triple-negative (TN), basal, HER2-enriched). Early phase clinical trials using PD-1 or PD-L1 inhibitors alone or in combination have shown objective tumor responses and durable long-term disease control, in heavily pre-treated patients, notably in the TN subtype.

Summary

Blockade of PD-1 or PD-L1 shows impressive antitumor activity in some subsets of breast cancer patients. Many clinical trials are ongoing in the metastatic and neoadjuvant setting, alone and in combination with chemotherapy, targeted therapy, radiotherapy, and/or other immune therapy. The identification of biomarkers predictive for a clinical benefit is warranted.

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A combination of anti-PD-L1 mAb plus Lm-LLO-E6 vaccine efficiently suppresses tumor growth and metastasis in HPV-infected cancers

Abstract

PD-1/PD-L1 immunotherapy is viewed as having clinical benefits in advanced cancers but is effective in only a few patients, suggesting that an efficient combination approach is needed to improve efficacy. Immunohistochemistry analysis indicated that PD-L1 expression was correlated with the E6 expression in tumors from 122 lung cancer patients. The poorest survival occurred in PD-L1-positive/E6-positive tumor. PD-L1 expression was increased by the expression of E6, but not the E7, oncoprotein in lung and cervical cancer cells. PD-L1 expression was responsible for E6-mediated colony formation and soft agar growth. Therefore, PD-L1 secreted from tumor cells may directly promote tumor progression, particularly in E6-positive tumors. Immune deficiency nude mice were used to test the possibility that combining anti-PD-L1 mAb with Lm-LLO-E6 vaccine could have a higher antitumor activity compared with anti-PD-L1 mAb or Lm-LLO-E6 vaccine alone. A greater antitumor activity was obtained with anti-PD-L1 mAb + Lm-LLO-E6 vaccine than with anti-PD-L1 mAb or Lm-LLO-E6 alone in subcutaneous and metastatic tumors induced by TL-1 and SiHa cells. The longest survival time for nude mice was observed in the anti-PD-L1 mAb + Lm-LLO-E6 vaccine group. In conclusion, an anti-PD-L1 mAb + Lm-LLO-E6 vaccine may be an efficient treatment for suppression of tumor growth and metastasis induced by HPV-infected cells.

We have provided evidence that an anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination is an efficient therapeutic approach against HPV-infected NSCLC. In addition, the anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination also efficiently suppresses SiHa cell-induced tumors in nude mice. Therefore, we suggest that anti-PD-L1 mAb + Lm-LLO-E6 vaccine combination therapy may have a greater clinical benefit than anti-PD-L1 or HPV DNA vaccine immunotherapy in cancer patients with HPV-infected tumors.

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Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis

Abstract

Purpose

An epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis.

Methods

We retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables.

Results

The overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival.

Conclusions

Peripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.

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Pancreatic Sphincter Precutting using a Dual Knife to Relieve Acute Pancreatic Duct Obstruction

A 47-year-old woman diagnosed with chronic pancreatitis was admitted to our hospital. Computed tomography (CT) revealed main pancreatic duct (MPD) dilatation with multiple calcifications (Fig. 1a). Pancreatic extracorporeal shock wave lithotripsy (P-ESWL) was performed for stone disintegration starting from the pancreatic head (Fig. 1c). After P-ESWL, the patient complained of intense abdominal pain. Intramuscular injection of pethidine was repeatedly applied but did not relieve the pain. Repeated CT revealed that the diameter of the MDP had increased from 8.11mm to 17.99mm (Fig.

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The contribution of long non-coding RNAs in Inflammatory Bowel Diseases

Inflammatory Bowel Diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood.

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Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial

A single dose of the apolipoprotein (apo)A-I mimetic peptide D-4F rendered high-density lipoprotein (HDL) less inflammatory, motivating the first multiple-dose study. We aimed to assess safety/tolerability, pharmacokinetics, and pharmacodynamics of daily, orally administered D-4F. High-risk coronary heart disease (CHD) subjects added double-blinded placebo or D-4F to statin for 13 days, randomly assigned 1:3 to ascending cohorts of 100, 300, then 500 mg (n = 62; 46 men/16 women). D-4F was safe and well-tolerated. Mean ± SD plasma D-4F area under the curve (AUC, 0–8h) was 6.9 ± 5.7 ng/mL*h (100 mg), 22.7 ± 19.6 ng/mL*h (300 mg), and 104.0 ± 60.9 ng/mL*h (500 mg) among men, higher among women. Whereas placebo dropped HDL inflammatory index (HII) 28% 8 h postdose (range, 1.25–0.86), 300–500 mg D-4F effectively halved HII: 1.35–0.57 and 1.22–0.63, respectively (P < 0.03 vs. placebo). Oral D-4F peptide dose predicted HII suppression, whereas plasma D-4F exposure was dissociated, suggesting plasma penetration is unnecessary. In conclusion, oral D-4F dosing rendered HDL less inflammatory, affirming oral D-4F as a potential therapy to improve HDL function.

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Palliative Care Development in Kyrgyzstan

Palliative care began in Kyrgyzstan in 2005 as a pilot home based care program in Osh Cancer Center and was supported by a small group of nurses and one physician from Scotland. In 2010, the Soros Foundation-Kyrgyzstan (SFK) and the Open Society Foundation's International Palliative Care Initiative (IPCI) began supporting work on palliative care policy, legislation, essential medicine availability, education, advocacy and implementation. A Ministry of Health working group was established to lead this initiative and technical assistance was provided by an international palliative care consultant.

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The impact of combined use of opioids, antipsychotics and anxiolytics on survival in the hospice setting

Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients.

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Palliative Care in Vietnam: Long-term Partnerships Yield Increasing Access

Palliative care began in Vietnam in 2001, but steady growth in palliative care services and education commenced several years later when partnerships for ongoing training and technical assistance by committed experts were created with the Ministry of Health (MoH), major public hospitals, and medical universities. An empirical analysis of palliative care need by the MoH in 2006 was followed by national palliative care clinical guidelines, initiation of clinical training for physicians and nurses, and revision of opioid prescribing regulations.

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Development and psychometric properties of a survey to assess barriers to implementing advance care planning in primary care

Valid and reliable measurement of barriers to advance care planning (ACP) in health care settings can inform the design of robust interventions.

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Palliative Care in South Africa

The Hospice Palliative Care Association (HPCA) was established in 1987 by hospices in South Africa who felt the need for a national body to share best practices and to promote palliative care services in South Africa. HPCA supports member hospices in providing palliative care to people of any age with a life-limiting condition. HPCA has the further aim to ensure access to palliative care in settings other than member hospices. Many projects were launched over the years to influence policy, and to educate medical practitioners, nurses, social workers, theologians, and community caregiver; and to develop services.

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The International Palliative Care Initiative

This journal series describes the Open Society Foundation's International Palliative Care Initiative (IPCI) and the work of its national, regional, and international grantees to advance and develop palliative care globally. It provides examples of IPCI's funding initiatives honoring both IPCI's grass roots and elite strategies to integrate palliative care into national and international health policy based on a human rights approach.

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The Palliative Care Chaplain as Story Catcher

The role of the professional chaplain on the palliative care team in the health care setting formalizes the concern for the emotional, spiritual and social well-being of the care recipients and their caregivers. The chaplain also has a peculiar role on the team, in that her most fundamental task is her intentional listening-and-hearing of the other person's story. One palliative chaplain introduces herself as a Story Catcher to care recipients, in an effort both to overcome the resistance some may have to her presence on the team and communicate her essential role and intent in providing spiritual care.

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Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial

Episodic dyspnea is one of the most common, debilitating and difficult-to-treat symptoms.

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Empathy, compassion and beyond: the lesson learned from a child patient

The following story describes a situation which could happen in the professional life of every physician, especially in the oncology field.

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A Patient-Centered Approach to Research on Palliative Care for Patients with Advanced Illnesses and Their Caregivers

People with advanced, serious illnesses experience a high burden of physical and psychosocial symptoms, limitations in functioning, and declining quality of life (QOL) over the course of their illness. Caring for these patients can take a significant physical and emotional toll on their caregivers as well.

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Palliative Care Development in Tajikistan

Tajikistan's health system has undergone a series of complex changes associated with reforms aimed at the transition to a more sophisticated control mechanism, financing and operation. As in many developing countries, there is an increase in morbidity and mortality from cancer and chronic diseases, including tuberculosis and HIV. Attention is needed by the state for the development of cost-effective palliative care that will be integrated into the existing public health system.A recent palliative care country needs assessment identified the following areas of work that need to be addressed for palliative care to be implemented:• educating and training of health care professionals,• raising public awareness about palliative care,• making essential palliative care medicines available,• developing the necessary regulatory documents for palliative care development,• developing educational curricula and materials,• integrating palliative care into the medical and nursing universities and schools,• Creating models of palliative care services for home and inpatient facilities.

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Leadership Development Initiative: Growing Global Leaders… Advancing Palliative Care

The International Palliative Care Leadership Development Initiative (LDI) is a model demonstration project that aimed to expand the global network of palliative care leaders in low and moderate-resource countries who are well positioned to apply their new leadership skills.Thirty-nine palliative medicine physicians from 25 countries successfully completed the 2-year curriculum that included three thematic residential courses, mentorship and site visits by senior global palliative care leaders, and personal projects to apply their new leadership skills.

