Adamantinoma-like Ewing sarcoma of the parotid gland: Cytopathologic findings and differential diagnosis

Adamantinoma-like Ewing sarcoma (AES) is a rare variant of Ewing sarcoma family of tumors (EFTs), primarily affecting bone and soft tissue. AES has mixed features of Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) and adamantinoma with a complex immunoprofile and EWSR1 gene rearrangements. Herein, we report a 72-year-old male who presented with left parotid mass, right neck mass and thyroid nodules. Fine needle aspiration of the left parotid mass displayed nests of monotonous epithelioid cells with basaloid features in a background of small round blue cells and lymphocytes. AES can involve head and neck region and is characterized by groups of primitive small round blue cells admixed with groups of epithelioid cells with amphophilic cytoplasm and focal squamous differentiation. The proportion of these components can be variable, creating diagnostic challenges, particularly in unusual anatomic sites such as the parotid gland. However, when additional material is available, CD99 and/or FLI1 immunostains need to be included for diagnostic confirmation.

http://ift.tt/2xJHcib

Useful aspects of diagnosis of imprint cytology in intraoperative consultation of ovarian tumors: comparison between imprint cytology and frozen sections

Background

In the intraoperative consultation of ovarian tumors, the histological diagnosis of frozen sections (FS) of large tumors is frequently difficult because of the limited number of tumor samples. The application of imprint cytology (IC), in which samples are obtained from wide areas of the tumors, is useful for intraoperative consultation. However, the useful aspects of IC have not been clearly defined. The present study is a detailed comparison of IC and FS that clearly defines the useful aspects of IC.

Methods

Fifty-five cases of ovarian tumors that were examined using both IC and FS were evaluated. The histological diagnoses consisted of benign (16), borderline (6), and malignancy (33). All of the malignant tumors consisted of various types of carcinoma.

Results

Benignity and malignancy were accurately diagnosed by both IC and FS. In the borderline group, the diagnostic accuracy of IC was very low (1/6: 16.6%) compared with FS (4/6: 66.6%). The diagnostic accuracy including benign, borderline, and malignant groups was 90.9% (50/55) for IC and 96.3% (53/55) for FS. Concerning the diagnosis of the types of carcinoma, the overall diagnostic accuracy of IC (25/31: 80.6%) was greater than that of FS (21/31: 67.7%), especially for the diagnosis of clear cell carcinoma (IC, 100%; FS, 80%) and mixed carcinoma (IC, 66.6%; FS, 16.6%).

Conclusion

The useful aspects of IC in the intraoperative consultation are the diagnosis of benignity or malignancy and the accuracy of diagnosing clear cell carcinoma and mixed carcinoma.

http://ift.tt/2kUmKW6

Morphometric and histologic characterization of alveolar bone from hypertensive patients

Abstract

Background

Hypertension is considered a risk factor in implant dentistry but the underlying reasons remain unclear. It may be that hypertension has a negative impact on the local bone quality.

Purpose

Here we evaluated the structural and histological parameters of bone collected from hypertensive patients treated by antagonists of the renin-angiotensin system, and of bone collected from normotensive patients.

Material and methods

A total of 30 patients were referred for rehabilitation with dental implants to be placed in the posterior mandible. The first group were hypertensive patients treated with RAS antagonists. The second group were normotensive patients not taking medication. Bone biopsies collected during implant installation were subjected to analysis. Micro CT revealed the structural parameters. Histological analyses together with immunohistochemical staining of osteogenic markers were performed.

Results

The structural parameters of bone volume, trabecular thickness, trabecular number, separation of the trabecular, and total porosity were similar between the 2 groups (P > .05). The histological appearance of bone derived from hypertensive patients was normal. The staining pattern of Runx-2, osteopontin, and osteocalcin were comparable in both groups.

Conclusions

These observations suggest that hypertensive patients treated with renin-angiotensin system antagonists have regular alveolar bone with respect to bone structure and histological parameters.

http://ift.tt/2kQNUNj

A prospective, split-mouth study comparing tilted implants with angulated connection versus conventional implants with angulated abutment

Abstract

Background

An angulation of the implant connection could overcome the problems related to angulated abutments.

Purpose

This study compares conventional implants with angulated abutment to tilted implants with an angulated connection.

Materials and Methods

Twenty patients were treated in the edentulous mandible. In the posterior jaw locations, one conventional tilted implant with angulated abutment and one angulated implant without abutment were placed. In the anterior jaw, two conventional implants were placed, one with and one without abutment. Implants were immediately loaded and 3 months later, the final bridge (PFM or monolithic zirconia) was placed.

Results

After a follow-up of 48 months, 17 patients were available for clinical examination. The mean overall marginal bone loss (MBL) was 1.26 mm. No significant differences in implant survival, MBL, periodontal indices, patients' satisfaction, or complications was found between implants restored on abutment or implant level, between the posteriorly located angulated implant nor angulated abutment, and between both anterior implants with or without abutment. The posterior implants demonstrated less MBL compared to the anterior implants (P < .001). There was no significant difference in MBL between the implants restored with zirconia or PFM bridges (P = .294). Overall mean pocket depth was 2.83 mm. More plaque was found in the PFM group compared to the full-zirconia group, at the bridge (P = .042) and the implants (P = .029). There was no difference between both materials in pocket depth (P = .635) or bleeding (P = .821). One zirconia bridge fractured, two angulated abutment were replaced and four loose bridge screws connected to the angulated abutments had to be tightened. Patients were overall satisfied (4.74/5).

Conclusion

An implant with angulated connection may results in a stronger connection but does not affect the marginal bone loss. No difference in MBL was seen between implants restored on abutment or implant level. Zirconia seems to reduce the amount of plaque.

http://ift.tt/2xIZQGU

A prospective randomized controlled trial of the two-window technique without membrane versus the solo-window technique with membrane over the osteotomy window for maxillary sinus augmentation

Abstract

Background

Maturation of the grafted volume after lateral sinus elevation is crucial for the long-term survival of dental implants.

Purpose

To compare endo-sinus histomorphometric bone formation between the solo- and two-window maxillary sinus augmentation techniques with or without membrane coverage for the rehabilitation of multiple missing posterior teeth.

Materials and Methods

Patients with severely atrophic posterior maxillae were randomized to receive lateral sinus floor elevation via the solo-window technique with membrane coverage (Control Group) or the two-window technique without coverage (Test Group). Six months after surgery, bone core specimens harvested from the lateral aspect were histomorphometrically analyzed.

