Publication date: Available online 4 August 2018
Source: Seminars in Spine Surgery
Author(s): Andrew J. Schoenfeld, Christopher M. Bono
https://ift.tt/2OJlFLm
Σάββατο 4 Αυγούστου 2018
Minimally Invasive Conquest to The Lumbar Interbody Space
Publication date: Available online 1 August 2018
Source: Seminars in Spine Surgery
Author(s): Chadi Tannoury
https://ift.tt/2Mj49fz
Lumbar Interbody Fusion: Is it Necessary?
Publication date: Available online 30 July 2018
Source: Seminars in Spine Surgery
Author(s): Alejandro Cazzulino, Comron Saifi, Howard An
Abstract
Lumbar interbody fusion techniques are growing in popularity and they encompass transforaminal, direct lateral, and anterior approaches. Although there is some evidence of superiority of interbody fusions in reducing pseudarthrosis and improving overall surgical outcomes, high-quality data remains lacking.
Furthermore, and irrespective of the given approach, interbody surgeries can pose harm and predispose to certain complications. Careful patient selection is therefore crucial. This manuscript will review the proper indications of interbody fusion in patients with degenerative spondylolisthesis, degenerative scoliosis, isthmic spondylolisthesis, and the role of interbody techniques in achieving successful arthrodesis and deformity correction.
https://ift.tt/2LXYgaJ
Transpsoas Lateral Lumbar Interbody Fusion for Degenerative Spine and Adult Deformity: Surgical Technique and The Evidence
Publication date: Available online 29 July 2018
Source: Seminars in Spine Surgery
Author(s): Comron Saifi, Joseph M. Lombardi, Frank M. Phillips
ABSTRACT
The use of Lateral Lumbar Interbody Fusion (LLIF) initially applied for degenerative lumbar conditions, was expanded to the treatment of degenerative scoliosis as first reported by Phillips and Pimenta in 20051. Since then LLIF has been increasingly applied in the treatment of complex sagittal and coronal plane deformities. This approach can be performed "stand-alone" or in conjunction with posterior open or percutaneous pedicle screw placement. The lateral approach avoids the vascular risks of the anterior lumbar approach and the extensive soft tissue dissection and neural manipulation during a posterior approach. LLIF has been shown to be a safe, effective and low morbidity technique for achieving interbody fusion for a variety of lumbar conditions. LLIF has been shown to facilitate the restoration of disc height, sagittal balance and indirect decompression of neural elements. Injuries to the lumbar plexus have been described with this approach and risks can be reduced with use of real time neural surveillance as well as minimizing the duration of psoas retraction.
https://ift.tt/2Kv76b4
Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients.
Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients.
Cancer Biol Ther. 2018 Aug 01;:1-8
Authors: Omarini C, Bettelli S, Caprera C, Manfredini S, Caggia F, Guaitoli G, Moscetti L, Toss A, Cortesi L, Kaleci S, Maiorana A, Cascinu S, Conte PF, Piacentini F
Abstract
BACKGROUND: HER2+ metastatic breast cancer (MBC) is a poor prognosis disease, unusually curable. To date, no predictive factors have been clearly correlated with long-term response to anti-HER2 agents.
METHODS: 54 HER2+ MBC patients treated with HER2 targeted therapy as first line treatment were analysed: 40 with a time to progression longer than 3 years in Long Responders (LR) group and 14 with a progression disease within one year of anti-HER2 therapy in a control group named Early Progressors (EP). The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on FFPE BC tissues.
RESULTS: Considering baseline patients and tumor characteristics, EP women had more CNS spread and more metastatic burden of disease compared to LR (p > 0.05). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down regulated, all in EP group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways. MAPK pathway was differently expressed between LR and EP (p = 0.05). PI3K was the only pathway overexpressed in EP patients.
CONCLUSIONS: Whole genome expression analysis comparing LR vs. EP identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathway could be a positive predictive factors. Further clinical implications are warranted.
ABBREVIATIONS: BC: breast cancer; MBC: metastatic breast cancer; LR: long responder; EP: early progressor; FFPE: formalin-fixed paraffin-embedded; CNS: central nervous system; PFS: progression free survival; OS: overall survival.
PMID: 30067438 [PubMed - as supplied by publisher]
https://ift.tt/2KjlMdk
Harnessing CRISPR to combat human viral infections.
  | Related Articles |
Harnessing CRISPR to combat human viral infections.
Curr Opin Immunol. 2018 Jul 26;54:123-129
Authors: de Buhr H, Lebbink RJ
Abstract
CRISPR/Cas9 is a technology that allows for targeted and precise genome editing in eukaryotic cells. The technique has changed the landscape of molecular biology and may be applied to repair genetic disorders in future therapies. Besides targeting the human genome, it can be used to cleave and edit viral DNA present in infected cells, and as such provides a promising new strategy for anti-viral therapy. Here, we discuss recent studies on the use of anti-viral CRISPRs to target pathogenic human viruses, with a focus on in vivo studies, challenges, and potential for future clinical applications.
PMID: 30056335 [PubMed - as supplied by publisher]
https://ift.tt/2AiZFUB
Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects.
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Targeting ubiquitin specific protease 7 in cancer: A deubiquitinase with great prospects.
Cell Biochem Funct. 2018 Jul;36(5):244-254
Authors: Yeasmin Khusbu F, Chen FZ, Chen HC
Abstract
Deubiquitinase (DUB)-mediated cleavage of ubiquitin chain balances ubiquitination and deubiquitination for determining protein fate. USP7 is one of the best characterized DUBs and functionally important. Numerous proteins have been identified as potential substrates and binding partners of USP7; those play crucial roles in diverse array of cellular and biological processes including tumour suppression, cell cycle, DNA repair, chromatin remodelling, and epigenetic regulation. This review aims at summarizing the current knowledge of this wide association of USP7 with many cellular processes that enlightens the possibility of abnormal USP7 activity in promoting oncogenesis and the importance of identification of specific inhibitors.
PMID: 29781103 [PubMed - indexed for MEDLINE]
https://ift.tt/2GFSvHQ
Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer.
| Related Articles |
Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer.
Biochim Biophys Acta. 2018 04;1869(2):248-255
Authors: Birnbaum DJ, Bertucci F, Finetti P, Birnbaum D, Mamessier E
Abstract
Clinico-pathological factors fail to consistently predict the outcome after pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). PDACs show a high level of inter- and intra- tumor genetic heterogeneity. A molecular classification should help sort patients into less heterogeneous and more appropriate groups regarding the metastatic risk and the therapeutic response, with the consequences of better predicting evolution and better orienting the treatment. PDAC can be classified based on mutational subtypes and 18gene alterations. Whole-genome sequencing identified mutational signatures, mutational burden and hyper-mutated tumors with specific DNA repair defects. Their overlap/similarities allow the definition of molecular subtypes. DNA and RNA classifications can be used in prognosis assessment. They are useful in therapeutic choice for they allow the design of approaches that can predict the respective drug sensitivity of each molecular subtype. This review provides a comprehensive analysis of available molecular classifications in PDAC and how this can help guide clinical decisions.