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Palliative Care in Rwanda: Aiming for Universal Access

In 2011, Rwanda's Ministry of Health (MoH) set a goal of universal access to palliative care by 2020. Toward this audacious egalitarian and humanitarian goal, the MoH worked with partners to develop palliative care policies and a strategic plan, secure adequate supplies of opioid for the country, initiate palliative care training programs, and begin studying a model for integrating coordinated palliative care into the public healthcare system at all levels. It also initiated training of a new cadre of home-based care practitioners (HBCPs) to provide palliative care in the home.

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Hospice-Palliative Care Development in Hungary

During the past 25 years many developmental steps have occurred in Hungary in palliative care. Further education and service development is needed to provide a quality palliative care for all the Hungarian people.Hungary has a universal health care system with a developed infrastructure. The first Hungarian hospice team started in 1991. At that time the concept of hospice care was unknown. Symptom control and psychosocial support for the dying patient was inadequate. The regulatory framework was based on the 1997 Health Care Act which was followed by significant palliative care legislation including documents on the legal requirements for palliative care (2004).

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Death with Dignity: Is There Such a Thing?

"There's no dignity with death, just levels of un-dignity."Anonymous

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Safety and effectiveness of palliative drug treatment in the last days of life - a systematic literature review

Dying patients commonly experience potentially distressing symptoms. Palliative care guidelines recommend opioids, anticholinergics, antipsychotics and benzodiazepines for symptom relief.

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Building an Outpatient Kidney Palliative Care Clinical Program

A diagnosis of advanced chronic kidney disease (CKD), or end stage renal disease (ESRD) represents a significant life change for patients and families. Individuals often experience high symptom burden, decreased quality of life, increased health care utilization, and end-of-life care discordant with their preferences. Early integration of palliative care with standard nephrology practice in the outpatient setting has the potential to improve quality of life through provision of expert symptom management, emotional support, and facilitation of advance care planning that honors the individual's values and goals.

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Treat the Pain program

Globally, low and middle-income countries are home to 70% of cancer deaths and 99% of HIV deaths, but they consume just 7% of opioid analgesics.

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Depression - a major contributor to poor quality of life in patients with advanced cancer

Quality of life (QoL) and depression are important patient-reported outcomes in cancer care. However, the relative importance of depression severity in predicting QoL remains unclear due to few methodologically sound studies.

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Standardized Computer-based Organized Reporting of EEG: SCORE – second version

The combination of clinically relevant signal features in an EEG recording is huge. This wide variety is typically described in free text EEG-reports. Although the International Federation of Clinical Neurophysiology (IFCN) published a glossary of terms for describing EEGs, the free-text format allows deviations from the standardized terminology. In practice, a wide variety of local terminologies flourish, where the same term is used with different meanings in different centers, and the same feature is described by different terms in different centers.

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Comparison of Visual Evoked Potential Monitoring During Spine Surgeries under Total Intravenous Anesthesia versus Balanced General Anesthesia

Visual Evoked Potential (VEP) is the illustration of electrical activity recorded from sensors placed on the subject's scalp overlying the visual cortex in response to visual stimuli. Changes in this electroencephalographic signal are characterized by a waveform, where changes in latency, amplitude, and morphology could be associated with specific pathologies (Holy et al., 2009; Ota et al., 2010; Andersson et al., 2012; Chung et al., 2012; Kamio et al., 2014; Luo et al., 2015). There exists a variety of stimuli that can be used in awake subjects, the most common being checkboard pattern-reversal VEP (Andersson et al., 2012).

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Parkinsonian rest tremor can be detected accurately based on neuronal oscillations recorded from the subthalamic nucleus

Deep brain stimulation (DBS) is a widely used treatment for patients with advanced Parkinson's disease (Perlmutter and Mink 2006). While its efficacy is well established, its efficiency can potentially be optimized. Conventional DBS is applied continuously although motor symptoms are usually fluctuating. Moreover, the benefit of DBS is often compromised by side-effects, which can usually be alleviated by reducing stimulation power, i.e. the energy applied per unit of time. Suggested approaches to reduce power include electric field steering (Contarino et al.

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Electroencephalogram dynamics in children during different levels of anaesthetic depth

Loss of consciousness induced by general anaesthetic agents has been proposed to be related to disruptions of connectivity between neuronal networks of the thalamus and the cerebral cortex (Alkire et al., 2000). Accordingly, the electroencephalogram (EEG), as a tool to measure synchronicity of network connectivity, has gained a position as the de-facto standard to monitor the depth of anaesthesia. However, EEG signatures used to identify different levels of anaesthesia are not well characterized in children, and still need to be properly described before implementation in clinical practice.

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When eukaryotes and prokaryotes look alike: the case of regulatory RNAs

Abstract

The discovery that all living entities express many RNAs beyond mRNAs, tRNAs and rRNAs has been a surprise in the past two decades. In fact, regulatory RNAs (regRNAs) are plentiful, and we report stunning parallels between their mechanisms and functions in prokaryotes and eukaryotes. For instance, prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats) defense systems are functional analogs to eukaryotic RNA interference processes that preserve the cell against foreign nucleic acid elements. Regulatory RNAs shape the genome in many ways: by controlling mobile element transposition in both domains, via regulation of plasmid counts in prokaryotes, or by directing epigenetic modifications of DNA and associated proteins in eukaryotes. RegRNAs control gene expression extensively at transcriptional and post-transcriptional levels, with crucial roles in fine-tuning cell environmental responses, including intercellular interactions. Although the lengths, structures and outcomes of the regRNAs in all life kingdoms are disparate, they act through similar patterns: by guiding effectors to target molecules or by sequestering macromolecules to hamper their functions. In addition, their biogenesis processes have a lot in common. This unifying vision of regRNAs in all living cells from bacteria to humans points to the possibility of fruitful exchanges between fundamental and applied research in both domains.

http://ift.tt/2vlcrgZ

Randomized sham-controlled trials in endoscopy: a systematic review and meta-analysis of adverse events

Sham procedures in endoscopy are used with the intention of controlling for placebo response, potentially allowing more precise evaluation of treatment effect. Nevertheless, this type of study may impose significant risk without potential benefit for those in the sham group. The aim of the current study is to systematically review and analyze the endoscopic literature to assess the safety of sham controls.

http://ift.tt/2vQb9uH

The Glyphosate-Based Herbicide Roundup(R) Does Not Elevate Genome-Wide Mutagenesis of Escherichia coli

Mutations induced by pollutants may promote pathogen evolution for example by accelerating mutations conferring antibiotic resistance. Generally, evaluating the genome-wide mutagenic effects of long-term sublethal pollutant exposure at single-nucleotide resolution is extremely difficult. To overcome this technical barrier, we use the mutation accumulation/whole genome sequencing (MA/WGS) method as a mutagenicity test, to quantitatively evaluate genome-wide mutagenesis of Escherichia coli after long-term exposure to a wide gradient of the glyphosate-based herbicide (GBH) Roundup® Concentrate Plus. The genome-wide mutation rate decreases as GBH concentration increases, suggesting that even long-term GBH exposure does not compromise the genome stability of bacteria.

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High-Quality de Novo Genome Assembly of the Dekkera bruxellensis Yeast Isolate Using Nanopore MinION Sequencing

Genetic variation in natural populations represents the raw material for phenotypic diversity. Species-wide characterization of genetic variants is crucial to have a deeper insight into the genotype-phenotype relationship. With the advent of new sequencing strategies and more recently the release of long-read sequencing platforms, it is now possible to explore the genetic diversity of any non-model organisms, representing a fundamental resource for biological research. In the frame of population genomic surveys, a first step is to obtain the complete sequence and high quality assembly of a reference genome. Here, we sequenced and assembled a reference genome of the non-conventional Dekkera bruxellensis yeast. While this species is a major cause of wine spoilage, it paradoxically contributes to the specific flavor profile of some Belgium beers. In addition, an extreme karyotype variability is observed across natural isolates, highlighting that D. bruxellensis genome is very dynamic. The whole genome of the D. bruxellensis UMY321 isolate was sequenced using a combination of Nanopore long-read and Illumina short-read sequencing data. We generated the most complete and contiguous de novo assembly of D. bruxellensis to date and obtained a first glimpse into the genomic variability within this species by comparing the sequences of several isolates. This genome sequence is therefore of high value for population genomic surveys and represents a reference to study genome dynamic in this yeast species.

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Diagnostic and Therapeutic Strategies for Patients with Malignant Epidural Spinal Cord Compression

Opinion statement

Malignant epidural spinal cord compression (MESCC) is an oncologic emergency with the potential for devastating consequences for patients if not promptly diagnosed and treated. MESCC is diagnosed by imaging. MRI is by far the most sensitive test, preferably with gadolinium. Once the diagnosis of MESCC is suspected, patients with neurologic deficits should receive prompt administration of dexamethasone with a 10-mg IV loading dose followed by 4 mg every 6 h. Quick taper is recommended once the definitive treatment is established. Consultation with medical oncology, radiation oncology, and neurosurgery is imperative in order to facilitate a multidisciplinary approach. Although spine surgery is the most effective method for relief of cord compression and is necessary if there is spinal instability, surgery is only used in selected patients because most patients have a poor overall condition and short life expectancy. Radiation therapy, therefore, is the most commonly used therapy for patients with MESCC after surgical decompression or in patients who are not surgical candidates. Conventional fractionated radiation alone can achieve modest neurologic outcomes in selected radiosensitive tumors. Radiosurgery techniques which deliver intense focal irradiation to a delimited area with imaging guidance and contoured radiation delivery to the shape of the tumor have recently emerged as increasing effective treatments in MESCC, especially in radioresistant tumors. Stereotactic radiosurgery and different radiation technologies have been studied in recent clinical trials.