Results

Ten patients in each group underwent 21 maxillary sinus augmentations. Histomorphometric analysis revealed mean newly formed bone values of 26.08 ± 16.23% and 27.14 ± 18.11%, mean connective tissue values of 59.34 ± 12.42% and 50.03 ± 17.13%, and mean residual graft material values of 14.6 ± 14.56% and 22.78 ± 10.83% in the Test and Control Groups, respectively, with no significant differences.

Conclusions

The two-window technique obtained comparative maturation of the grafted volume even without membrane coverage, and is a viable alternative for the rehabilitation of severely atrophic posterior maxillae with multiple missing posterior teeth.

http://ift.tt/2kSBdll

SemFYC y WONCA: creciendo juntos en la diversidad

María Fernández García, José Miguel Bueno Ortiz
Aten Primaria 2017;49:445-7

Texto completo - PDF

http://ift.tt/2hKrIj0

Atención sanitaria a refugiados o la historia de una asignatura pendiente

Ethel Sequeira
Aten Primaria 2017;49:448-9

Texto completo - PDF

http://ift.tt/2yNnYZm

Mayores que viven solos y malnutrición. Estudio SOLGER

Lidia Paino Pardal, Laia Poblet i Montells, Laura Ríos Álvarez
Aten Primaria 2017;49:450-8

Resumen - Texto completo - PDF

http://ift.tt/2hJG43d

Traducción y adaptación transcultural al español del cuestionario ARMS para la medida de la adherencia en pacientes pluripatológicos

Javier González-Bueno, Elena Calvo-Cidoncha, Daniel Sevilla-Sánchez, Joan Espaulella-Panicot, Carles Codina-Jané, Bernardo Santos-Ramos
Aten Primaria 2017;49:459-64

Resumen - Texto completo - PDF

http://ift.tt/2hHWNUy

Violencia de pareja: tipo y riesgos en usuarias de atención primaria de salud en Cancún, Quintana Roo, México

Luis Sandoval-Jurado, María Valeria Jiménez-Báez, Gloria Rovira Alcocer, Omar Vital Hernandez, Fany Guadalupe Pat Espadas
Aten Primaria 2017;49:465-72

Resumen - Texto completo - PDF

http://ift.tt/2hJlIHm

Efecto de un programa lúdico de actividad física general de corta duración y moderada intensidad sobre las cifras de presión arterial y otros factores de riesgo cardiovascular en hipertensos mayores de 50 años

Ana Torija Archilla, Javier Pérez González, Álvaro Sarmiento Ramírez, Enrique Fernández Sánchez, Josué Rubén González Ruiz, Rafael Guisado Barrilao
Aten Primaria 2017;49:473-83

Resumen - Texto completo - PDF

http://ift.tt/2hJG57h

Análisis de los cuidados y los conocimientos parentales sobre la fiebre en la infancia

Maria-Cristina Pérez-Conesa, Inés Sánchez Pina, Saida Ridao Manonellas, Antoni Tormo Esparza, Verónica García Hernando, Marta López Fernández
Aten Primaria 2017;49:484-91

Resumen - Texto completo - PDF

http://ift.tt/2hIUbG9

Queratosis actínica: nuevo concepto y actualización terapéutica

Rafael Carmena-Ramón, Almudena Mateu-Puchades, Sergio Santos-Alarcón, Sofía Lucas-Truyols
Aten Primaria 2017;49:492-7

Resumen - Texto completo - PDF

http://ift.tt/2hJc07U

Reclasificación de función renal en varones entre 65-75 años, según el filtrado glomerular calculado por MDRD y CKD-EPI

Gabriela Romero Fresco, María Carnicero Iglesias, Ana Clavería, Pilar Gayoso-Diz
Aten Primaria 2017;49:498-9

Texto completo - PDF

http://ift.tt/2hJG3wb

El experto y la ley de Agrest

Pablo Young, Bárbara Cristina Finn, Julio Enrique Bruetman
Aten Primaria 2017;49:500

Texto completo - PDF

http://ift.tt/2yLYCed

¿Qué se está haciendo ya desde los equipos de atención primaria contra la soledad?

Laura Coll-Planas, Rosa Monteserín, Ester Cob, Sergi Blancafort
Aten Primaria 2017;49:501-2

Texto completo - PDF

http://ift.tt/2hHWWay

Madres solteras por elección. Una realidad creciente y no reciente

Cristobal Coronel Rodríguez, Ana María Chávez Barco, María Dolores González Soria, Maria Cinta Guisado Rasco
Aten Primaria 2017;49:502-3

Texto completo - PDF

http://ift.tt/2yLXmYr

Severe Drug-Induced Liver Injury as an Adverse Drug Event of Antibiotics: A Case Report and Review of the Literature

Drug-induced liver injury is one of the main reasons for acute liver failure. We report the case of a young patient who experienced a drug-induced liver injury resulting in life-threatening acute liver failure after treatment with different antibiotics (amoxicillin, ciprofloxacin, cefazolin, clindamycin) and acetaminophen, or a combination of these drugs. Moreover, we provide an overview of the hepatotoxic potential of these drugs.
Chemotherapy 2017;62:367-373

http://ift.tt/2gICiaF

Tenofovir, entecavir, and lamivudine in patients with severe acute exacerbation and hepatic decompensation of chronic hepatitis B

To compare the efficacy of and mortality after lamivudine (LAM), tenofovir (TDF), and entecavir (ETV) treatment in patients with severe acute chronic hepatitis B (CHB) exacerbation.

http://ift.tt/2hHWU2q

ERC vs. direct cholangioscopy: dawn of a new reference standard

http://ift.tt/2yLYuvf

Transglutaminase 6 antibodies are not yet mainstream in Neuro- Coeliac Disease

http://ift.tt/2hHWTvo

TRANSMURAL HEALING IN CROHŃS DISEASE: BEYOND MURAL FINDINGS

http://ift.tt/2yLkd6s

TRANSMURAL HEALING IN CROHN’S DISEASE: BEYOND MURAL FINDINGS − AUTHORS’ REPLY

http://ift.tt/2hJlIak

Role of diuretics in the harmful effects of beta blockers in patients with ascites. Author’s reply

http://ift.tt/2yNKhOx

Depression and anxiety in caregivers of patients with celiac disease

http://ift.tt/2hJbYgi

H&H Medical introduces the H*VENT Vented Chest Dressing

Product expands world leading chest seal line WILLIAMSBURG, Va. — H&H Medical Corporation, a leading provider of emergency trauma products, is proud to announce the introduction of our newest product in our chest seal line, the H*VENT vented chest dressing. Open chest wounds that develop into a tension pneumothorax, commonly referred as a sucking chest wound, can be life threatening if not ...