PMID: 29499330 [PubMed - indexed for MEDLINE]
https://ift.tt/2F8MWWv
Novel poly-ADP-ribose polymerase inhibitor combination strategies in ovarian cancer.
 | Related Articles |
Novel poly-ADP-ribose polymerase inhibitor combination strategies in ovarian cancer.
Curr Opin Obstet Gynecol. 2018 Feb;30(1):7-16
Authors: McCann KE
Abstract
PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum-sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations. In this review, I describe the rationale behind current PARP combination clinical trials with chemotherapies, angiogenesis inhibitors, cell cycle checkpoint inhibitors, and inhibitors of the phosphoinositide 3-kinase/AK thymoma/mechanistic target of rapamycin pathway.
RECENT FINDINGS: PARP inhibitors have primarily been studied as monotherapy in cancers with homologous recombination repair defects based on an early understanding of PARP-1 as a base excision repair enzyme and the idea that abrogation of two DNA repair pathways cripples rapidly dividing cancer cells. It is now known that PARP-1 is a DNA damage sensor with much wider reaching roles in DNA repair processes and normal cellular functions, opening possibilities for PARP inhibitor use in other clinical contexts.
SUMMARY: PARP inhibitor combination clinical trials are in the early stages, but will deepen our understanding of DNA repair mechanisms, cancer biology, and targeted therapies, thus contributing to the next iteration of therapeutic options for our patients.
PMID: 29251678 [PubMed - indexed for MEDLINE]
https://ift.tt/2Bh5KAU
Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case report of sequential immune checkpoint therapy.
  | Related Articles |
Mismatch repair deficient metastatic colon cancer and urothelial cancer: A case report of sequential immune checkpoint therapy.
Cancer Biol Ther. 2017 Sep 02;18(9):651-654
Authors: Ghatalia P, Nagarathinam R, Cooper H, Geynisman DM, El-Deiry WS
Abstract
A major recent advance in cancer therapy involves the use of immune checkpoint therapy for tumors with mismatch repair deficiency, as they have a high tumor mutation load and neoantigen burden. Approximately 4% of advanced colorectal cancer harbors a mismatch repair deficiency. When mismatch repair deficiency exists in the germline, there is increased susceptibility to a variety of cancers including colorectal cancer, uterine cancer, urothelial carcinoma, and skin cancer. Herein we report the case of a 62-year-old man with mismatch repair deficient metastatic colorectal adenocarcinoma, urothelial carcinoma and a history of sebaceous carcinomas. As the patient in 2016 was ineligible for clinical trials he received immune checkpoint anti-PD-1 therapy with pembrolizumab (200 mg every 3 weeks), on compassionate use basis, after the failure of second-line treatment. The patient's CEA initially responded to pembrolizumab for 4 months and then kept rising for 5 months before mildly declining again. His treatment was then switched to anti-PD-L1 therapy with atezolizumab as it was approved for urothelial carcinoma at that time, and his CEA declined again. This case raises interesting questions about caring for patients with mismatch repair deficient colorectal cancer, including the role of PD-L1 therapy, sequencing of immunotherapy, relying on CEA trends and determining future therapies after progression on pembrolizumab.
PMID: 28726535 [PubMed - indexed for MEDLINE]
https://ift.tt/2uh2M92
Cancer Stem Cell Vaccination With PD-L1 and CTLA-4 Blockades Enhances the Eradication of Melanoma Stem Cells in a Mouse Tumor Model.
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Cancer Stem Cell Vaccination With PD-L1 and CTLA-4 Blockades Enhances the Eradication of Melanoma Stem Cells in a Mouse Tumor Model.
J Immunother. 2018 Jul 30;:
Authors: Zheng F, Dang J, Zhang H, Xu F, Ba D, Zhang B, Cheng F, Chang AE, Wicha MS, Li Q
Abstract
Immune checkpoint inhibitors and monoclonal antibodies reinvigorate cancer immunotherapy. However, these immunotherapies only benefit a subset of patients. We previously reported that ALDH tumor cells were highly enriched for cancer stem cells (CSCs), and ALDH CSC lysate-pulsed dendritic cell (CSC-DC) vaccine was shown to induce CSC-specific cytotoxic T lymphocytes. In this study, we investigated the CSC targeting effect of the CSC-DC vaccine combined with a dual blockade of programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein (CTLA-4) in B16-F10 murine melanoma tumor model. Our data showed that animals treated with the dual blockade of programmed death-ligand 1 and CTLA-4 and CSC-DC vaccine conferred significantly more tumor regression than the CSC-DC vaccine alone. Importantly, the triple combination treatment dramatically eliminated ALDH CSCs in vivo. We observed that CSC-DC vaccine in combination with anti-PD-L1 and anti-CTLA-4 administration resulted in ∼1.7-fold fewer PD-1CD8 T cells and ∼2.5-fold fewer CTLA-4CD8 T cells than the populations observed following the CSC-DC vaccination alone. Moreover, significant antitumor effects and dramatically eliminated ALDH CSCs following the triple combination treatment were accompanied by significantly enhanced T-cell expansion, suppressed transforming growth factor β secretion, enhanced IFN-γ secretion, and significantly enhanced host specific CD8 T-cell response against CSCs. Collectively, these data showed that administration of a-PD-L1 and a-CTLA-4 combined with CSC-DC vaccine may represent an effective immunotherapeutic strategy for cancer patients in clinical.
PMID: 30063587 [PubMed - as supplied by publisher]
https://ift.tt/2LPtNLH
Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines.
 | Related Articles |
Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines.
Genome Med. 2018 Jul 27;10(1):59
Authors: Scepanovic P, Alanio C, Hammer C, Hodel F, Bergstedt J, Patin E, Thorball CW, Chaturvedi N, Charbit B, Abel L, Quintana-Murci L, Duffy D, Albert ML, Fellay J, Milieu Intérieur Consortium
Abstract
BACKGROUND: Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that human genetic variation influences (i) serum immunoglobulin levels, (ii) seroconversion rates, and (iii) intensity of antigen-specific immune responses. Here, we evaluated the impact of intrinsic (age and sex), environmental, and genetic factors on the variability of humoral response to common pathogens and vaccines.