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Dermatofibrosarcoma Protuberans

Opinion statement

Dermatofibrosarcoma protuberans (DFSP) is a slow growing tumor with a very low metastatic potential but with significant subclinical extension and great capacity for local destruction. Thus, the first surgeon approached with such challenging tumor must attempt to cure the patient with a method that spares healthy tissue and ensures an optimal oncological, functional, and esthetic result. The treatment of DFSP often requires a multidisciplinary approach. Depending on location, dermatologic surgeons, surgical oncologists, head and neck surgeons, neurosurgeons, plastic surgeons, and occasionally medical oncologists may be involved with the management. Mohs micrographic surgery (MMS) is the preferred method when available. In our institution, most of the DFSP cases are often advanced cases; thus, dermatologic surgeons obtain clear margins peripherally and other surgical specialties assist with resection of the fascia and any critical deeper structures. When MMS is not available, wide local excision (at least 2- to 3-cm margins of resection) with exhaustive pathologic assessment of margin status is recommended, and it is best to confirm tumor extirpation prior to any reconstruction. Subclinical extension of the tumor could be related to the size; how long it has been growing or histological markers that are unknown right now. No clinical trials comparing MMS vs WLE are available, and further research should be focused on these subjects as well as the use of imatinib and other targeted therapies for recurrent and metastatic tumors and for neoadjuvant treatment.

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Letter to the Editor: Implications of BRAF Mutations in dMMR Colorectal Cancers

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Studies on Non-synonymous Polymorphisms Altering Human DNA Topoisomerase II-Alpha Interaction with Amsacrine and Mitoxantrone: An In Silico Approach

Background: DNA topoisomerase II-α (Top2-α), an essential enzyme for the management of DNA during replication, transcription, recombination, and chromatin remodeling, is one of the most important anticancer targets. Numerous molecules have been designed as Top2-α inhibitors. However, several studies have shown that polymorphisms and mutations in Top2 have conferred resistance to most of these anticancer drugs. The aim of this study was to computationally examine the mechanisms by which genomic variations in Top2-α could affect its resistance to Amsacrine and Mitoxantrone as important inhibitors of the enzyme. Results: The results showed that variants K529E, R568H, R568G and T530M could affect Top2-α inhibition by Amsacrine causing possible drug-resistant. Moreover, R487K, and Y481C variants could change the response of the enzyme to Mitoxantrone. Conclusion: These results could facilitate the prediction and development of more effective drugs for Top2-α variants, making the cancer chemotherapy more effectiv

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HR+, HER2– Advanced Breast Cancer and CDK4/6 Inhibitors: Mode of Action, Clinical Activity, and Safety Profiles

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Objectives: 1. Discuss the mode of action of the three CDK4/6 inhibitors in late clinical development: palbociclib (PD-0332991; Pfizer), ribociclib (LEE011; Novartis), and abemaciclib (LY2835219; Lilly). 2. Describe the efficacy and safety data relating to their use in HR+, HER2– advanced breast cancer. 3. Discuss the key side effects associated with CDK4/6 inhibitors along with considerations for adverse event management and patient monitoring. Method: Relevant information and data were assimilated from manuscripts, congress publications, and online sources. Results: CDK4/6 inhibitors have demonstrated improved progression-free survival in combination with endocrine therapy compared with endocrine therapy alone. The side-effect profile of each agent is described, along with implications for patient monitoring, and considerations for patient care providers and pharmacists. Conclusion: Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Insight into the unique side-effect profiles of this class of agents and effective patient monitoring will facilitate the successful use of CDK4/6 inhibitor-based therapies in the clinic.

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Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes

Background: Involvement of mutations in epigenetic mechanism in the development of heterogeneous MDS and its evolution to AML has been understood with at least one mutation and median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic and natural products and established proof-of-concept for mitigation of mutagenic effects. Objective: The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation, histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and small molecule inhibitors of these mutational expressions. Method: Information has been collected from the recently published literature available mainly through Google search in Medline and PubMed database. Special emphasis was paid on the literature available during 2009-2016. Result: The up-to-date information accumulated on signature-mutations and their inhibitors has to integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity and its transformation to AML is expanding at fast pace with expanding knowledge on abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will further develop personalized medicines based on individual genetic blue-prints. Conclusion: Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers and regulators, may promise attestation of 'del5q and lenalidomide'-like specific drugs for every mutational signature independently or in combination with standard therapeutic elements used for MDS-management, and that will add to understand their antagonistic/synergistic effects.

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Meet Our Editorial Board Member

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Influence of Aldo-keto Reductase 1C3 in Prostate Cancer - A Mini Review

Background: Aldo-keto reductase 1C3 (AKR1C3) is an important oxidoreductase with multiple substrates, that are involved in producing extra-testicular androgens. Its activity is influenced by environmental exposures, as well as by genetic variants. These genetic variants could therefore produce variable testosterone levels and subsequent androgen receptor (AR) activation. This could lead to differential downstream production of the prostate-specific antigen (PSA). As PSA level is used for clinical evaluation of the prostate, these variations could impact prostate cancer (PC) diagnosis, as well as PC management outcomes. This review brings together information with regards to key functions of this enzyme, its relevance in PC, its transcriptional regulation, clinical aspects associated with genetics, differential regulation in cancer and cancer progression, and the types of AKR1C3 inhibitors with future therapeutic value. Conclusion: Based on these discussions, hypotheses are forwarded for future applicability of this enzyme and its genetic variants in transformational medical practices in PC. Options for the use of personalised AKR1C3 inhibitor drugs for late stage PC are also discussed.

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The Role of Mifamurtide in Chemotherapy-induced Osteoporosis of Children with Osteosarcoma

Background: Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome. Objective: To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma. Method: Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro-osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-β-2 (PKCβ2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches. Results: Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCβ2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide. Conclusion: Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma.

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Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants

Background: Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy. Objective: We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC. Methods: We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken. Results: We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases. Conclusion: Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants.

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Anti-Tumorigenic Effects of Resveratrol in Lung Cancer Cells Through Modulation of c-FLIP

Background: Resveratrol has been shown to have antioxidant and anti-proliferative properties in multiple cancer types. Here we demonstrate that H460 lung cancer cells are more susceptible to resveratrol treatment in comparison to human bronchial epithelial Beas-2B cells. Resveratrol decreases cell viability and proliferation, and induces significant apoptosis in H460 cells. The apoptosis observed was accompanied by an increase in hydrogen peroxide (H₂O₂) production, Bid, PARP and caspase 8 activation, and downregulation of pEGFR, pAkt, c-FLIP and NFkB protein expression. Furthermore, treatment with HH₂O₂ scavenger catalase significantly inhibited resveratrol-induced c-FLIP downregulation, caspase-8 activation and apoptosis. Overexpression of c-FLIP in H460 cells (FLIP cells) resulted in the inhibition of resveratrol-induced HH₂O₂ production, and a significant increase in resveratrolinduced apoptosis in comparison to H460 cells. In FLIP cells, catalase treatment did not rescue cells from a decrease in cell viability and apoptosis induction by resveratrol as compared to H460 cells. Resveratrol treatment also led to VEGF downregulation in FLIP cells. Furthermore, inhibition of pEGFR or pAkt using erlotinib and LY294002 respectively, enhanced the negative effect of resveratrol on FLIP cell viability and apoptosis. The reverse was observed when FLIP cells were supplemented with EGF, or transfected with WT-AKT plasmid; resulting in a 20% decrease in resveratrol-induced apoptosis. In addition, transfection with WT-AKT plasmid resulted in the inhibition of pro-apoptotic protein activation, and c-FLIP and pAkt downregulation. Conclusion: Overall, resveratrol induced apoptosis in H460 lung cancer cells by specifically targeting pAkt and c-FLIP dowregulation by proteasomal degradation in a EGFR-dependent manner.

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Effect of circulating glucagon and free fatty acids on hepatic FGF21 production in dairy cows

Modern dairy cows meet the energy demand of early lactation by calling on hormonally-driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and non-esterified fatty acids (NEFA). To assess the relative contribution of these factors in regulating FGF21, two experiments were performed in energy sufficient, non-pregnant, non-lactating dairy cows. In the first study, cows were injected with saline or GCG every 8 h over 72 h. GCG increased hepatic FGF21 mRNA by an average of 5-fold over matched controls but had no effect on plasma FGF21. In the second study, cows were infused and injected with saline, infused with intralipid and injected with saline or infused with intralipid and injected with GCG. Infusions and injections were respectively administered IV over 16 hours and SC every 8 h. Intralipid infusion increased plasma NEFA from 92 to 550 µM within 3 h and increased plasma FGF21 from 1.3 ng/ml to >11 ng/ml 6 h later; FGF21 mRNA increased by 34-fold in liver but remained invariant in adipose tissue. GCG injections during the intralipid infusion had no additional effects on plasma NEFA, liver FGF21 mRNA or plasma FGF21. These data implicate plasma NEFA as a key factor triggering hepatic production and increased circulating concentrations of FGF21 in early lactation.