http://ift.tt/2kS3Jn7

KARL STORZ to exhibit video laryngoscope at EMS World Booth #1025

LAS VEGAS — Plan to visit us at EMS World Booth #1025 to test drive the latest airway management products from KARL STORZ. We will showcase the latest additions to the most comprehensive airway management devices for the pre-hospital market, including our C-MAC® S Single-use video laryngoscope for adults, pediatrics and neonates; as well as our re-useable blades. The C-MAC® platform can ...

http://ift.tt/2xHIdHz

Genlantis introduces FirstResponder Sterilizer product to help EMTs and paramedics

Genlantis – a BioTech Company has a revolutionary product tailored just for you. Download this eBook to learn more about the FirstResponder Sterilizer. SAN DIEGO — The FirstResponder® Sterilizer is one of a kind as it can be used to sterilize spaces and vehicles from infestations that might lead to severe infections. Such infections can also often lead to lifelong medical conditions ...

http://ift.tt/2kSbJEs

6 ePCR best practices

Look for these features when choosing an electronic patient care reporting program

http://ift.tt/2xHxblT

EMS budget planning primer for new paramedic chiefs

Climbing the ranks of EMS often fails to prepare new chiefs to discuss financial issues with local elected and appointed officials

http://ift.tt/2kS3Grr

The 3 Ps: Applying Policy, Procedure and Process to EMS

Paramedic chiefs can use the three Ps to communicate the organization's expectations regarding operational preparedness to EMS providers

http://ift.tt/2xIZ2BS

Exclusive end-of-year special for RISE™ vest by Angel Armor™ - for public safety officers only

Angel Armor is excited to announce an end-of-year special for the RISE body armor platform. If agencies order before December 31, 2017, they will receive up to $100 off each RISE vest.

http://ift.tt/2kTy44I

Drones to deliver defibrillators to 911 callers to treat cardiac arrest

A start-up called Flirtey partnered with REMSA Health to dispatch drones with portable defibrillators when 911 callers report cardiac arrest symptoms

http://ift.tt/2xHx8GJ

Inventors present drone that could help treat patients in disasters

The drone could be loaded with a medical kit containing supplies and a headset so civilians at a disaster site could receive medical instructions

http://ift.tt/2kQAG34

CPRP to exhibit support pillow at EMS World Expo, Booth 926

The Cardiopulmonary Resuscitation Support Pillow is designed to aid with performing proper CPR for single or dual first responders

http://ift.tt/2xJI1HW

Rapid cardiothoracic ultrasound protocol for diagnosis of acute heart failure in the emergency department.

Objectives: The aim of this study was to evaluate the performance of a rapid cardiothoracic ultrasound protocol (CaTUS), combining echocardiographically derived E/e' and lung ultrasound (LUS), for diagnosing acute heart failure (AHF) in patients with undifferentiated dyspnea in an emergency department (ED). Patients and results: We enrolled 100 patients with undifferentiated dyspnea from a tertiary care ED, who all had CaTUS done immediately upon arrival in the ED. CaTUS was positive for AHF with an E/e' > 15 and congestion, that is bilateral B-lines or bilateral pleural fluid, on LUS. In addition, an inferior vena cava index was also recorded to analyze whether including a central venous pressure estimate would add diagnostic benefit to the CaTUS protocol. All 100 patients had a brain natriuretic peptide (BNP) sample withdrawn, and 96 patients underwent chest radiography in the ED, which was analyzed later by a blinded radiologist. The reference diagnosis of AHF consisted of either a BNP of more than 400 ng/l or a BNP of less than 100 ng/l in combination with congestion on chest radiography and structural heart disease on conventional echocardiography. CaTUS had a sensitivity of 100% (95% confidence interval: 91.4-100%), a specificity of 95.8% (95% confidence interval: 84.6-99.3%), and an area under the curve of 0.979 for diagnosing AHF (P

http://ift.tt/2ysjV3J

Practical management of concomitant acute heart failure and worsening renal function in the emergency department.

Worsening renal function (i.e. any increase in creatinine or decrease in the estimated glomerular filtration rate) is common in patients admitted for acute heart failure in the emergency department. Although worsening renal function (WRF) has been associated with the occurrence of dismal outcomes, this only appears to be the case when associated with clinical deterioration. However, if the clinical status of the patient is improving, a certain increase in serum creatinine may be acceptable. This WRF, which is not associated with clinical deterioration or adverse outcomes (e.g. during treatment up-titration), has been referred to as 'pseudo-WRF' and should not detract clinicians from targeting 'guideline-recommended' therapies. This is an important message for emergency physicians to pursue diuretics as long as signs of pulmonary congestion persist to improve the clinical status of the patient. In the present review, we aim to provide clinicians in acute settings with an integrative and comprehensive approach to cardiorenal interactions in acute heart failure. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2glarRa

Analysis of the citation of articles published in the European Journal of Emergency Medicine since its foundation.

Objectives: The aim of this study was to evaluate the evolution of the citation of articles from the European Journal of Emergency Medicine (EJEM) from 1994 (EJEM foundation) to 2015 and identify highly cited articles and their principal characteristics and determine a possible correlation between the citations counted in different databases. Materials and methods: We obtained the articles published in EJEM from 1994 to 2015 in ISI-WoS (main source) and Scopus, Google Scholar, and Medline databases (accessory sources). The citations were quantified and their annual evolution and the bibliometric indices derived (impact factor and SCImago Journal Rank) were evaluated. We identified and analyzed the highly cited EJEM articles and evaluated the possible correlation between the citations counted for these articles in the databases. Results: Overall, 1705 EJEM articles were cited 9422 times in 8122 different articles. The evolution of the global citation, impact factor, and SCImago Journal Rank from 1994 to 2015 increased significantly. The h-index of EJEM was 30, and 31 articles were considered highly cited (>=30 citations), 16.1% of them being clinical trials. By subjects, 22.5% corresponded to cardiology, 19.3% to emergency department management, and 12.9% to pediatrics; by countries, 81% were from Europe, with Belgian authors publishing four (12.9%) highly cited articles, and French, Spanish, British, and Swedish authors having three (9.7%) each. Two studies in the EJEM achieved the definition of 'citation classics' (more than 100 citations). The number of citations in all the databases, except Medline, showed statistically significant correlations. Conclusion: Citation of EJEM articles has progressively increased and EJEM bibliometric indicators have improved; most highly cited articles are mainly by European authors. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2yqT6g8