METHODS: We characterized the serological response to 15 antigens from common human pathogens or vaccines, in an age- and sex-stratified cohort of 1000 healthy individuals (Milieu Intérieur cohort). Using clinical-grade serological assays, we measured total IgA, IgE, IgG, and IgM levels, as well as qualitative (serostatus) and quantitative IgG responses to cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1 and 2, varicella zoster virus, Helicobacter pylori, Toxoplasma gondii, influenza A virus, measles, mumps, rubella, and hepatitis B virus. Following genome-wide genotyping of single nucleotide polymorphisms and imputation, we examined associations between ~ 5 million genetic variants and antibody responses using single marker and gene burden tests.
RESULTS: We identified age and sex as important determinants of humoral immunity, with older individuals and women having higher rates of seropositivity for most antigens. Genome-wide association studies revealed significant associations between variants in the human leukocyte antigen (HLA) class II region on chromosome 6 and anti-EBV and anti-rubella IgG levels. We used HLA imputation to fine map these associations to amino acid variants in the peptide-binding groove of HLA-DRβ1 and HLA-DPβ1, respectively. We also observed significant associations for total IgA levels with two loci on chromosome 2 and with specific KIR-HLA combinations.
CONCLUSIONS: Using extensive serological testing and genome-wide association analyses in a well-characterized cohort of healthy individuals, we demonstrated that age, sex, and specific human genetic variants contribute to inter-individual variability in humoral immunity. By highlighting genes and pathways implicated in the normal antibody response to frequently encountered antigens, these findings provide a basis to better understand disease pathogenesis.
TRIALS REGISTRATION: ClinicalTrials.gov , NCT01699893.
PMID: 30053915 [PubMed - in process]
https://ift.tt/2MhsZMJ
Complement C3 Plays a Key Role in Inducing Humoral and Cellular Immune Responses to Influenza Virus Strain Specific HA or Cross Protective M2e vaccination.
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Complement C3 Plays a Key Role in Inducing Humoral and Cellular Immune Responses to Influenza Virus Strain Specific HA or Cross Protective M2e vaccination.
J Virol. 2018 Aug 01;:
Authors: Kim YJ, Kim KH, Ko EJ, Kim MC, Lee YN, Jung YJ, Lee YT, Kwon YM, Song JM, Kang SM
Abstract
The complement pathway is involved in eliminating antigen immune complexes. However, the role of the C3 complement system remains largely unknown in influenza virus M2 extracellular (M2e) domain or hemagglutinin (HA) vaccine-mediated protection after vaccination. Using a C3 knockout (C3 KO) mouse model, we found that complement protein C3 was required for effective induction of immune responses to vaccination with M2e-based or HA-based vaccines, which include isotype class-switched antibodies and effector CD4 and CD8 T cell responses. C3 KO mice after active immunization with cross protective non-neutralizing M2e-based vaccine were not protected against influenza virus although low levels of M2e specific antibodies were protective after passive co-administration with virus in wild type mice. In contrast, C3 KO mice that were immunized with strain-specific neutralizing HA-based vaccine were protected against homologous virus challenge despite lower levels of HA antibody responses. C3 KO mice showed impaired maintenance of innate immune cells and a defect in innate immune responses upon exposure to antigens. The findings in this study suggest that C3 is required for effective induction of humoral and cellular adaptive immune responses as well as protective immunity after non-neutralizing influenza M2e vaccination.IMPORTANCEComplement is the well-known innate immune defense system by involving in the opsonization and lysis of pathogens but less studied in establishing adaptive immunity after vaccination. Influenza virus HA-based vaccination confers protection via strain-specific neutralizing antibodies whereas M2e-based vaccination induces a broad spectrum of protection by immunity against the conserved M2e epitopes. This study revealed the critical roles of C3 complement in inducing humoral and cellular immune responses after immunization with M2e or HA vaccines. C3 was found to be required for protection by M2e-based but not by HA-based active vaccination as well as for maintaining innate antigen presenting cells. Findings in this study have insight into better understanding the roles of C3 complement in inducing effective innate and adaptive immunity as well as in conferring protection by cross protective conserved M2e vaccination.
PMID: 30068650 [PubMed - as supplied by publisher]
https://ift.tt/2Mk7haM
Immunotherapeutic strategies for treatment of hepatocellular carcinoma with antigen-loaded dendritic cells: in vivo study.
 | Related Articles |
Immunotherapeutic strategies for treatment of hepatocellular carcinoma with antigen-loaded dendritic cells: in vivo study.
Clin Exp Med. 2018 Jul 30;:
Authors: El-Ashmawy NE, El-Zamarany EA, Khedr EG, El-Bahrawy HA, El-Feky OA
Abstract
Hepatocellular carcinoma (HCC) is one of the major health problems in the world. DCs-based vaccines are a promising immunotherapeutic strategy that aims at the optimal for induction of a specific antitumor immune response and destruction of tumor cells. The present study was conducted to investigate the immunogenic characters of whole tumor lysate-pulsed DCs vaccine and its ability to induce a specific antitumor immune response in HCC mice model. We also evaluate the effectiveness of prophylactic and therapeutic immunization strategies against HCC in mice models. Mice-derived DCs were in vitro loaded with whole tumor lysate prepared from liver tissue of HCC mice and evaluated for expression of surface maturation markers CD83 and CD86. In vivo immunization of mice with whole tumor lysate-pulsed DCs was performed in two strategies; prophylactic (pre-exposure to HCC) and therapeutic (post-exposure to HCC). Effectiveness of both protocols was investigated in terms of histopathological examination of liver sections and measurement of serum levels of immune cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2). Loading of DCs with whole tumor cell lysate exhibited a significant increase in expression of CD83 and CD86. In vivo administration of prophylactic doses of whole tumor lysate-pulsed DCs in mice before induction of HCC evokes a strong antitumor immune response presented by absence of malignant cells in liver sections and the significant increase in IFN-γ and IL-2. Data herein indicated that prophylactic vaccination with whole tumor lysate-pulsed DCs exhibited an effective antitumor immune response against HCC more than therapeutic protocol.
PMID: 30062618 [PubMed - as supplied by publisher]
https://ift.tt/2MiwzWQ
The differences in immunoadjuvant mechanisms of TLR3 and TLR4 agonists on the level of antigen-presenting cells during immunization with recombinant adenovirus vector.
| | Related Articles |
The differences in immunoadjuvant mechanisms of TLR3 and TLR4 agonists on the level of antigen-presenting cells during immunization with recombinant adenovirus vector.