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Left ventricular diastolic dysfunction in women with non-obstructive ischemic heart disease: Insights from magnetic resonance imaging and spectroscopy

Ischemic Heart Disease, in the absence of obstructive coronary artery disease, is prevalent in women, and constitutes a major risk factor for developing major adverse cardiovascular events, including myocardial infarction, stroke, and heart failure. For decades, diagnosis was considered benign and often minimized; however, it is now known that this etiology caries much risk and is a significant burden to the health care system. This review summarizes the current state-of-knowledge on non-obstructive ischemic heart disease (NOIHD), the association between NOIHD and left ventricular diastolic dysfunction, potential links between NOIHD and the development of heart failure with preserved ejection fraction (HFpEF), and therapeutic options and knowledge gaps for patients living with NOIHD.

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Modulation of Taste Processing by Temperature

Taste stimuli have a temperature that can stimulate thermosensitive neural machinery in the mouth during gustatory experience. Although taste and oral temperature are sometimes discussed as different oral sensory modalities, there is a body of literature that demonstrates temperature is an important component and modulator of the intensity of gustatory neural and perceptual responses. Available data indicate that the influence of temperature on taste, herein referred to as "thermogustation", can vary across taste qualities, can also vary among stimuli presumed to share a common taste quality, and is conditioned on taste stimulus concentration, with neuronal and psychophysical data revealing larger modulatory effects of temperature on gustatory responding to weakened taste solutions compared to concentrated. What is more, thermogustation is evidenced to involve interplay between mouth and stimulus temperature. Given these and other dependencies, identifying principles by which thermal input affects gustatory information flow in the nervous system may be important for ultimately unravelling the organization of neural circuits for taste and defining their involvement with multisensory processing related to flavor. Yet thermal effects are relatively understudied in gustatory neuroscience. Major gaps in our understanding of the mechanisms and consequences of thermogustation include delineating supporting receptors, the potential involvement of oral thermal and somatosensory trigeminal neurons in thermo-gustatory interactions, and the broader operational roles of temperature in gustatory processing. This review will discuss these and other issues in the context of the literature relevant to understanding thermogustation.

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Prenatal Hypoxia and Placental Oxidative Stress: Linkages to Developmental Origins of Cardiovascular Disease

Intrauterine growth restriction (IUGR, a pregnancy complication where the fetus does not reach its genetic growth potential) is a leading cause of fetal morbidity and mortality with a significant impact on population health. IUGR is associated with gestational hypoxia; which can lead to placental oxidative stress and fetal programming of cardiovascular disease. Mitochondria are a major source of placental oxidative stress and may provide a therapeutic target to mitigate the detrimental effects of placental oxidative stress on pregnancy outcomes. A nanoparticle-mediated delivery of a mitochondrial antioxidant to the placenta is a potential novel approach that may avoid unwanted off-target effects on the developing offspring.

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Flow mediated dilation and peripheral arterial tonometry are disturbed in pre-eclampsia and reflect different aspects of endothelial function.

BACKGROUND: Endothelial function and arterial stiffness are known to be altered in pre-eclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function (including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness) in pre-eclamptic patients and compared them to normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. METHODS: Fourteen patients with pre-eclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT, arterial stiffness by carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-leucocyte ratio (NLR). RESULTS: The reactive hyperemia index (RHI), assessed using PAT is decreased at the third trimester in comparison to the first trimester in a normal uncomplicated pregnancy (p=0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy (p<0.001). Endothelial function obtained by FMD is deteriorated in PE versus normal pregnancy (p=0.015), while endothelial function assessment by PAT is improved in PE versus normal pregnancy (p=0.001). Systemic inflammation (MPV, NLR) increases during normal pregnancy. CONCLUSIONS: Flow mediated dilation and peripheral arterial tonometry are disturbed in pre-eclampsia. Endothelial function assessed by FMD and PAT show distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as measure of endothelial function in pregnancy.

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Optogenetics and Pharmacogenetics: Principles and Applications

Remote and selective spatiotemporal control of the activity of neurons to regulate behavior and physiological functions has been a long-sought goal in system neuroscience. Identification and subsequent bioengineering of light-sensitive ion channels (e.g., channelrhodopsins, halorhodopsin and archaerhodopsins) from the bacteria has made it possible to utilize light to artificially modulate neuronal activity, namely optogenetics. Recent advance in genetics has also allowed development of novel pharmacological tools to selectively and remotely control neuronal activity using engineered G-protein coupled receptors which can be activated by otherwise inert drug-like small molecules such as the Designer Receptors Exclusively Activated by Designer Drug (DREADD) - a form of chemogenetics. The cutting-edge optogenetics and pharmacogenetics are powerful tools in neuroscience which allow selective and bidirectional modulation of the activity of defined populations of neurons with unprecedented specificity. These novel toolboxes are enabling significant advances in deciphering how the nervous system works and its influence on various physiological processes in health and disease. Here, we discuss the fundamental elements of optogenetics and chemogenetics approaches and some of the applications that yielded significant advances in various areas of neuroscience and beyond.

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Recent Advances in the Classification and Treatment of Ependymomas

Opinion Statement

Ependymomas are a subgroup of ependymal glia-derived neoplasms that affect children as well as adults. Arising within any CNS compartment, symptoms at presentation can range from acute onset due to increased intracranial pressure to insidious myelopathy. The overall survival (OS) outcomes in adult patients across the subgroups is heterogeneous with subependymoma having an excellent prognosis often even in the absence of any treatment, whereas supratentorial ependymomas tend to be higher grade in nature and may have an OS of 5 years despite gross total resection and adjuvant radiation. The rarity of ependymal tumors, together still only representing 1.8% of all primary CNS tumors, has been a long-standing challenge in defining optimal treatment guidelines via prospective randomized trials. Retrospective studies have supported maximal safe resection, ideally gross total resection, as the optimal treatment with adjuvant radiation therapy proffering additional tumor control. The evidence for efficacy of chemotherapy and targeted agents in adult ependymomas is minimal. Recent investigations of the molecular, genetic, and DNA methylation profiles of ependymal tumors across all age groups and CNS compartments have identified distinct oncogenic gene products as well as nine molecular subgroups correlating with similar outcomes. The 2016 World Health Organization of Tumors of the Central Nervous System update addresses some of these findings, although their clinical significance has not yet been fully validated. There are inconsistent survival outcomes in retrospective studies for ependymomas graded as II versus III, bringing into question the validity of histologic grading which is subject to high interobserver variability in part due to inconsistent application of mitotic count parameters.

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Treatment of Lung Carcinosarcoma and Other Rare Histologic Subtypes of Non-small Cell Lung Cancer

Opinion statement

Lung carcinosarcoma (PCS) and other histological subtypes of non-small cell lung cancer, such as primary pulmonary lymphoma (PPL), pulmonary carcinoid (PC), and primary pulmonary lymphoepithelioma-like carcinoma (LELC), are rare. For their low incidence, the diagnosis and treatment are still controversial. Some patients only need surgery, while others may need chemotherapy, radiotherapy, or targeted therapy. In this paper, we retrospectively reviewed the literature of some rare histological subtype of NSCLC for the recent 20 years, and try to get some conclusions.

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Novel Agents in the Treatment of Thymic Malignancies

Opinion statement

The management of thymic tumours is a paradigm of multidisciplinary collaboration. Chemotherapy may be administered part of curative-intent sequential strategy integrating subsequent surgery or radiotherapy, or as an exclusive treatment if local treatment is not achievable. Recurrences of thymic epithelial tumors should be managed according to the same strategy as newly diagnosed tumors. Given the limited activity of cytotoxic agents in the advanced, refractory setting, novel and innovative agents are needed. The better understanding of thymic carcinogenesis may provide a rationale in this setting.

Targeted agents approved for other solid tumors that have shown activity in thymic tumors include mTOR, KIT inhibitors, as well as somatostatin analogues. Anti-angiogenic agent sunitinib may be considered a standard in advanced lines of treatment. Ongoing studies are assessing the opportunity of targeting emerging targets, including PI3K, CDK, and immune checkpoint PD-1/PD-L1.

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Pediatric MATCH Trial Opens Enrollment [News in Brief]

Massive basket study aims to tailor treatments to tumor genetics of children and adolescents.

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Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study

Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients.

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A New Mouse Model of APOL1-Associated Kidney Diseases: When Traffic Gets Snarled, the Podocyte Suffers

Variants in APOL1, the gene encoding apolipoprotein L1, associate with nondiabetic kidney diseases in African Americans.1,2 Genetic and epidemiologic evidence support a kidney disease model with striking parallels to the genetic basis of sickle cell disease. The APOL1 kidney disease risk variants became common in sub-Saharan Africa because a single copy of the risk allele is trypanolytic and prevents African sleeping sickness. However, only individuals with 2 copies of the variants, consistent with a recessive mode of inheritance, are at risk for developing kidney diseases.

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Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD

Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models.

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Small Change, Big Consequences — Partial Medicaid Expansions under the ACA

Though congressional efforts to repeal and replace the Affordable Care Act (ACA) seem to have stalled, the Trump administration retains broad executive authority to reshape the health care landscape. Perhaps the most consequential choices that the administration will make pertain to Medicaid, which…

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Repeal, Replace, Repair, Retreat — Republicans’ Health Care Quagmire

For 7 years, Republicans vowed to repeal and replace the Affordable Care Act (ACA). With Donald Trump in the White House and Republican majorities in Congress, the GOP was poised to make good on that pledge. Yet less than 7 months into the Trump administration, the GOP's crusade to dismantle…

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Association between elevated central venous pressure and outcomes in critically ill patients

Some prior studies have shown that elevated mean central venous pressure in certain patient populations and disease processes may lead to poor prognosis. However, these studies failed to generalize the concept...