Complementary and Integrative Medicine in Hematologic Malignancies: Questions and Challenges

Abstract

Hematologic malignancies represent 9.7% of all cancers, making them the fourth most common type of cancer in the United States. The aggressive and complex treatments administered in hematologic malignancies result in a high burden of psychological needs. Complementary and integrative medicine (CIM) is becoming one of the options that patients use to address their distress during and after cancer treatments. It is not clear whether appropriate CIM can relieve distress in patients affected by these malignancies. This review covers the potential benefits of CIM as relates to nutrition, nutritional supplements, exercise, circadian rhythm, methods for reducing distress during bone marrow aspiration, massage therapy, and acupuncture, in treating patients with hematological malignancies. This review may provide a framework to enhance patient-doctor dialogue regarding CIM use in hematologic malignancies.

http://ift.tt/2yntWPc

The Role of Next-Generation Sequencing in Sarcomas: Evolution From Light Microscope to Molecular Microscope

Abstract

Purpose of Review

Sarcomas are rare, heterogeneous group of soft tissue and bone tumors. Precise diagnosis of specific subtypes is challenging using conventional methods. Herein, we review the role of next-generation sequencing (NGS) technology that is used for rapid sequencing of DNA and RNA.

Recent Findings

Recent sarcoma specific studies recommend that molecular genetic testing should be added at diagnosis for appropriate clinical management in addition to diagnosis by expert pathologists. NGS has already been used to identify potentially actionable mutations, copy number alterations, and gene fusions. Rationally, choosing a drug based on an individual patient profile aka: "precision oncology" has been so far limited to few case reports in sarcomas.

Summary

As we improve our ability to deliver personalized medicine using all modalities including conventional therapy, more patients may eventually benefit. As the cost and capacity of NGS outpace Moore's law, so does the probability of success.

http://ift.tt/2znmQIS

Treatment-Free Remission: a New Therapeutic Goal in Chronic Myelogenous Leukemia

Abstract

Purpose of Review

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of Philadelphia chromosome [t(9:22)] leading to the presence of pathognomonic fusion gene product, BCR-ABL1. This leads to constitutive activation of ABL1 kinase. CML was a difficult-to-treat illness until the advent of small molecule tyrosine kinase inhibitor (TKI), imatinib which revolutionized therapy of CML. Since then, multiple second- and third-generation TKIs have been formulated which have proven effective and has led to marked improvement in survival. In this article, we review currently available data on possibility of holding TKI therapy in patients in deep remission [treatment-free remission (TFR)] and safety of this approach.

Recent Findings

As CML treatment has become more effective, new questions have emerged, most important being whether the treatment with TKIs can ever be stopped. This is especially relevant in patient experiencing side effects from therapy or who may be subject to increased health risks due to treatment. There is now evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI. Furthermore, patients can safely re-establish remission after restarting their TKI therapy in the situation of relapse.

Summary

CML is highly treatable disease, but the treatment has untoward physical and socioeconomic consequences. The idea of TFR is hence attractive. There is a growing body of evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI.

http://ift.tt/2y01yTQ

B Vitamin Complex and Chemotherapy-Induced Peripheral Neuropathy

Abstract

Purpose of Review

The purpose of this mini review is to evaluate the literature on B vitamins and chemotherapy-induced peripheral neuropathy.

Recent Findings

One hundred and five journal articles were evaluated and nine manuscripts were included. There was one in vitro, one was an animal and seven were human studies. The in vitro study was a safety study on vitamin B₆ and oxaliplatin which was not directly related to CIPN. The animal study evaluated vitamin B₃ on paclitaxel administration with positive results. The human studies varied using a vitamin B complex, vitamin B₁₂ only and vitamin B₆.

Summary

Chemotherapy-induced peripheral neuropathy (CIPN) continues to plague patients and the medical fraternity. Currently, there are still no conclusive protective or treatment options. B vitamins have been found to play a role in CIPN prevention, but further studies are required to ascertain possible protection and treatment options.

http://ift.tt/2fLNP8p

Using Geriatric Assessment Strategies to Lead End-of-Life Care Discussions

Abstract

End-of-life discussions with geriatric oncology patients are a vital part of the comprehensive care of the senior adult patient. Developing a roadmap for these conversations can be challenging. Patients and caregivers may have expectations that are not concordant with what is reasonably achievable if the patient is frail. Measuring baseline cognition, nutritional status, and physical function and discussing goals of care are all essential pieces of information that can be obtained through a comprehensive geriatric assessment (CGA). Objective findings from the CGA can be crucial in developing end-of-life care plans that reflect both the patient's health status and personal values.

http://ift.tt/2yiqzKe

Double-Hit Large B Cell Lymphoma

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of NHL cases. It is a heterogeneous group of diseases. BCL2, BCL6, and MYC are the most frequent mutated genes in DLBCL. Double-hit lymphoma (DHL) is an aggressive form of DLBCL with an unmet treatment need, in which MYC rearrangement is present with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass with B symptoms. DHL has been linked to very poor outcomes when treated with RCHOP chemotherapy. Dual-expressor lymphoma is a form of DLBCL with overexpression of MYC and BCL2/BCL6. There is a paucity of prospective trials evaluating the treatment of DHL. Retrospective series suggest that more aggressive treatment regimens such as DA-EPOCH and hyper CVAD may be more efficacious. However, there remains a lack of consensus regarding optimal treatment for DHL. Further clinical trials, including novel agents, are needed for improvement in outcomes.

http://ift.tt/2fmOFrU

Polypharmacy in the Geriatric Oncology Population

Abstract

Purpose of Review

This review explores the multiple definitions, epidemiology, and impact of polypharmacy in geriatric oncology patients. Risk factors and clinical implications of polypharmacy are delineated and potential clinical approaches to reduce polypharmacy are reviewed.