BMC Immunol. 2018 Jul 28;19(1):26
Authors: Lebedeva E, Bagaev A, Pichugin A, Chulkina M, Lysenko A, Tutykhina I, Shmarov M, Logunov D, Naroditsky B, Ataullakhanov R
Abstract
BACKGROUND: Agonists of TLR3 and TLR4 are effective immunoadjuvants for different types of vaccines. The mechanisms of their immunostimulatory action differ significantly; these differences are particularly critical for immunization with non-replicating adenovirus vectors (rAds) based vaccines. Unlike traditional vaccines, rAd based vaccines are not designed to capture vaccine antigens from the external environment by antigen presenting cells (APCs), but rather they are targeted to the de novo synthesis of vaccine antigens in APCs transfected with rAd. To date, there is no clear understanding about approaches to improve the efficacy of rAd vaccinations with immunoadjuvants. In this study, we investigated the immunoadjuvant effect of TLR3 and TLR4 agonists on the level of activation of APCs during vaccination with rAds.
RESULTS: We demonstrated that TLR3 and TLR4 agonists confer different effects on the molecular processes in APCs that determine the efficacy of antigen delivery and activation of antigen-specific CD4+ and CD8+ T cells. APCs activated with agonists of TLR4 were characterized by up-regulated production of target antigen mRNA and protein encoded in rAd, as well as enhanced expression of the co-activation receptors CD80, CD86 and CD40, and pro-inflammatory cytokines TNF-α, IL6 and IL12. These effects of TLR4 agonists have provided a significant increase in the number of antigen-specific CD4+ and CD8+ T cells. TLR3 agonist, on the contrary, inhibited transcription and synthesis of rAd-encoded antigens, but improved expression of CD40 and IFN-β in APCs. The cumulative effect of TLR3 agonist have resulted in only a slight improvement in the activation of antigen-specific T cells. Also, we demonstrated that IFN-β and TNF-α, secreted by APCs in response to TLR3 and TLR4 agonists, respectively, have an opposite effect on the transcription of the targeted gene encoded in rAd. Specifically, IFN-β inhibited, and TNF-α stimulated the expression of target vaccine antigens in APCs.
CONCLUSIONS: Our data demonstrate that agonists of TLR4 but not TLR3 merit further study as adjuvants for development of vaccines based on recombinant adenoviral vectors.
PMID: 30055563 [PubMed - in process]
https://ift.tt/2vg4LMw
Dual-route targeted vaccine protects efficiently against botulinum neurotoxin A complex.
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Dual-route targeted vaccine protects efficiently against botulinum neurotoxin A complex.
Vaccine. 2018 01 02;36(1):155-164
Authors: Sahay B, Colliou N, Zadeh M, Ge Y, Gong M, Owen JL, Valletti M, Jobin C, Mohamadzadeh M
Abstract
Clostridium botulinum readily persists in the soil and secretes life-threatening botulinum neurotoxins (BoNTs) that are categorized into serotypes A to H, of which, serotype A (BoNT/A) is the most commonly occurring in nature. An efficacious vaccine with high longevity against BoNT intoxication is urgent. Herein, we developed a dual-route vaccine administered over four consecutive weeks by mucosal and parenteral routes, consisting of the heavy chain (Hc) of BoNT/A targeting dendritic cell peptide (DCpep) expressed by Lactobacillus acidophilus as a secretory immunogenic protein. The administered dual-route vaccine elicited robust and long-lasting memory B cell responses comprising germinal center (GC) B cells and follicular T cells (Tfh) that fully protected mice from lethal oral BoNT/A fatal intoxication. Additionally, passively transferring neutralizing antibodies against BoNT/A into naïve mice induced robust protection against BoNT/A lethal intoxication. Together, a targeted vaccine employing local and systemic administrative routes may represent a novel formulation eliciting protective B cell responses with remarkable longevity against threatening biologic agents such as BoNTs.
PMID: 29180028 [PubMed - indexed for MEDLINE]
https://ift.tt/2vg4GII
In vivo electroporation enhances vaccine-mediated therapeutic control of human papilloma virus-associated tumors by the activation of multifunctional and effector memory CD8+ T cells.
| Related Articles |
In vivo electroporation enhances vaccine-mediated therapeutic control of human papilloma virus-associated tumors by the activation of multifunctional and effector memory CD8+ T cells.
Vaccine. 2017 12 19;35(52):7240-7249
Authors: Sales NS, Silva JR, Aps LRMM, Silva MO, Porchia BFMM, Ferreira LCS, Diniz MO
Abstract
In vivo electroporation (EP) has reignited the clinical interest on DNA vaccines as immunotherapeutic approaches to control different types of cancer. EP has been associated with increased immune response potency, but its capacity in influencing immunomodulation remains unclear. Here we evaluated the impact of in vivo EP on the induction of cellular immune responses and therapeutic effects of a DNA vaccine targeting human papillomavirus-induced tumors. Our results demonstrate that association of EP with the conventional intramuscular administration route promoted a more efficient activation of multifunctional and effector memory CD8+ T cells with enhanced cytotoxic activity. Furthermore, EP increased tumor infiltration of CD8+ T cells and avoided tumor recurrences. Finally, our results demonstrated that EP promotes local migration of antigen presenting cells that enhances with vaccine co-delivery. Altogether the present evidences shed further light on the in vivo electroporation action and its impact on the immunogenicity of DNA vaccines.
PMID: 29174677 [PubMed - indexed for MEDLINE]
https://ift.tt/2O9OsYs
Insecticide Resistance Associated with kdr Mutations in Aedes albopictus: An Update on Worldwide Evidences
Insecticide resistance is an increasing problem worldwide that limits the efficacy of control methods against several pests of health interest. Among them, Aedes albopictus mosquitoes are efficient vectors of relevant pathogens causing animal and human diseases worldwide, including yellow fever, chikungunya, dengue, and Zika. Different mechanisms are associated in conferring resistance to chemical insecticides. One of the most widespread and analysed mechanisms is the knockdown resistance (kdr) causing resistance to DDT and pyrethroids. The mechanism is associated with mutations in the voltage sensitive sodium channel, which is involved in beginning and propagation of action potentials in nervous cells. The mechanism was originally discovered in the housefly and then it was found in a large number of arthropods. In 2011, a kdr associated mutation was evidenced for the first time in A. albopictus and afterward several evidences were reported in the different areas of the world, including China, USA, Brazil, India, and Mediterranean Countries. This review aims to update and summarize current evidences on kdr in A. albopictus, in order to stimulate further researches to analyse in depth A. albopictus resistance status across the world, especially in countries where the presence of this vector is still an emerging issue. Such information is currently needed given the well-known vector role of A. albopictus in the transmission of severe infectious diseases. Furthermore, the widespread use of chemical insecticides for control strategies against A. albopictus progressively lead to pressure selection inducing the rise of insecticide resistance-related mutations in the species. Such event is especially evident in some countries as China, often related to a history of uncontrolled use of chemical insecticides. Thus, a careful picture on the diffusion of kdr mutations worldwide represents a milestone for the implementation of control plans and the triggering of novel research on alternative strategies for mosquito-borne infections.