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DMKN contributes to the epithelial-mesenchymal transition through increased activation of STAT3 in pancreatic cancer

Summary

DMKN was first identified in relation to skin lesion healing and skin carcinoma. Recently, its expression has been associated with pancreatic cancer tumorigenesis, although its involvement remains poorly understood. Herein, we show that DMKN loss of function in Patu-8988 and PANC-1 pancreatic cancer cell lines results in reduced phosphorylation of signal transducer and activator of transcription-3 (STAT3), and increased activation of extracellular signal-regulated kinase (ERK1/2) and AKT serine/threonine kinase. This decreases the proliferation ability of pancreatic ductal adenocarcinoma (PDAC) cells. In addition, DMKN knockdown decreased the invasion and migration of PDAC cells, partially reversed the epithelial-mesenchymal transition, retarded tumor growth in a xenograft animal model by decreasing the density of microvessels, and attenuated the distance metastasis of human PDAC in a mouse model. Taken together, these data suggest that DMKN may be a potential prognostic biomarker and therapeutic target in pancreatic cancer.

This article is protected by copyright. All rights reserved.

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CENP-R acts bilaterally as a tumor suppressor and an oncogene in the two-stage skin carcinogenesis model

Abstract

CENP-R is a component of the CENP-O complex, including CENP-O, CENP-P, CENP-Q, CENP-R, and CENP-U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP-R deficient chicken DT40 cells are viable and show very minor effect on mitosis. To investigate the functional roles of CENP-R in vivo, we generated CENP-R deficient mice (Cenp-r^-/-). Mice heterozygous or homozygous for Cenp-r null mutation are viable and healthy, with no apparent defect in growth and morphology, indicating Cenp-r is not essential for normal development. Accordingly, to investigate the role of the Cenp-r gene in skin carcinogenesis, we subjected Cenp-r^-/- mice to the DMBA/TPA chemical carcinogenesis protocol and monitored their tumor development. As a result, Cenp-r^-/- mice initially developed significantly more papillomas than control wild type mice. However, papillomas in Cenp-r^-/- mice showed a decrease of proliferative cells and an increase of apoptotic cells. As a result, they did not grow bigger and some papillomas showed substantial regression. Furthermore, papillomas in Cenp-r^-/- mice showed lower frequency of malignant conversion to squamous cell carcinomas. These results indicate Cenp-r functions bilaterally in cancer development: during early developmental stages, Cenp-r behaves as a tumor suppressor, but during the expansion and progression of papillomas it behaves as a tumor-promoting factor.

This article is protected by copyright. All rights reserved.

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The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients

Abstract

Background

To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively.

Methods

A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by ⁶⁸Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients.

Results

A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1–29.0 ng/mL). A median dose of 43.5 Gy (range 30–64 Gy) was delivered by IMRT-IGRT in 12–27 fractions. At a median follow-up of 7 months (range 2–17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8–83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed.

Conclusions

By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that ⁶⁸Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

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Expression, Docking, and Molecular Dynamics of Endo-β-1,4-xylanase I Gene of Trichoderma virens in Pichia stipitis

It is essential that major carbohydrate polymers in the lignocellulosic biomass are converted into fermentable sugars for the economical production of energy. Xylan, the major component of hemicelluloses, is the second most naturally abundant carbohydrate polymer comprising 20–40% of the total biomass. Endoxylanase (EXN) hydrolyzes xylan into mixtures of xylooligosaccharides. The objective of this study was to genetically modify Pichia stipitis, a pentose sugar fermenting yeast species, to hydrolyze xylan into xylooligosaccharides via cloning and heterologous extracellular expression of EXNI gene from locally isolated Trichoderma virens species. Pichia stipitis was engineered to carry the EXNI gene of T. virens using pGAPZα expression vector. The open reading frame encodes 191 amino acids and SDS-PAGE analysis revealed a 24 kDA recombinant protein. The EXNI activity expressed by recombinant P. stipitis clone under standard conditions using 1% beechwood xylan was 31.7 U/ml. Molecular docking and molecular dynamics simulations were performed to investigate EXNI-xylan interactions. Free EXNI and xylan bound EXNI exhibited similar stabilities and structural behavior in aqueous medium. Furthermore, this in silico work opens avenues for the development of newer generation EXN proteins that can perform better and have enhanced catalytic activity.

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The Effect of RGD/NGR Peptide Modification of Melanoma Differentiation-Associated Gene-7/Interleukin-24 on Its Receptor Attachment, an In Silico Analysis

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Adjuvant Trastuzumab Therapy for Early HER2-Positive Breast Cancer in Iran: A Cost-Effectiveness and Scenario Analysis for an Optimal Treatment Strategy

Abstract

Introduction

Clinical guidelines have recommended a 1-year trastuzumab regimen as standard care for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer; however, this recommendation can have a dramatic impact on total drug expenditures in middle-income countries (MICs). We performed a cost-effectiveness analysis from the Iranian healthcare perspective to find an optimum duration of trastuzumab use in Iran.

Method

We compared four treatment strategies comprising chemotherapy and varying durations of trastuzumab use (no trastuzumab, 6, 9 months, and 1 year), and a Markov model and probabilistic sensitivity analysis were used to estimate the costs and effects of the strategies. We then examined the cost effectiveness of the strategies at different willingness-to-pay (WTP) thresholds and ages at onset of treatment.

Results

Incremental costs (versus no trastuzumab) were €8826 (6 months), €13,808 (9 months) and €18,588 (12 months), while incremental quality-adjusted life-years (QALYs) were 0.65 (6 months), 0.87 (9 months) and 1.14 (12 months). At a threshold of 3 × gross domestic product (GDP)/capita (€21,000/QALY) and for patients younger than 59 years, the 6-month protocol was most likely to be cost effective (probability of 42%). At a threshold of 4 × GDP/capita (€28,000/QALY), the 6-month and 1-year regimens were essentially equal in cost effectiveness (37 and 35%, respectively). At this WTP threshold, the 6-month and 1-year regimens were optimal strategies only for patients up to 66 and 44 years of age, respectively.

Conclusion

In contrast to clinical guidelines, 6 months of trastuzumab may be the most cost-effective option for Iran. The lower absolute WTP threshold and lower life expectancy compared with high-income countries are two crucial parameters in the cost effectiveness of interventions in MICs. It is therefore necessary to strike a balance between maximum population health and maintaining affordability in these countries.

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Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Abstract

Background

Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose-intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme.

Methods

A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF.

Results

A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8–41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%.

Conclusions

Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates.

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Aqueous extract of Phragmitis rhizoma ameliorates myelotoxicity of docetaxel in vitro and in vivo

A variety of anticancer chemotherapeutics induce adverse side effects including myelotoxicity. Dried roots of Phragmites communis Trinius, Phragmitis rhizoma, have been clinically used in traditional folk medicin...

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Subarachnoid small vein occlusion due to inflammatory fibrosis—a possible mechanism for cerebellar infarction in cryptococcal meningoencephalitis: a case report

Cryptococcal meningoencephalitis (CM) causes cerebral infarction, typically, lacunar infarction in the basal ganglia. However, massive cerebral infarction leading to death is rare and its pathophysiology is un...

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Patient satisfaction with ExtaviPro™ 30G, a new auto-injector for administering interferon β-1b in multiple sclerosis: results from a real-world, observational EXCHANGE study

Patients with multiple sclerosis (MS) receiving long-term, subcutaneous interferon β-1b (IFN β-1b; Extavia®) often experience injection-site reactions and injection-site pain, which together with other side-ef...

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Viral and bacterial upper respiratory tract infection in hospital health care workers over time and association with symptoms

Bacterial colonisation of the respiratory tract is commonly described and usually thought to be of no clinical significance. The aim of this study was to examine the presence and significance of bacteria and v...

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What I wish the public knew about EMS

By EMS1 Staff Why did you become an EMS provider" Chances are you wanted to help people. And along the way, you've probably run your fair share of calls. Some may end in a good outcome, while others can linger and haunt you. We asked our Facebook fans what they wish the general public knew about EMS. Some said they wish the public knew the difference between an EMT and a paramedic, while others ...

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What I wish my EMS supervisor knew about me

By EMS1 Staff Respect and trust is vital for any type of successful relationship. The same stands true for those in EMS. When you're on scene, you want to trust that the guy or girl behind you has your back in case of an emergency. You also want to trust that your EMS supervisor has your (and your crews') best interests in mind. In return, any superior, including an EMS supervisor, deserves ...

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Diagnostic value of Pentraxin-3 in patients with sepsis and septic shock in accordance with latest sepsis-3 definitions

Pentraxin-3 (PTX-3) is an acute-phase protein involved in inflammatory and infectious processes. This study assesses its diagnostic and prognostic value in patients with sepsis or septic shock in a medical int...

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CXCL9, a promising biomarker in the diagnosis of chronic Q fever

In the aftermath of the largest Q fever outbreak in the world, diagnosing the potentially lethal complication chronic Q fever remains challenging. PCR, Coxiella burnetii IgG phase I antibodies, CRP and 18F–FDG-PE...

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Cardiovascular risk and dyslipidemia among persons living with HIV: a review

Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or...

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Epidemiological trends and outcomes of extensively drug-resistant tuberculosis in Shandong, China

Extensively Drug-Resistant (XDR) Tuberculosis (TB) has posed a great threat to global health and finance systems, especially for developing countries with high TB and Multidrug-Resistant (MDR) TB burden.