Recent Findings

Most sources currently define polypharmacy as the administration of multiple medications that are non-essential, unnecessary, duplicative, or ineffective. Possible risk factors associated with polypharmacy in geriatric cancer patients include comorbid conditions, prescribing cascades, and hospitalization. Consequences of polypharmacy in this population include adverse drug events, drug-drug interactions, reduced adherence, frailty, and increased morbidity. Clinical approaches to the reduction of polypharmacy include thorough medication histories and an interprofessional team approach to care.

Summary

Polypharmacy is common and has a direct clinical impact on geriatric oncology patients.

There is a clear deficit in our understanding of the scope and impact of polypharmacy in this population and only limited evaluation of various interventions exist. The paucity of information is at least partially linked to the consistent exclusion of older adults in cancer studies and the complex interaction between polypharmacy and potential morbidities/mortality.

http://ift.tt/2yx54SP

Flexible Aqueous Li-Ion Battery with High Energy and Power Densities

Abstract

A flexible and wearable aqueous symmetrical lithium-ion battery is developed using a single LiVPO₄F material as both cathode and anode in a "water-in-salt" gel polymer electrolyte. The symmetric lithium-ion chemistry exhibits high energy and power density and long cycle life, due to the formation of a robust solid electrolyte interphase consisting of Li₂CO₃-LiF, which enables fast Li-ion transport. Energy densities of 141 Wh kg⁻¹, power densities of 20 600 W kg⁻¹, and output voltage of 2.4 V can be delivered during >4000 cycles, which is far superior to reported aqueous energy storage devices at the same power level. Moreover, the full cell shows unprecedented tolerance to mechanical stress such as bending and cutting, where it not only does not catastrophically fail, as most nonaqueous cells would, but also maintains cell performance and continues to operate in ambient environment, a unique feature apparently derived from the high stability of the "water-in-salt" gel polymer electrolyte.

A flexible and wearable aqueous lithium-ion battery is introduced based on a unique "water-in-salt" gel polymer electrolyte and single electrode material with far superior energy density to reported aqueous energy storage devices at the same power level. The full cell can operate in open air, exhibiting ambient insensitivity, high safety, and unprecedented tolerance to against mechanical stress.

http://ift.tt/2hHMdNi

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

Many estrogen receptor α (ERα)–positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER–containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER–expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy–resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602–13. ©2017 AACR.

http://ift.tt/2glwIhB

Cancer Self-Defense: An Immune Stealth

The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer-stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441–4. ©2017 AACR.

http://ift.tt/2glErfq

Highlights from Recent Cancer Literature

http://ift.tt/2yrgeuW

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445–51. ©2017 AACR.

http://ift.tt/2yrU23G

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2–driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652–63. ©2017 AACR.

http://ift.tt/2gjQRV8

HIF-2{alpha} Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.

http://ift.tt/2glEpEk

ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576–90. ©2017 AACR.

http://ift.tt/2gmlkSJ

STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer. Silencing STRAP sensitized colorectal cancer cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of colorectal cancer cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which forms repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 colorectal cancer clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP–NOTCH1–HES1 molecular axis as a CSC regulator in colorectal cancer, with potential implications to improve treatment of this disease. Cancer Res; 77(20); 5464–78. ©2017 AACR.

http://ift.tt/2yrTYks

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti–Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T-cell–based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti–Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628–38. ©2017 AACR.

http://ift.tt/2glEgRi

LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

http://ift.tt/2glEVCg

T Cells Deficient in Diacylglycerol Kinase {zeta} Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.

http://ift.tt/2glOxNp

Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.

http://ift.tt/2yrgcDk

Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564–75. ©2017 AACR.

http://ift.tt/2yrg9HE

De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503–17. ©2017 AACR.

http://ift.tt/2glEo3e

Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591–601. ©2017 AACR.

http://ift.tt/2yrTRFy

Sensitivity to BUB1B Inhibition Defines an Alternative Classification of Glioblastoma

Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore–microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518–29. ©2017 AACR.

http://ift.tt/2yrTWck

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro. Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry–based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614–27. ©2017 AACR.

http://ift.tt/2yrUhf6

Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530–42. ©2017 AACR.

http://ift.tt/2glEmZa

{beta}-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.

http://ift.tt/2yrUgry

Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1

Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3′UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells. Cancer Res; 77(20); 5543–53. ©2017 AACR.

http://ift.tt/2yrTUkI

Timeframe of socket cortication after tooth extraction: A retrospective radiographic study

Abstract

Objectives

To assess the timeframe between tooth extraction and radiographically detectable socket cortication in humans.

Methods

Two hundred and fifty patients with a CT scan ≤36 months after tooth extraction were included. First, three orthoradial multiplanar reconstruction slices, representing the major part of the extraction socket, were scored regarding the degree of bone healing as (i) healed, that is, complete/continuous cortication of the socket entrance, or (ii) non-healed. Thereafter, based on the results of all three slices, the stage of cortication of the extraction socket, as one unit, was classified as (i) non-corticated, that is, all three slices judged as non-healed, (ii) partially corticated, that is, 1 or 2 slices judged as non-healed, or (iii) completely corticated, that is, all three slices judged as healed. The possible effect of several independent parameters, that is, age, gender, timeframe between tooth extraction and CT scan, tooth type, extent of radiographic bone loss of the extracted tooth, tooth-gap type, smoking status, presence of any systemic disease, and medication intake, on cortication status was statistically evaluated.

Results

Three to 6 months after tooth extraction, 27% of the sockets were judged as non-corticated and 53% were judged as partially corticated. After 9–12 months, >80% of the sockets were corticated, while some incompletely corticated sockets were detected up to 15 months after extraction. Each additional month after tooth extraction contributed significantly to a higher likelihood of a more advanced stage of cortication, while radiographic bone loss ≥75% significantly prolonged cortication time; no other independent variable had a significant effect.

Conclusions

The results indicate a considerably long timeframe until complete cortication of an extraction socket, that is, 3–6 months after tooth extraction 3 of 4 sockets were still not completely corticated, and only after 9–12 months, complete cortication was observed in about 80% of the sockets.

http://ift.tt/2ymHEQt

Federal leadership needed to realize national data set for cardiovascular care [Letters]

http://ift.tt/2zqUY6L

We need a "made in Canada" orphan drug framework [Commentary]

http://ift.tt/2zqV26v

Pay gap growing between family doctors, other specialists [News]

http://ift.tt/2zqm2mq

Persistence of immunity after vaccination with a capsular group B meningococcal vaccine in 3 different toddler schedules [Research]

BACKGROUND:

One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12–23 months, with a booster dose 12–24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12–24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children.