https://ift.tt/2vFMW8M
Particle Disposition in the Realistic Airway Tree Models of Subjects with Tracheal Bronchus and COPD
Dispositions of inhalable particles in the human respiratory tract trigger and exacerbate airway inflammatory diseases. However, the particle deposition (PD) in airway of subjects with tracheal bronchus (TB) and chronic obstructive pulmonary diseases (COPD) is unknown. We therefore propose to clarify the disrupted PD associated with TB and COPD using the computational fluid dynamics (CFD) simulation. Totally nine airway tree models are included. Six are extracted from CT images of different individuals (two with TB, two with COPD, and two healthy controls (HC)). The others are the artificially modified models (AMMs) generated by the virtual lesion. Specifically, they are constructed through artificially adding a tracheal bronchus or a stenosis on one HC model. The deposition efficiency (DE) and deposition fraction (DF) in these models are obtained by the Euler-Lagrange approach, analyzed, and compared across models, locations, and particle sizes (0.1-10.0 micrometers). It is found that the PD in models with TB and COPD has been disrupted by the geometrical changes and followed airflow alternations. DE of the tracheal bronchus is higher for TB models. For COPD, the stenosis location determines the effects on DE and DF. Higher DF at the trachea is observed in TB1, TB2, and COPD2 models. DE increases with the particle size, and DE of the terminal bronchi is higher than that of central regions. Combined with AMMs, the CFD simulation using realistic airway models demonstrates disruptions of DP. The methods and findings might help understand the etiology of pulmonary diseases and improve the efficacy of inhaled medicines.
https://ift.tt/2LRgV8X
Translation and Evaluation of a Lung Cancer, Palliative Care Intervention for Community Practice
A notable gap in the evidence-base for palliative care (PC) for cancer is that most trials were conducted in specialized centers with limited translation and further evaluation in "real-world" settings. Health systems are desperate for guidance on effective, scalable models.
https://ift.tt/2AHseuT
Complementary and Alternative Medicine in Hospice and Palliative Care: A Systematic Review
The aim of palliative care is to improve quality of life for patients with serious illnesses by treating their symptoms and adverse effects. Hospice care also aims for this for patients with a life expectancy of six months or less. When conventional therapies do not provide adequate symptom management or produce their own adverse effects, patients, families and caregivers may prefer complementary or alternative approaches in their care.
https://ift.tt/2OKNwuT
Assessing symptoms, concerns and quality of life in non-cancer patients at end of life: How concordant are patients and family proxy members?
It has become commonplace to use family caregivers as proxy responders where patients are unable to provide information about their symptoms and concerns to health care providers.
https://ift.tt/2AIbsfl
Mechanism of action of vedolizumab: do we really understand it?
For many years, physicians had only antitumour necrosis factor (anti-TNF) antibodies as biologicals for the treatment of IBD. With the regulatory approval of vedolizumab, a completely new mechanism of action was introduced into the therapeutic armamentarium of IBD specialists: vedolizumab is an 'integrin antagonist' binding to the α4β7 integrin expressed on the surface of mononuclear cells such as T-lymphocytes.1 Circulating blood T-cells require binding of α4β7 integrin to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by the endothelial cells of the GI tract to be able to migrate into the mucosal layers.1 To prevent the migration of inflammatory mononuclear cells into the inflamed mucosa in patients with IBD, integrin antagonists have been developed. Several antagonists of integrin–adhesion molecule interactions are approved or under clinical development targeting either the α4β7 integrin heterodimer, the α4 integrin, the β7 integrin or MAdCAM-1 (such as etrolizumab, a β7 integrin antibody; and...
https://ift.tt/2LRYnVW
{beta}-catenin oncogenic activation rewires fatty acid catabolism to fuel hepatocellular carcinoma
Liver cancer is a major public health issue and generally considered an inflammation-related cancer developing in response to genotoxic exposure or in patients with viral, alcoholic or non-alcoholic hepatitis. It is a leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) representing 90% of primary liver cancer cases. Various pathways are dysregulated in HCC, including p53 and other cell cycle regulators, chromatin modifiers, oxidative stress, insulin and growth factor signalling, and Wnt/β-catenin signalling. In this issue, Senni and colleagues1 demonstrate the role of fatty acid oxidation as a source of energy in the metabolic adaptation triggered by β-catenin oncogenic activation in hepatocytes. This work describes an atypical cancer cell addiction to fatty acids and represents an important discovery that may pave the way for novel therapeutics.
The Wnt/β-catenin pathway2 plays a key role in many aspects of hepatic homeostasis, including the regulation of unique liver features,...
https://ift.tt/2vAbdgr
Automated, Long-term Behavioral Assay for Cognitive Functions in Multiple Genetic Models of Alzheimer's Disease, Using IntelliCage
https://ift.tt/2vkMVrs
Where You Cut Matters: A Dissection and Analysis Guide for the Spatial Orientation of the Mouse Retina from Ocular Landmarks
This protocol provides a comprehensive dissection and analysis guide for the use of deep ocular landmarks, s-opsin immunohistochemistry, Retistruct, and custom code to accurately and reliably orient the isolated mouse retina in anatomical space.
https://ift.tt/2Oau6yc
Multimodal Volumetric Retinal Imaging by Oblique Scanning Laser Ophthalmoscopy (oSLO) and Optical Coherence Tomography (OCT)
Here, we present a protocol to get a large field of view (FOV) three-dimensional (3D) fluorescence and OCT retinal image by using a novel imaging multimodal platform. We will introduce the system setup, the method of alignment, and the operational protocols. In vivo imaging will be demonstrated, and representative results will be provided.
https://ift.tt/2vi2zUr
Antimicrobial Characterization of Advanced Materials for Bioengineering Applications
We present a protocol for the antimicrobial characterization of advanced materials. Here, the antimicrobial activity on material surfaces is measured by two methods that complement each other: one is based on the agar disk diffusion test, and the other is a standard procedure based on the ISO 22196:2007 norm.