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Radiation-induced gliomas: a report of four cases and analysis of molecular biomarkers

Abstract

Radiation-induced glioma (RIG) is a rare secondary glioma. The tumors morphologically resemble their sporadically arising counterparts. Recently, the WHO classification of tumors of the central nervous system was revised to incorporate molecular biomarkers together with classic histological features. The status of molecular biomarkers in RIG, however, remains unclear. The objective of this study was to investigate if commonly accepted glioma-specific biomarkers are relevant in RIGs. Among 269 gliomas diagnosed as WHO grade 2, 3 and 4 in our institution, four were diagnosed as RIGs. Immunohistochemical (IHC) staining for isocitrate dehydrogenase 1 (IDH1), p53, alpha thalassemia/mental retardation syndrome X-linked (ATRX), and H3K27M, and direct DNA sequencing of IDH1/2, telomerase reverse transcriptase (TERT) promoter, Histone H3.3 (H3F3A) and B-Raf (BRAF) genes was performed. All tumor specimens were IDH1-, p53- and H3K27M-negative. The nuclei of tumor cells in all cases exhibited positive staining for ATRX. In direct DNA sequencing analysis, no IDH1, IDH2, TERT promoter, H3F3A or BRAF mutations were found in any of the cases. Our findings suggest that these characteristic glioma-associated molecular mutations may be rare events in RIGs. More RIGs need to be tested for analysis of molecular biomarkers to clarify the clinical and histopathological spectra of this tumor.

http://ift.tt/2vP4eSD

Safety of Adrenaline Use in Anaphylaxis: A Multicentre Register

Background: The use of intramuscular adrenaline to treat anaphylaxis is suboptimal, despite being the first-line treatment recommended by national and international anaphylaxis guidelines. Fear of potentially severe side effects may be one of the underlying factors. The aim of this study was to assess the incidence and severity of adverse side effects after the use of adrenaline in anaphylaxis, as well as potential risk factors. Methods: Observational study based on a multicenter online registry of cases of adrenaline administration for suspected anaphylaxis. Results: 277 registered valid cases were included: 138 (51.49%) female, median age 29 years (12-47), and 6 children under 2 years with a median age of 9 months (1-21). Side effects occurred in 58 cases (21.64%), with tremors, palpitations, and anxiety being the most frequent. There was a significant association of developing side effects with older age, higher dose of adrenaline, or use of the intravenous route. Potentially severe adverse effects (high blood pressure, chest discomfort, or ECG alterations) occurred only in 8 cases (2.99%); in these cases, no differences were found according to age or adrenaline dose, but again, intravenous administration was associated with more severe adverse events. Conclusion: This study shows that side effects affect less than 1 in 5 patients who receive adrenaline for an anaphylactic reaction, and are usually mild and transient. Therefore, in an emergency situation such as anaphylaxis, restricting adrenaline administration due to potential adverse effects would, in general, not be justified.
Int Arch Allergy Immunol 2017;173:171-177

http://ift.tt/2wuTdE9

Aberrant connections between climbing fibres and Purkinje cells induce alterations in the timing of an instrumental response in the rat

Abstract

Cerebellar participation in timing and sensory-motor sequences has been supported by several experimental and clinical studies. A relevant role of the cerebellum in timing of conditioned responses in the range of milliseconds has been demonstrated, but less is known regarding the role of the cerebellum in supra-second timing of operant responses. A dissociated role of the cerebellum and striatum in timing in the millisecond and second range had been reported, respectively. The climbing fibre-Purkinje cell synapse is crucial in timing models; thus, the aberrant connection between these cellular elements is a suitable model for evaluating the contribution of the cerebellum in timing in the supra-second range. The aberrant connection between climbing fibres and Purkinje cells was induced by administration of the antagonist of NMDA receptors MK-801 to Sprague–Dawley rats at postnatal days 7–14. The timing of an operant response with two fixed intervals (5 and 8 s) and egocentric sequential learning was evaluated in 60-day-old adult rats. The aberrant connections caused a reduced accuracy in the timing of the instrumental response that was more evident in the 8-s interval and a reduced number of successive correct responses (responses emitted in the correct second without any other response between them) in the 8-s interval. In addition, an inability to incorporate new information in a sequence previously learned in egocentric-based sequence learning was apparent in rats with aberrant CF–PC synapses. These results support a relevant role for the cerebellum in the fine-tuning of the timing of operant responses in the supra-second range.

http://ift.tt/2uqmmCM

Neurophysiological features of tactile versus visual guidance of ongoing movement

Abstract

Although studies have investigated tactile and visual processing for perception, sensory processing for ongoing action remains poorly understood. The purpose of this study was to explore modality-specific patterns of cortical activation and functional connectivity in a practiced trajectory tracking task. Participants traced irregular shapes with their index finger using either touch or vision for guidance. In 60 tactile-motor (TM) trials, movement was guided only by tactile feedback of semicircular bumps on a plastic tile. In 60 visuo-motor (VM) trials, movement was guided only by vision of dots on a screen seen through a small window at the finger tip. The order of TM and VM trials was counterbalanced across 16 participants. Electroencephalography (EEG) was used to estimate cortical activation (task-related spectral power) and functional connectivity (task-related magnitude-squared coherence) in the alpha (8–12 Hz) and beta (13–30 Hz) bands during the last 12 movement trials in each sensorimotor task. TM vs. VM tasks exhibited a larger drop in global beta cortical activation, and greater alpha coherence between central, parietal, and occipital regions. VM vs. TM tasks were characterized by low global alpha coherence. Trace time and cortical activation of the last 12 VM trials were reduced in the group performing the VM task after the TM task compared to those performing the VM task first. Beta connectivity initiated by the first task was maintained on the subsequent second task, regardless of the task order. Identification of modality- and order-specific EEG characteristics provides insight into the sensory control of movement.

http://ift.tt/2uHIB2h

The motor cortical representation of a muscle is not homogeneous in brain connectivity

Abstract

Functional connectivity patterns of the motor cortical representational area of single muscles have not been extensively mapped in humans, particularly for the axial musculature. Functional connectivity may provide a neural substrate for adaptation of muscle activity in axial muscles that have both voluntary and postural functions. The purpose of this study was to combine brain stimulation and neuroimaging to both map the cortical representation of the external oblique (EO) in primary motor cortex (M1) and supplementary motor area (SMA), and to establish the resting-state functional connectivity associated with this representation. Motor-evoked potentials were elicited from the EO muscle in stimulation locations encompassing M1 and SMA. The coordinates of locations with the largest motor-evoked potentials were confirmed with task-based fMRI imaging during EO activation. The M1 and SMA components of the EO representation demonstrated significantly different resting-state functional connectivity with other brain regions: the SMA representation of the EO muscle was significantly more connected to the putamen and cerebellum, and the M1 representation of the EO muscle was significantly more connected to somatosensory cortex and the superior parietal lobule. This study confirms the representation of a human axial muscle in M1 and SMA, and demonstrates for the first time that different parts of the cortical representation of a human axial muscle have resting-state functional connectivity with distinct brain regions. Future studies can use the brain regions of interest we have identified here to test the association between resting-state functional connectivity and control of the axial muscles.

http://ift.tt/2uHNB7g

Effect of post-weaning isolation on anxiety- and depressive-like behaviors of C57BL/6J mice

Abstract

Effects of post-weaning isolation on depressive- and anxiety-like behaviors in rodents have been well studied in the past. However, few studies included both sexes in a single experiment to study the sex difference in this animal model. The present study investigated the effect of post-weaning isolation on anxiety- and depressive-like behaviors in both male and female C57BL/6 J mice. Mice were individually or grouped housed from postnatal day 21 for 5 weeks until behavioral tests began. The results showed that social isolation resulted in increased anxiety in the open field. Isolated-reared female, but not male mice showed an increased transition between two compartments in the light–dark box and a decreased immobile time in the forced swim test. We conclude that post-weaning isolation has a sex-specific effect on emotional behaviors.

http://ift.tt/2upW0Ry

Disturbed cervical proprioception affects perception of spatial orientation while in motion

Abstract

The proprioceptive, visual and vestibular sensory systems interact to maintain dynamic stability during movement. The relative importance and interplay between these sensory systems is still not fully understood. Increased knowledge about spatial perception and postural orientation would provide better understanding of balance disorders, and their rehabilitation. Displacement of the body in space was recorded in 16 healthy subjects performing a sequence of stepping-in-place tests without any visual or auditory cues. Spatial displacement and orientation in space were determined by calculating two parameters, "Moved distance (sagittal + lateral displacement)" and "Rotation". During the stepping-in-place tests vibration were applied in a randomized order on four different cervical muscles, and the effects were compared between muscles and to a non-vibration baseline condition. During the tests a forward displacement ("Moved distance") was found to be the normal behavior, with various degrees of longitudinal rotation ("Rotation"). The moved distance was significantly larger when the vibration was applied on the dorsal muscles (916 mm) relative to on ventral muscles (715 mm) (p = 0.003) and the rate of displacement was significantly larger for dorsal muscles (36.5 mm/s) relative to ventral (28.7 mm/s) vs (p = 0.002). When vibration was applied on the left-sided muscles, 16° rotation to the right was induced (p = 0.005), whereas no significant rotation direction was induced with right-sided vibration (3°). The rate of rotation was significantly larger for vibration applied on ventral muscles (0.44°/s) relative to on dorsal (0.33°/s) (p = 0.019). The results highlight the influence of cervical proprioception on the internal spatial orientation, and subsequent for postural control.

http://ift.tt/2uHrcqA

The efficacy of airflow and seat vibration on reducing visually induced motion sickness