METHODS:

Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12–24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children.

RESULTS:

Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%–11% v. 1% (H44/76), 84%–100% v. 4% (5/99), 0%–18% v. 0% (NZ98/254) and 59%–60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%–100% (NZ98/254) and 90%–100% (M10713).

INTERPRETATION:

We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12–24 months, and doses at 12–24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. Trial registration: ClinicalTrials.gov, no. NCT01717638

http://ift.tt/2zcrus3

Health Canada to warn young people of cannabis risks in campaign [News]

http://ift.tt/2zqRe54

Testosterone use causing erythrocytosis [Practice]

http://ift.tt/2zqO5SM

Healthy interpretation [Editorial]

http://ift.tt/2zcrBnt

Thumb and vallecula signs in acute infectious epiglottitis [Practice]

http://ift.tt/2zbEjTO

Saskatchewan First Nations drafts suicide prevention plan [News]

http://ift.tt/2zcr5Wz

Saturday night at St. Marys [Humanities]

http://ift.tt/2zqV0eT

Beacon in developmental biology [News]

http://ift.tt/2zcr44X

Real-world data really matter [Letters]

http://ift.tt/2zbE772

Why public health is the most challenging specialty of all [Coda]

http://ift.tt/2zaEQp3

Correction to: Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma

http://ift.tt/2xHFadK

Advances in the Treatment of Paraproteinemic Neuropathy

Abstract

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy.

Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib.

Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials.

http://ift.tt/2gc42no

Carotid chemoreceptor control of muscle sympathetic nerve activity in hypobaric hypoxia

Abstract

High altitude hypoxia causes pronounced sympathoexcitation but the underlying mechanisms remain unclear. We tested the hypothesis that intravenous infusion of dopamine to attenuate carotid chemoreceptor responsiveness would reduce muscle sympathetic nerve activity (MSNA) at high altitude. Nine healthy individuals (mean [SD]; 26 [4] yr) were studied at sea level (SL, Zurich) and at high altitude (ALT, 3454 m, 15–17 days after arrival), both while breathing the ambient air and during an acute incremental hypoxia test (8 × 3 min stages, P_ETO₂ 90-45 mmHg). Intravenous infusion of dopamine (3 μg·kg⁻¹·min⁻¹) and placebo (saline) were administered on both study days, according to a single blind randomized cross-over design. Sojourn to high altitude decreased P_ETO₂ (to ≈60 mmHg) and increased minute ventilation (V_E; mean±SE; saline [SL, ALT], 8.6 ± 0.5 to 11.3 ± 0.6; dopamine, 8.2 ± 0.5 to 10.6 ± 0.8 L·min⁻¹; P < 0.05) and MSNA burst frequency by ≈80% (saline [SL, ALT], 16 ± 3 to 28 ± 4; dopamine, 16 ± 4 to 31 ± 4 bursts·min⁻¹; P < 0.05) when breathing the ambient air, but were not different with dopamine. Increases in MSNA burst frequency and V_E during the acute incremental hypoxia test were greater at ALT than SL (P < 0.05). Dopamine did not affect the magnitude of the MSNA burst frequency response to acute incremental hypoxia at either SL or ALT. However, V_E was lower with dopamine than saline administration throughout the acute incremental hypoxia test at ALT. These data indicate that intravenous infusion of low-dose dopamine to blunt the responsiveness of the carotid chemoreceptors does not significantly decrease MSNA at high altitude.

This article is protected by copyright. All rights reserved

http://ift.tt/2gbtmKr

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

Abstract

Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5'-diphosphoribose (ADPR) analogues were synthesized and their activities and selectivity were evaluated. Whole-cell patch clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a were identified as TRPM2 inhibitors with IC₅₀ of 5.7 μM and 5.4 μM, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure-activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds.

This article is protected by copyright. All rights reserved.

A series of adenosine 5'-diphosphoribose (ADPR) analogues were synthesized for discovering novel and selective TRPM2 inhibitors. Two compounds, 7i and 8a were identified as TRPM2 inhibitors with IC₅₀ of 5.7 μM, respectively, selective against TRPM7, TRPM8, TRPV1 and TRPV3. These two novel and TRP-subtype selective TRPM2 inhibitors can be used as tool for further investigation of the channel pharmacology.

http://ift.tt/2xHPToc

Fetal Overnutrition and Adolescent Hepatic Fat Fraction: the Exploring Perinatal Outcomes in Children Study

To determine if fetal overnutrition resulting from maternal obesity or gestational diabetes mellitus (GDM) is associated with increased liver fat during adolescence, adjusting for past and current metabolic risk factors.

http://ift.tt/2ifgmaN

MRI-based assessment of 3D intrafractional motion of head and neck cancer for radiation therapy

To determine the 3D intrafractional motion of head and neck squamous cell carcinoma (HNSCC).

http://ift.tt/2yjEYWb

Partial Optic Nerve Transection in Rats: A Model Established with a New Operative Approach to Assess Secondary Degeneration of Retinal Ganglion Cells

Secondary degeneration of retinal ganglion cells (RGCs) occurs commonly in glaucoma. This study describes an innovative operative approach for partial optic nerve transection. The use of this space-saving operative approach extends the model's application range, and allows exploration of secondary injury mechanisms in RGCs in a new way.

http://ift.tt/2yoMKvF

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

Ivacaftor and ivacaftor-lumacaftor combination are two new CF drugs. However, there is still a dearth of understanding on their PK/PD and pharmacology. We present an optimized HPLC-MS technique for the simultaneous analysis of ivacaftor and its major metabolites, and lumacaftor.

http://ift.tt/2gkO3Hi

iSepsis -Death by Fluids, Part 2

The FEAST study, a large RCT done in children with sepsis, unequivocally demonstrated the harm of an aggressive approach to fluid management.