https://ift.tt/2vfpVdu
The Plant Infection Test: Spray and Wound-Mediated Inoculation with the Plant Pathogen Magnaporthe Grisea
https://ift.tt/2AHLpF4
Characteristics and outcome of patients with newly diagnosed advanced or metastatic lung cancer admitted to intensive care units (ICUs)
Although patients with advanced or metastatic lung cancer have poor prognosis, admission to the ICU for management of life-threatening complications has increased over the years. Patients with newly diagnosed ...
https://ift.tt/2naZd16
Assessment of Plasma Coagulation on Liver Tissue in a Large Animal Model In Vivo
https://ift.tt/2ARJKgr
A Soft Tooling Process Chain for Injection Molding of a 3D Component with Micro Pillars
A protocol for fabricating injection molding inserts for complex geometry with micro features on surfaces employing Additive Manufacturing (AM) is presented.
https://ift.tt/2vhMChc
A Targeted Literature Review Examining Biologic Therapy Compliance and Persistence in Chronic Inflammatory Diseases to Identify the Associated Unmet Needs, Driving Factors, and Consequences
Abstract
Chronic inflammatory diseases (CIDs) represent a substantial clinical and economic burden to patients, providers, payers and society overall. Biologics, such as tumor necrosis factor inhibitors (TNFi), have emerged as effective treatment options for patients with CIDs. However, the therapeutic potential of biologics is not always achieved in clinical practice, with results from studies examining the use of biologics in real-world settings suggesting lower levels of treatment effectiveness compared with clinical trial results. Using a targeted approach, this literature review demonstrates that compliance and persistence with biologic therapy is suboptimal and that this has implications for both clinical outcomes and treatment costs. The review identified a variety of predictors of treatment compliance and persistence, including increased age, female gender, presence of comorbidities, increased disease activity, longer disease duration, smoking, increased body mass index, higher biologic treatment dose, higher treatment cost and lower health-related quality-of-life scores. Patients often cited factors associated with medication delivery as a reason for non-compliance and non-persistence, and device-related improvements to treatment delivery were associated with higher rates of compliance and persistence. The articles identified in this review provide insights that have the potential to help guide the development of new solutions to improve disease management and optimize treatment regimens. This has the potential to benefit patients' health by improving clinical outcomes and to reduce the burden to society by limiting the economic impact of patients' disease.
Funding
UCB Pharma.
https://ift.tt/2M3M7AS
A New Automatically Fixating Stone Basket (2.5 F) Prototype with a Nitinol Spring for Accurate Ureteroscopic Stone Size Measurement
Abstract
Introduction
Intraoperative assessment of stone size is crucial for the successful and safe extraction of stones. The first automatically fixating measuring stone basket prototype showed a mismatch between the steel spring and the nitinol basket; therefore, to improve this prototype, the steel spring was replaced with a nitinol spring and a modified scale was implemented on the basket handle for accurate intraoperative stone size measurement.
Methods
The proposed tipped basket was composed of nitinol. A standard handle with a spring-supported self-closing mechanism (2.5 F, Urotech®) was used, and a modified nonlinear millimeter scale was established on the handle. The grasping force was provided by the new nitinol spring mechanism in the handgrip. Various colors associated with the stone size were applied on the scale.
Results
The material difference between the basket and the spring was eliminated. The measuring scale ranged from 2 mm (green) through 5 mm (yellow) to 8 mm (red), and the scale was nonlinear because of the nonlinear relationship between the diameter of the stone and the distance marked on the scale.
Conclusion
The proposed automatically fixating stone basket with a nitinol spring has the potential to improve the safety and effectiveness of endourological stone retrieval. Further validation of this new scale and basket should follow.
https://ift.tt/2MkQFzI
12-Month Outcomes of Goniotomy Performed Using the Kahook Dual Blade Combined with Cataract Surgery in Eyes with Medically Treated Glaucoma
Abstract
Introduction
To describe the 12-month efficacy and safety of goniotomy performed using the Kahook Dual Blade (KDB) in combination with cataract surgery in eyes with medically treated open-angle glaucoma (OAG).
Methods
This was a prospective, interventional case series conducted at seven centers in North America. Consecutive patients with medically treated OAG and visually significant cataract underwent phacoemulsification combined with goniotomy (PE + goniotomy) using KDB. Indications for glaucoma surgery included reduction of intraocular pressure (IOP) and reduction of IOP-lowering medications. De-identified data were collected and included pre-, intra-, and postoperative data on IOP, the use of IOP-lowering medications, and adverse events through 12 months of follow-up.
Results
Among 52 eyes undergoing surgery, mean IOP was reduced from 16.8 ± 0.6 mmHg at baseline to 12.4 ± 0.3 mmHg at month 12 (P < 0.001), a 26.2% reduction. Mean IOP across time points ranged from 12.4–13.3 mmHg during follow-up. The mean number of topical IOP-lowering medications was reduced from 1.6 ± 0.2 at baseline to 0.8 ± 0.1 at month 12 (P < 0.05), a 50.0% reduction. At month 12, 57.7% of eyes had IOP reduction ≥ 20% from baseline, and 63.5% were on ≥ 1 fewer IOP-lowering medications. In subgroup analysis, 84.6% of eyes with lower mean baseline IOP were using ≥ 1 fewer medications at month 12, and 100% of eyes with higher mean baseline IOP had IOP reductions ≥ 20%. The most common postoperative adverse events were pain/irritation (n = 4, 7.7%), opacification of the posterior lens capsule (n = 2, 3.8%), and IOP spike > 10 mmHg (n = 2, 3.8%).
Conclusion
PE + goniotomy using the KDB significantly lowers both IOP and dependence on IOP-lowering medications in eyes with OAG. Adverse events were not sight-threatening and typically resolved spontaneously.
Funding
New World Medical, Inc.
https://ift.tt/2LZQqxb
The knowns and unknowns of boredom: a review of the literature
Abstract
Despite the ubiquitous nature of boredom, the definition, function, and correlates of boredom are still poorly understood. In this review, we summarize the "known" (consistent evidence) and "unknown" (inconsistent evidence) correlates of boredom. We show that boredom is consistently related to negative affect, task-unrelated thought, over-estimation of elapsed time, reduced agency, as well as to over- and under-stimulation. Activation of the default mode network was consistent across the few available fMRI studies, while the recruitment of other brain areas such as the hippocampus and anterior insular cortex, was a notable but less consistent correlate of boredom. Other less consistent correlates of boredom are also reviewed, such as the level of arousal and the mental attributions given to fluctuations of attention. Finally, we identify two critical factors that may contribute to current inconsistencies in the literature and may hamper further progress in the field. First, there is relatively little consistency in the way in which boredom has been operationalized across studies to date, with operationalizations of boredom ranging from negative affect paired with under-stimulation, over-stimulation, to negative affect paired with a lack of goal-directed actions. Second, preliminary evidence suggests the existence of distinct types of boredom (e.g., searching vs. apathetic) that may have different and sometimes even opposing correlates. Adopting a more precise and consistent way of operationalizing boredom, and arriving at an empirically validated taxonomy of different types of boredom, could serve to overcome the current roadblocks to facilitate further progress in our scientific understanding of boredom.