Abstract

Visually induced motion sickness (VIMS) is a well-known sensation in virtual environments and simulators, typically characterized by a variety of symptoms such as pallor, sweating, dizziness, fatigue, and/or nausea. Numerous methods to reduce VIMS have been previously introduced; however, a reliable countermeasure is still missing. In the present study, the effect of airflow and seat vibration to alleviate VIMS was investigated. Eighty-two participants were randomly assigned to one of four groups (airflow, vibration, combined airflow and vibration, and control) and then exposed to a 15 min long video of a bicycle ride shot from first-person view. VIMS was measured using the Fast Motion Sickness Scale (FMS) and the Simulator Sickness Questionnaire (SSQ). Results showed that the exposure of airflow significantly reduced VIMS, whereas the presence of seat vibration, in contrast, did not have an impact on VIMS. Additionally, we found that females reported higher FMS scores than males, however, this sex difference was not found in the SSQ scores. Our findings demonstrate that airflow can be an effective and easy-to-apply technique to reduce VIMS in virtual environments and simulators, while vibration applied to the seat is not a successful method.

http://ift.tt/2uqklGQ

Saccades evoked in response to electrical stimulation of the posterior bank of the arcuate sulcus

Abstract

To test the hypothesis that the premotor cortex in and behind the caudal bank of the arcuate sulcus can generate saccades, we stimulated electrically the periarcuate region of alert rhesus monkeys. We were able to produce saccades from sites of the premotor cortex that were contiguous with the frontal eye fields and extended up to 2 mm behind the smooth pursuit area. However, premotor sites often elicited saccades with ipsiversive characteristic vectors, lower peak velocities, and flatter velocity profiles when compared to saccades evoked from the frontal eye field.

http://ift.tt/2uHgv7A

Spatial limits of visuotactile interactions in the presence and absence of tactile stimulation

Abstract

The presence of a light flash near to the body not only increases the ability to detect a weak touch but also increases reports of feeling a weak touch that did not occur. The somatic signal detection task (SSDT) provides a behavioural marker by which to clarify the spatial extent of such visuotactile interactions in peripersonal space. Whilst previous evidence suggests a limit to the spatial extent over which visual input can distort the perception of tactile stimulation during the rubber hand illusion, the spatial boundaries of light-induced tactile sensations are not known. In a repeated measures design, 41 participants completed the SSDT with the light positioned 1 cm (near), 17.5 cm (mid) or 40 cm (far) from the tactile stimulation. In the far condition, the light did not affect hit, or false alarm rates during the SSDT. In the near and mid conditions, the light significantly increased hit rates and led to a more liberal response criterion, that is, participants reported feeling the touch more often regardless of whether or not it actually occurred. Our results demonstrate a spatial boundary over which visual input influences veridical and non-veridical touch perception during the SSDT, and provide further behavioural evidence to show that the boundaries of the receptive fields of visuotactile neurons may be limited to reach space.

http://ift.tt/2uqhNbP

Atopy and prostate cancer: Is there a link between circulating levels of IgE and PSA in humans?

Abstract

Background

Atopy has been investigated as a potential risk factor for prostate cancer. IgE antibodies may be major players in protective responses against tumours, through engendering antigen presentation and enhancing adaptive immune responses targeted towards a specific allergen, but potentially also against tumour-associated antigens such as prostate-specific antigen (PSA). We therefore cross-sectionally investigated associations between circulating levels of PSA and IgE in the National Health and Nutrition Examination Survey 2005–2006.

Methods

We focused on all men aged 40+ years with measurements for PSA and IgE, and no previous diagnosis of prostate cancer (n = 1312). We estimated the association between total and specific IgE concentration and levels of PSA with logistic regression models, adjusted for age, ethnicity/race, education, smoking status, body mass index (BMI), physical activity status, and history of asthma.

Results

Both total IgE and the sum of specific IgE were inversely associated with the risk of having PSA levels ≥10 ng/mL, though most findings were not statistically significant. The odds ratios for the second and third tertile of total IgE as compared to the first were 0.21 (95% CI 0.06–0.72) and 0.42 (0.08–2.31). The odds ratio for sum of abnormal specific IgE measurements was 0.77 (0.44–1.34).

Conclusion

Despite statistical insignificance, the observed trend warrants further research given the increasing evidence of the role of atopy and IgE antibodies in protective responses against tumours. A lifecourse approach of measuring IgE, specific subtypes, and other markers of the humoral immune system (i.e. IgG) could shed more light on its potential anti-cancer characteristics.

http://ift.tt/2vnlHzt

Atopy and prostate cancer: Is there a link between circulating levels of IgE and PSA in humans?

Abstract

Background

Atopy has been investigated as a potential risk factor for prostate cancer. IgE antibodies may be major players in protective responses against tumours, through engendering antigen presentation and enhancing adaptive immune responses targeted towards a specific allergen, but potentially also against tumour-associated antigens such as prostate-specific antigen (PSA). We therefore cross-sectionally investigated associations between circulating levels of PSA and IgE in the National Health and Nutrition Examination Survey 2005–2006.

Methods

We focused on all men aged 40+ years with measurements for PSA and IgE, and no previous diagnosis of prostate cancer (n = 1312). We estimated the association between total and specific IgE concentration and levels of PSA with logistic regression models, adjusted for age, ethnicity/race, education, smoking status, body mass index (BMI), physical activity status, and history of asthma.

Results

Both total IgE and the sum of specific IgE were inversely associated with the risk of having PSA levels ≥10 ng/mL, though most findings were not statistically significant. The odds ratios for the second and third tertile of total IgE as compared to the first were 0.21 (95% CI 0.06–0.72) and 0.42 (0.08–2.31). The odds ratio for sum of abnormal specific IgE measurements was 0.77 (0.44–1.34).

Conclusion

Despite statistical insignificance, the observed trend warrants further research given the increasing evidence of the role of atopy and IgE antibodies in protective responses against tumours. A lifecourse approach of measuring IgE, specific subtypes, and other markers of the humoral immune system (i.e. IgG) could shed more light on its potential anti-cancer characteristics.

http://ift.tt/2vnlHzt

An analysis of 97 previously diagnosed de novo adult acute erythroid leukemia patients following the 2016 revision to World Health Organization classification

Abstract

Background

The incidence of acute erythroid leukemia subtype (AEL) is rare, accounting for 5% of cases of acute myeloid leukemia (AML), and the outcome is dismal. However, in 2016 revision to the WHO classification, the subcategory of AEL has been removed. Myeloblasts are redefined as the percentage of total marrow cells, not non-erythroid cells. Therefore, the previously diagnosed AEL cases are currently diagnosed as AML or myelodyspalstic syndrome (MDS) according to new criteria.

Methods

We respectively reviewed cases of 97 de novo previously diagnosed AEL and all the patients were diagnosed as AML or MDS according to the new classification scheme, and then the clinical characteristics of these two subtypes were compared. Statistical analyses were performed by SPSS software version 18.0.

Results

The median age was 37 years-old, the two-thirds of previous AEL cases were diagnosed as MDS, and there was no obvious difference between two subtypes except for male/female ratio and age. Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. When the cytogenetic risk of patients belonged to MRC intermediate category and age were below 40 years-old in previous AEL cases, the patients who received induction chemotherapy without transplantation had a similar survival compared with the patients who underwent transplantation (3-year OS: 67.2% vs 68.5%).

Conclusions

Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. Transplantation was a better choice for those whose cytogenetic category was unfavorable.

http://ift.tt/2vFBXy5

The effect of Nullomer-derived peptides 9R, 9S1R and 124R on the NCI-60 panel and normal cell lines

Abstract

Background

Nullomer peptides are the smallest sequences absent from databases of natural proteins. We first began compiling a list of absent 5-amino acid strings in 2006 (1). We report here the effects of Nullomer-derived peptides 9R, 9S1R and 124R on the NCI-60 panel, derived from human cancers of 9 organs (kidney, ovary, skin melanoma, lung, brain, lung, colon, prostate and the hematopoietic system), and four normal cell lines (endothelial HUVEC, skin fibroblasts BJ, colon epithelial FHC and normal prostate RWPE-1).

Methods

NCI-60 cancer cell panel and four normal cell lines were cultured in vitro in RPMI1640 supplemented with 10% Hyclone fetal bovine serum and exposed for 48 h to 5 μM, 25 μM and 50 μM of peptides 9R, 9S1R and 124R. Viability was assessed by CCK-8 assay. For peptide ATP depletion effects, one cell line representing each organ in the NCI-60 panel, and four normal cell lines were exposed to 50 μM of peptides 9R, 9S1R and 124R for 3 h. The ATP content was assessed in whole cells, and their supernatants.

Results

Peptides 9S1R and 9R are respectively lethal to 95 and 81.6% of the 60 cancer cell lines tested. Control peptide 124R has no effect on the growth of these cells. Especially interesting the fact that peptides 9R and 9S1R are capable of killing drug-resistant and hormone-resistant cell lines, and even cancer stem cells. Peptides 9R and 9S1R have a broader activity spectrum than many cancer drugs in current use, can completely deplete cellular ATP within 3 h, and are less toxic to 3 of the 4 normal cell lines tested than they are to several cancers.