EMCrit by Paul Marik.

http://ift.tt/2ymQg9T

Evans Syndrome Complicated by Intratubular Hemoglobin Cast Nephropathy

Evans syndrome (ES) is a rare autoimmune disorder whose exact pathophysiology is unknown. It is characterized by the simultaneous or subsequent development of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Intravascular hemolysis, with hemoglobinemia, is known to produce acute kidney injury; however, the development of intratubular hemoglobin casts (hemoglobin cast nephropathy) in the setting of acute hemolysis is uncommon. Likewise, the association of ES and acute renal failure is equally uncommon. We present a case of a 7-year-old girl with ES who developed acute kidney injury in the setting of intravascular hemolysis and had widespread intratubular hemoglobin casts.

http://ift.tt/2yksz4A

Beating Heart Motion Accurate Prediction Method Based on Interactive Multiple Model: An Information Fusion Approach

Robot-assisted motion compensated beating heart surgery has the advantage over the conventional Coronary Artery Bypass Graft (CABG) in terms of reduced trauma to the surrounding structures that leads to shortened recovery time. The severe nonlinear and diverse nature of irregular heart rhythm causes enormous difficulty for the robot to realize the clinic requirements, especially under arrhythmias. In this paper, we propose a fusion prediction framework based on Interactive Multiple Model (IMM) estimator, allowing each model to cover a distinguishing feature of the heart motion in underlying dynamics. We find that, at normal state, the nonlinearity of the heart motion with slow time-variant changing dominates the beating process. When an arrhythmia occurs, the irregularity mode, the fast uncertainties with random patterns become the leading factor of the heart motion. We deal with prediction problem in the case of arrhythmias by estimating the state with two behavior modes which can adaptively "switch" from one to the other. Also, we employed the signal quality index to adaptively determine the switch transition probability in the framework of IMM. We conduct comparative experiments to evaluate the proposed approach with four distinguished datasets. The test results indicate that the new proposed approach reduces prediction errors significantly.

http://ift.tt/2zpDdoh

Bioinformatics Genes and Pathway Analysis for Chronic Neuropathic Pain after Spinal Cord Injury

It is well known spinal cord injury (SCI) can cause chronic neuropathic pain (NP); however its underlying molecular mechanisms remain elusive. This study aimed to disclose differentially expressed genes (DEGs) and activated signaling pathways in association with SCI induced chronic NP, in order to identify its diagnostic and therapeutic targets. Microarray dataset GSE5296 has been downloaded from Gene Expression Omnibus (GEO) database. Significant analysis of microarray (SAM), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and pathway network analysis have been used to compare changes of DEGs and signaling pathways between the SCI and sham-injury group. As a result, DEGs analysis showed there were 592 DEGs with significantly altered expression; among them Ccl3 expression showed the highest upregulation which implicated its association with SCI induced chronic NP. Moreover, KEGG analysis found 209 pathways changed significantly; among them the most significantly activated one is MAPK signaling pathway, which is in line with KEGG analysis results. Our results show Ccl3 is highly associated with SCI induced chronic NP; as the exosomes with Ccl3 can be easily and efficiently detected in peripheral blood, Ccl3 may serve as a potential prognostic target for the diagnosis and treatment of SCI induced chronic NP.

http://ift.tt/2zaHJ9l

Issue Information - Masthead

http://ift.tt/2ymd0XF

Issue Information - Copyright

http://ift.tt/2wWjmLL

142nd Annual Meeting of the American Neurological Association

http://ift.tt/2ymSohT

Issue Information - TOC

http://ift.tt/2wWjevL

Relative and Absolute Interrater Reliabilities of a Hand-Held Myotonometer to Quantify Mechanical Muscle Properties in Patients with Acute Stroke in an Inpatient Ward

Introduction. The reliability of using MyotonPRO to quantify muscles mechanical properties in a ward setting for the acute stroke population remains unknown. Aims. To investigate the within-session relative and absolute interrater reliability of MyotonPRO. Methods. Mechanical properties of biceps brachii, brachioradialis, rectus femoris, and tibialis anterior were recorded at bedside. Participants were within 1 month of the first occurrence of stroke. Relative reliability was assessed by intraclass correlation coefficient (ICC). Absolute reliability was assessed by standard error of measurement (SEM), SEM%, smallest real difference (SRD), SRD%, and the Bland-Altman 95% limits of agreement. Results. ICCs of all studied muscles ranged between 0.63 and 0.97. The SEM of all muscles ranged within 0.30–0.88 Hz for tone, 0.07–0.19 for decrement, 6.42–20.20 N/m for stiffness, and 0.04–0.07 for creep. The SRD of all muscles ranged within 0.70–2.05 Hz for tone, 0.16–0.45 for decrement, 14.98–47.15 N/m for stiffness, and 0.09–0.17 for creep. Conclusions. MyotonPRO demonstrated acceptable relative and absolute reliability in a ward setting for patients with acute stroke. However, results must be interpreted with caution, due to the varying level of consistency between different muscles, as well as between different parameters within a muscle.

http://ift.tt/2gHfNTz

Extracorporeal Shock Wave Rebuilt Subchondral Bone In Vivo and Activated Wnt5a/Ca2+ Signaling In Vitro

Background. This study aimed to identify the optimal extracorporeal shock wave (ESW) intensity and to investigate its effect on subchondral bone rebuilt in vivo and Wnt5a/Ca2+ signaling in vitro using an osteoarthritis (OA) rat model and bone marrow mesenchymal stem cells (BMMSCs), respectively. Methods. OA rats treated with (OA + ESW group) or without (OA group) ESW (/group) were compared with healthy controls (control group, ). Gait patterns and subchondral trabecular bone changes were measured. Western blot and quantitative real-time polymerase chain reaction detected protein expression and gene transcription, respectively. Results. The gait disturbances of OA + ESW group were significantly improved compared with the OA group at 6th and 8th weeks. The micro-CT analysis indicated that the BMD, BSV/BV, BV/TV, Tr.S, and Tr.Th are significantly different between OA group and OA + ESW group. Expression of Wnt5a was increased rapidly after ESW treatment at 0.6 bar and peaked after 30 min. Conclusions. ESW were positive for bone remodeling in joint tibial condyle subchondral bone of OA rat. ESW prevented histological changes in OA and prevented gait disturbance associated with OA progression. Optimal intensity of ESW induced changes in BMMSCs via activation of the Wnt5a/Ca2+ signaling pathway.

http://ift.tt/2iboxVx

Why does my tongue hurt?