https://ift.tt/2vAbos9
Does state boredom cause failures of attention? Examining the relations between trait boredom, state boredom, and sustained attention
Abstract
Boredom is an important personal and social problem, but the phenomena itself remains poorly understood. Recent work has shown that boredom is highly related to attention, and that this relationship may be instrumental in revealing boredom's causes and consequences. In this paper, experimental findings on trait boredom, state boredom, and sustained attention performance are presented. We demonstrate that trait boredom uniquely predicts sustained attention performance, over and above depression and self-report attention problems. We also present exploratory findings consistent with the claim that attention failures may cause boredom and that sustained attention tasks may themselves be boring. Discussion of each of these findings, and potential ramifications for cognitive research as a whole, is included.
https://ift.tt/2vzhauj
The troubling science of neurophenomenology
Abstract
Researchers suggest links between mind-wandering and impaired processing of external task stimuli: mind-wandering results in perceptual decoupling. The primary methodology employed to investigate the effects of mind-wandering requires people to report their conscious state and then predicts prior behavior or neurophysiological responses using the person's self-report. Unfortunately, this method employs reports that occur after the behavior occurs. An alternative methodology employs a word displayed prior to a performance check or catch trial. After the catch trial, participants then report their awareness of the word occurring, attempt to recognize the word, and also report whether they were on- or off-task. We show that participants' explicit and implicit awareness of the pre-catch trial word is independent of self-reports of conscious state. This finding conflicts with the perspective that mind-wandering reports indicate perceptual decoupling. Reports of mind-wandering may alternatively be how people explain behavioral outcomes.
https://ift.tt/2LQuu8k
Correction to: Postural responses to target jumps and background motion in a fast pointing task
The original publication of this paper contained an error. The background motion speeds were actually 20 and 60 cm/s instead of the 2 and 6 cm/s mentioned in the paper (also in figures). It does not affect any of the results, interpretation or conclusion.
https://ift.tt/2vET1SU
How do we decide what to do? Resting-state connectivity patterns and components of self-generated thought linked to the development of more concrete personal goals
Abstract
Human cognition is not limited to the available environmental input but can consider realities that are different to the here and now. We describe the cognitive states and neural processes linked to the refinement of descriptions of personal goals. When personal goals became concrete, participants reported greater thoughts about the self and the future during mind-wandering. This pattern was not observed for descriptions of TV programmes. Connectivity analysis of participants who underwent a resting-state functional magnetic resonance imaging scan revealed neural traits associated with this pattern. Strong hippocampal connectivity with ventromedial pre-frontal cortex was common to better-specified descriptions of goals and TV programmes, while connectivity between hippocampus and the pre-supplementary motor area was associated with individuals whose goals were initially abstract but became more concrete over the course of the experiment. We conclude that self-generated cognition that arises during the mind-wandering state can allow goals to be refined, and this depends on neural systems anchored in the hippocampus.
https://ift.tt/2LOMLmB
Exploring the relationship between boredom proneness and self-control in traumatic brain injury (TBI)
Abstract
Characterized as an agitated state in which the individual is motivated to engage in their environment but all attempts to do so fail to satisfy, boredom represents a disengaged attentional state that is associated with negative affect and poor self-control. There have been anecdotal reports of increased levels of boredom post-traumatic brain injury (TBI). For the first time, we provide objective evidence that TBI patients do indeed experience higher levels of boredom proneness. Hierarchical regression analyses showed that the presence and severity of head injury were a significant positive predictor of levels of boredom proneness and a negative predictor of self-control. As with healthy controls, TBI patients showed a strong negative correlation between boredom proneness and self-control—those with lower levels of self-control exhibited higher levels of boredom proneness. This was despite the fact that our TBI patients reported higher overall levels of self-control (probably concomitant with their older mean age). The TBI patients also showed strong positive correlations between boredom proneness and measures of physical aggression and anger. Together, this suggests that patients with TBI may be more susceptible to increased levels of boredom proneness and other negative affective states that arise as a consequence of failures of self-control.
https://ift.tt/2vAb9gJ
Reduced mind wandering in experienced meditators and associated EEG correlates
Abstract
One outstanding question in the contemplative science literature relates to the direct impact of meditation experience on the monitoring of internal states and its respective correspondence with neural activity. In particular, to what extent does meditation influence the awareness, duration and frequency of the tendency of the mind to wander. To assess the relation between mind wandering and meditation, we tested 2 groups of meditators, one with a moderate level of experience (non-expert) and those who are well advanced in their practice (expert). We designed a novel paradigm using self-reports of internal mental states based on an experiential sampling probe paradigm presented during ~1 h of seated concentration meditation to gain insight into the dynamic measures of electroencephalography (EEG) during absorption in meditation as compared to reported mind wandering episodes. Our results show that expert meditation practitioners report a greater depth and frequency of sustained meditation, whereas non-expert practitioners report a greater depth and frequency of mind wandering episodes. This is one of the first direct behavioral indices of meditation expertise and its associated impact on the reduced frequency of mind wandering, with corresponding EEG activations showing increased frontal midline theta and somatosensory alpha rhythms during meditation as compared to mind wandering in expert practitioners. Frontal midline theta and somatosensory alpha rhythms are often observed during executive functioning, cognitive control and the active monitoring of sensory information. Our study thus provides additional new evidence to support the hypothesis that the maintenance of both internal and external orientations of attention may be maintained by similar neural mechanisms and that these mechanisms may be modulated by meditation training.
https://ift.tt/2LU5XPV
Boredom, sustained attention and the default mode network
Abstract
Boredom is a ubiquitous human experience that can best be described as an inability to engage with one's environment despite the motivation to do so. Boredom is perceived as a negative experience and demonstrates strong associations with other negatively valenced states including depression and aggression. Although boredom has been shown to be elevated in neurological and psychiatric illnesses, little is known about the neural underpinnings of the state. We scanned the brains of healthy participants under four separate conditions: a resting state scan, a sustained attention task and two video-based mood inductions, one known to produce boredom and another we validated to produce a state of interest or engagement. Using independent components analyses, results showed common regions of correlated activation in posterior regions of the so-called default mode network (DMN) of the brain across all four conditions. The sustained attention and boredom induction scans were differentiated from the resting state scan by the presence of anticorrelated activity—i.e. when DMN regions were active, this region was deactivated—in the anterior insula cortex. This same region demonstrated correlated activity with both the DMN and the regions associated with attentional control during the interest mood induction. We interpret these findings to suggest that boredom represents a failure to engage executive control networks when faced with a monotonous task—in other words, when the task demands some level of engagement (watch the movie, search for infrequent targets), but is so mundane that attempts to do so fail.
https://ift.tt/2vD1dDn
Analysis and treatment of 45 platinum-allergic gynecologic malignant tumors
Abstract
Background
This study aimed to explore the potential risk factors of platinum allergy and follow-up treatment to provide a reference for the clinical prevention and treatment of platinum allergic reactions in patients with gynecological tumors.