Conclusions

Nullomer peptides 9R and 9S1R have a large broad lethal effect on cancer cell lines derived from nine organs represented in the NCI-60 panel. This broad activity crosses many of the categorical divisions used in the general classification of cancers: solid vs liquid cancers, drug sensitive vs drug resistant, hormone sensitive vs hormone resistant, cytokine sensitive vs cytokine non sensitive, slow growing vs rapid growing, differentiated vs dedifferentiated cancers. Furthermore peptides 9R and 9S1R are lethal to cancer stem cells and breast canrcinosarcoma.

http://ift.tt/2vnNi3e

Lipopolysaccharide aggravated DOI-induced Tourette syndrome: elaboration for recurrence of Tourette syndrome

Abstract

Tourette syndrome (TS) is a neurological disorder characterized by highest familial recurrence rate among neuropsychiatric diseases with complicated inheritance. Recurrence of Tourette syndrome was frequently observed in clinical. Unexpectedly, the mechanism of recurrence of Tourette syndrome was failure to elucidate. Here, we first shown that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome. The TS model in rats was induced by DOI (the selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl) -2- aminopropane). The rats were randomly divided into 4 groups:(1)Control;(2) Control + LPS; (2)TS; (3)TS + LPS. The results demonstrated that the LPS treatment significantly increased stereotypic score and autonomic activity. LPS treatment also significantly increased inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and striatum. Also, highly expressed TLR4, MyD88, P-NF-κBp65, P-IκBα in TS rats were increased respectively by LPS treatment as indicted in western blot analysis and immunohistochemistry analysis. Thus, it was supposed that lipopolysaccharide(LPS) may played an important role in the recurrence of Tourette syndrome and its mechanism was related to TLR/NF-κB pathway.

http://ift.tt/2uq1GHj

Animals living in polluted environments are a potential source of anti-tumor molecule(s)

Abstract

Despite advances in therapeutic interventions and supportive care, the morbidity and mortality associated with cancer have remained significant. Thus, there is a need for newer and more powerful anti-tumor agents. The search for new anti-tumor compounds originating from natural resources is a promising research area. Animals living in polluted environments are a potent source of anti-tumor agents. Under polluted milieus, species such as crocodiles, feed on rotten meat, are exposed to heavy metals, endure high levels of radiation, and are among the very few species to survive the catastrophic Cretaceous-Tertiary extinction event with a prolonged lifespan. Thus, it is reasonable to speculate that animals such as crocodiles have developed mechanisms to defend themselves against cancer. The discovery of antitumor activity in animals such as crocodiles, whales, sharks, etc. will stimulate research in finding therapeutic molecules from unusual sources, and has potential for the development of novel antitumor compound(s) that may also overcome current drug resistance. Nevertheless, intensive research in the next few years will be required to realize these expectations.

http://ift.tt/2vnpHzK

Assessment of health-related quality of life and psychological well-being of children and adolescents with obesity enrolled in a New Zealand community-based intervention programme: an observational study

Objective

To describe health-related quality of life (HRQOL) and psychological well-being of children and adolescents at enrolment in a multidisciplinary community-based obesity programme and to determine association with ethnicity. This programme targeted indigenous people and those from most deprived households. Further, this cohort was compared with other populations/normative data.

Methods

This study examines baseline demographic data of an unblinded randomised controlled clinical trial. Participants (recruited from January 2012-August 2014) resided in Taranaki, New Zealand, and for this study we only included those with a body mass index (BMI) ≥98th percentile (obese). HRQOL and psychological well-being were assessed using the Pediatric Quality of Life Inventory (PedsQL V.4.0^TM) (parent and child reports), and Achenbach's Child Behavior Checklist (CBCL)/Youth Self Report (YSR).

Results

Assessments were undertaken for 233 participants (45% Māori, 45% New Zealand European, 10% other ethnicities, 52% female, 30% from the most deprived household quintile), mean age 10.6 years. The mean BMI SD score (SDS) was 3.12 (range 2.01–5.34). Total PedsQL generic scaled score (parent) was lower (mean=63.4, SD 14.0) than an age-matched group of Australian children without obesity from the Health of Young Victorians study (mean=83.1, SD 12.5). In multivariable models, child and parental generic scaled scores decreased in older children (β=–0.70 and p=0.031, β=–0.64 and p=0.047, respectively). Behavioural difficulties (CBCL/YSR total score) were reported in 43.5% of participants, with the rate of emotional/behavioural difficulties six times higher than reported norms (p<0.001).

Conclusions

In this cohort, children and adolescents with obesity had a low HRQOL, and a concerning level of psychological difficulties, irrespective of ethnicity. Obesity itself rather than ethnicity or deprivation appeared to contribute to lower HRQOL scores. This study highlights the importance of psychologist involvement in obesity intervention programmes.

Trial registration number

Australian NZ Clinical Trials Registry ANZCTR 12611000862943; Pre-results.

http://ift.tt/2wILy44

The use of neoadjuvant therapy for resectable locally advanced thoracic esophageal squamous cell carcinoma in an analysis of 5016 patients from 305 designated cancer care hospitals in Japan

Abstract

Background

Recent studies have shown the benefits of neoadjuvant therapy with chemotherapy or chemoradiotherapy for resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC). The aim of our study was to elucidate the use of neoadjuvant therapy for thoracic ESCC in Japan.

Methods

Data on patients with stage IB–III thoracic ESCC were retrieved from the national database of hospital-based cancer registries combined with claims data between 2012 and 2013. These data were analyzed using a mixed-effect logistic regression analysis, with a focus on exploring patterns in the first-line treatment for ESCC, including proportion of patients who received neoadjuvant therapy, and investigating the hospital characteristics and patient factors associated with the use of neoadjuvant therapy.

Results

Of the 5016 patients with stage IB–III thoracic ESCC at the 305 participating hospitals, 34.2% received neoadjuvant therapy (neoadjuvant chemotherapy, 29.5%; neoadjuvant chemoradiotherapy, 4.7%). The therapy was less likely to be administered to older patients (≤64 years, 48.8%; 65–70 years, 42.0%; 70–75 years, 33.9%; 75–80 years, 22.2%; 80–85 years, 3.8%; ≥85 years, 1.4%) and at hospitals with a low volume of patients (very high, 42.1%; high, 37.5%; low, 30.7%; and very low, 26.4%). This trend was confirmed by regression analysis.

Conclusions

Based on our results, in Japan, relatively few patients with resectable locally advanced thoracic ESCC receive neoadjuvant therapy, with older patients and patients at lower volume hospitals being less likely than other patients to receive the neoadjuvant therapy. We recommend that the process of treatment decision-making be assessed at both the patient and hospital levels so that patients can consider various treatment options, including neoadjuvant therapy with surgery in Japan.

http://ift.tt/2vnyWAh

Multi-Photon Time Lapse Imaging to Visualize Development in Real-time: Visualization of Migrating Neural Crest Cells in Zebrafish Embryos

A combination of the advanced optical techniques of laser scanning microscopy with long wavelength multi-photon fluorescence excitation was implemented to capture high-resolution, three-dimensional, real-time imaging of neural crest migration in Tg(sox10:EGFP) and Tg(foxd3:GFP) zebrafish embryos.

http://ift.tt/2vPQSXk

Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine

Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine

British Journal of Cancer 117, 583 (08 August 2017). doi:10.1038/bjc.2017.210

Authors: Françoise Descotes, Norelyakin Kara, Myriam Decaussin-Petrucci, Eric Piaton, Florence Geiguer, Claire Rodriguez-Lafrasse, Jean E Terrier, Jonathan Lopez & Alain Ruffion

http://ift.tt/2uwsbLF

Lifestyle predictors for non-participation and outcome in the second round of faecal immunochemical test in colorectal cancer screening

Lifestyle predictors for non-participation and outcome in the second round of faecal immunochemical test in colorectal cancer screening

British Journal of Cancer 117, 461 (08 August 2017). doi:10.1038/bjc.2017.189

Authors: Markus Dines Knudsen, Paula Berstad, Anette Hjartåker, Elisabeth Haagensen Gulichsen, Geir Hoff, Thomas de Lange, Tomm Bernklev & Edoardo Botteri

http://ift.tt/2uoAM69

MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer

MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer

British Journal of Cancer 117, 525 (08 August 2017). doi:10.1038/bjc.2017.181

Authors: P Zhang, W M Tang, H Zhang, Y Q Li, Y Peng, J Wang, G N Liu, X T Huang, J J Zhao, G Li, A M Li, Y Bai, Y Chen, Y X Ren, G X Li, Y D Wang, S D Liu & J D Wang

http://ift.tt/2sRjRbs

Geriatric assessment is superior to oncologists’ clinical judgement in identifying frailty

Geriatric assessment is superior to oncologists' clinical judgement in identifying frailty

British Journal of Cancer 117, 470 (08 August 2017). doi:10.1038/bjc.2017.202

Authors: Lene Kirkhus, Jūratė Šaltytė Benth, Siri Rostoft, Bjørn Henning Grønberg, Marianne J Hjermstad, Geir Selbæk, Torgeir B Wyller, Magnus Harneshaug & Marit S Jordhøy

http://ift.tt/2ssgbs2

LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression

LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression

British Journal of Cancer 117, 563 (08 August 2017). doi:10.1038/bjc.2017.193

Authors: Qing Liao, Rui Li, Rui Zhou, Zhihua Pan, Lijun Xu, Yanqing Ding & Liang Zhao

http://ift.tt/2ssf63t

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma

British Journal of Cancer 117, 478 (08 August 2017). doi:10.1038/bjc.2017.206

Authors: A J Zurita, R C Gagnon, Y Liu, H T Tran, R A Figlin, T E Hutson, A M D'Amelio Jr, C N Sternberg, L N Pandite & J V Heymach

http://ift.tt/2uwkxkh