Learn about a number of common causes for tongue pain, including physical injury, thrush, and cold sores, along with treatment options.

http://ift.tt/2kRyYyA

Naturally Occurring Resistance-Associated Variants to Hepatitis C Virus Direct-Acting Antiviral Agents in Treatment-Naive HCV Genotype 6a-Infected Patients

Background and Objective. The direct-acting antiviral agents (DAAs) antiviral therapy has drastically improved the prognosis of hepatitis C virus (HCV) patients. However, the viral drug resistance-associated variants (RAVs) can limit the efficacy of DAAs. For the HCV-6a is not the predominant prevalent genotype; the data on the prevalence of naturally occurring RAVs in it is scarce. Our study aims to assess the prevalence of RAVs in treatment-naive HCV-6a patients. Methods. Nested PCR assays were performed on 95 HCV-6a patients to amplify HCV viral regions of NS3, NS5A, and NS5B. Results. In NS3/4A region, we detected Q80K in 95.5% isolates (84/88) and D168E in 2.3% isolates (2/88). In NS5A region, we detected Q30R in 93.2% isolates (82/88), L31M in 4.6% isolates (4/88), and H58P in 6.8% isolates (6/88). In NS5B region, we detected A15G in 2.3% isolates (2/88), S96T in 1.1% isolates (1/88), and S282T in 20.7% isolates (17/88) and we detected I482L in 100% isolates (4/4), V494A in 50% isolates (2/4), and V499A in 100% isolates (4/4). Conclusions. RAVs to DAAs preexist in treatment-naive HCV-6a patients. Further studies should address the issue of the impact of RAVs in response to DAA therapies for HCV-6a patients.

http://ift.tt/2yiBC61

Potential Anticancer Mechanisms of a Novel EGFR/DNA-Targeting Combi-Molecule (JDF12) against DU145 Prostate Cancer Cells: An iTRAQ-Based Proteomic Analysis

The development of multitargeting drugs is an emerging trend in cancer research. To promote further development and clinical application of multitargeting drugs, this research was performed. MTT assay and flow cytometry of Annexin V/propidium iodide staining were used to confirm the proapoptotic efficacy of a novel combi-targeting molecule, JDF12, against DU145 prostate cancer (PCa) cells. Differentially expressed proteins between control and JDF12-treated cultures were revealed by isobaric tags for relative and absolute quantitation (iTRAQ), and part of them was confirmed by quantitative PCR. Differentially expressed proteins were further analyzed for function, pathway association, and protein−protein interactions using GO, KEGG, and STRING databases. A total of 119 differentially expressed proteins, 70 upregulated and 49 downregulated, were implicated in the anticancer effects of JDF12. Many of these proteins are involved in biosynthesis, response to stress, energy metabolism, and signal transduction. This study provides important information for understanding the anti-PCa mechanisms of JDF12, and well-designed combi-targeting drugs may possess stronger anticancer efficacy than single-targeting drugs and are thus promising candidates for clinical application.

http://ift.tt/2wVSaww

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph-node-positive lung cancer patients

Summary

The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site-specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph-node-positive non-small-cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1–2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1–2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (p = 0.025 and 0.033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (p = 0.040). There was significant difference in OS between two groups according to expressions of CXCR4 in PS and CXCL12 in MLN (p = 0.0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08–3.04, p = 0.023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs. 25%, respectively, p < 0.0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph-node-positive NSCLC patients.

This article is protected by copyright. All rights reserved.

http://ift.tt/2gkygbD

Pyruvate Kinase Isozymes M2 and Glutaminase Might Be Promising Molecular Targets for the Treatment of Gastric Cancer

Abstract

The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and 4 parent cell lines were used. RT-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: pyruvate kinase isozymes M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose-6-phosphate dehydrogenase (G6PDH), and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, Shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all of hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment by Shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either one of the two agents. The in vivo study indicated that the tumor size treated by the combination of Shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors might be therapeutically promising for the treatment of gastric cancer.

This article is protected by copyright. All rights reserved.

http://ift.tt/2ypjabk

Dissection of Factors Affecting the Variability of the Peptide Bond Geometry and Planarity

Proteins frequently assume complex three-dimensional structures characterized by marginal thermodynamic stabilities. In this scenario, deciphering the folding code of these molecular giants with clay feet is a cumbersome task. Studies performed in last years have shown that the interplay between backbone geometry and local conformation has an important impact on protein structures. Although the variability of several geometrical parameters of protein backbone has been established, the role of the structural context in determining these effects has been hitherto limited to the valence bond angle τ (NCαC). We here investigated the impact of different factors on the observed variability of backbone geometry and peptide bond planarity. These analyses corroborate the notion that the local conformation expressed in terms of dihedrals plays a predominant role in dictating the variability of these parameters. The impact of secondary structure is limited to bond angles which involve atoms that are usually engaged in H-bonds and, therefore, more susceptible to the structural context. Present data also show that the nature of the side chain has a significant impact on angles such as NCαCβ and CβCαC. In conclusion, our analyses strongly support the use of variability of protein backbone geometry in structure refinement, validation, and prediction.

http://ift.tt/2giWF1g

Association between Recipient IL-15 Genetic Variant and the Prognosis of HBV-Related Hepatocellular Carcinoma after Liver Transplantation

Objective. To investigate the association of donor and recipient IL-15 genetic variants with HCC recurrence and prognosis after LT. Methods. A total of 112 liver transplant patients with HBV-related HCC were enrolled. IL-15 rs10519613 and rs13122930 were genotyped in donors and recipients. Results. Recipient IL-15 rs10519613 polymorphism was found to be significantly related to HCC recurrence after LT. In multivariate analysis, tumor thrombus, UCSF criteria, and recipient IL-15 rs10519613 genotypes were independent predictive factors of HCC recurrence after LT. Kaplan-Meier survival analysis demonstrated that patients with recipient IL-15 rs10519613 CA/AA genotypes had a decreased disease-free survival and overall survival than those with the CC genotype. Recipient IL-15 rs10519613 genetic variant could improve survival prediction when combined with the UCSF criteria. Furthermore, Cox proportional hazard regression analysis revealed that tumor size (, ), tumor thrombus (, ), UCSF criteria (, ), and recipient IL-15 rs10519613 genotype (, ) were independent factors of predicting DFS and OS. Conclusions. Recipient IL-15 rs10519613 polymorphism was associated with HCC recurrence after LT and might be a potential genetic marker for the clinical outcome of HCC patients treated with LT.

http://ift.tt/2wWTpvC