Methods
The study retrospectively analyzed 45 cases of platinum allergic reactions that occurred in Shengjing Hospital affiliated to China Medical University from August 2010 to July 2016. Analysis of risk factors included the cumulative dose, treatment course and time intervals.
Results
The cumulative carboplatin dose in allergic patients ranged from 900 to 10250 mg (average 4845 mg). The 45 allergic reactions occurred between the 3rd and 25th course of treatment (average 11.4 courses). The average re-treatment interval of carboplatin-allergic patients was 28.1 months, including 93.3% of patients with platinum re-treatment interval of more than 1 year. The allergic reaction occurred in the 2nd or 3rd course of re-treatment in 26 patients, accounting for 70.3% of all patients with recurrence. Seventeen patients were subjected to desensitization therapy, among which 13 cases were well tolerated.
Conclusions
Patients who received more than 8 courses of carboplatin or a cumulative dose of more than 3500 mg were the high-risk population for platinum allergy. The 2nd and 3rd treatment course after restarting carboplatin treatment after an interval time of more than 1 year was the high incident period of carboplatin allergy. Skin tests should be conducted in patients with high risk of carboplatin allergy. In cases of carboplatin allergy, patients could receive carboplatin or oxaliplatin desensitization therapy.
https://ift.tt/2Mj3ISk
Dual intestinal anomalies in dizygotic twins
We report on the case of two digestive malformations in dizygotic/dichorionic/diamniotic twins born at 31 weeks of gestation. The mother (gravida 1 para 0) was treated by hydroxychloroquine for systemic lupus erythematosus during pregnancy. Twin A presented an arch-like dilatation on antenatal ultrasounds, characteristic of segmental volvulus. After birth, twin B presented repeated vomiting on feeding, leading us to diagnose ileal atresia despite normal antenatal ultrasounds. Both twins underwent surgery and the postoperative period was uneventful. After 1 year of follow-up, the twins are in excellent health without digestive sequelae. Genetic testing for cystic fibrosis was negative. The placenta showed diffuse signs of hypoxia and ischaemia, indicating that the root cause was vascular. The pathophysiology of intestinal atresia is hypothesised to derive from a vascular incident during fetal development. We are therefore led to believe that an intrauterine vascular event is the most likely cause of the dual malformation.
https://ift.tt/2LR3t4W
Embolic stroke, left atrial myxoma and gigantism in a patient with Carney complex with additional features suggestive of Marfan syndrome
A 16-year-old boy presented to the emergency department with a sudden weakness on the right side of the body and was diagnosed as having embolic stroke. Later on, the patient was diagnosed as having Carney complex (CNC). The neurological complication might be caused by left atrial myxoma as a feature of CNC. Surprisingly, the patient showed some additional features such as positive wrist and thumb signs, pectus carinatum deformity and plain flat feet, suggestive of Marfan syndrome. This case demonstrated that both of these syndromes might coexist in the same patient, suggesting that proper diagnostic and management were key factors that affected prognosis. He showed an improved condition after he had received medical treatments, undergone tumour excision and physiotherapy. Further evaluation was needed to improve patient outcomes.
https://ift.tt/2vB2jPY
Unexpected manifestation of cardiac amyloidosis
This report discusses an unusual case of cardiac amyloidosis. We report a patient who presented with unexplained ascites on a background of stable hypertension and mild left ventricular systolic dysfunction, cardiovascular complaints commonly associated with age. Due to the unspecific nature of his cardiovascular symptoms, it took 2 years of recurrent, unresolved ascites, numerous investigations, shifting differential diagnoses and significant cardiovascular deterioration before cardiac amyloidosis was recognised, by which the disease was at end stage. This case emphasises the need for more discriminating clinical features in the diagnosis of cardiac amyloidosis and advocates unexplained, recurrent ascites as a possible candidate.
https://ift.tt/2nceHSO
Uterine didelphys with one cervix obscured by blind hemivagina: a lesson in rarity
A 14-year-old girl presented with increasing cyclical pain, scanty menses, pelvic mass and absence of the left kidney. With both radiological and clinical examinations (examination under anaesthesia), diagnosis of bicornuate uterus with single cervix could be made while on laparotomy, and it turned out to be uterine didelphys, with one cervix obscured by blind hemivagina with haematometra and haematocolpos in the left horn, for which hemihysterectomy was done. Post procedure the patient was relieved of cyclical pain and is menstruating properly.
https://ift.tt/2vBkdSt
Treatment of nasal myiasis with ivermectin irrigation
We describe a case of nasal myiasis due to Musca domestica in a 97-year-old Peruvian farmer with a previously undiagnosed mucocutaneous leishmaniasis. Initial attempts to remove the fly larvae using manual extraction with a toothed forceps and normal saline irrigation were unsuccessful. On subsequent nasal irrigation with ivermectin solution, the patient self-expulsed approximately 50 larvae within 15 min. He also received a course of oral ivermectin. A post-treatment CT scan revealed clear sinuses. Here, we propose that ivermectin irrigation is a simple and effective treatment for nasal myiasis.
https://ift.tt/2ndRkbb
Acute intestinal ischaemia from a portal vein thrombosis in a young female smoker on an oral contraceptive
We report the case of a 23-year-old woman who presented with bloody diarrhoea and multiple syncopal events. While the initial diagnosis clinically appeared to be inflammatory bowel disease, she was found to have a portal vein thrombosis (PVT) on MR cholangiopancreatography and acute intestinal ischaemia on colonic biopsy. The aetiology of this patient's PVT is attributed to her acquired prothrombotic state from an estrogen-containing contraceptive pill in conjunction with regular tobacco use. Extensive mesenteric venous thrombosis from an acute PVT has been shown to cause intestinal ischaemia, likely from venous obstruction and reflexive arterial constriction; however, the diagnosis is often delayed until surgery or autopsy. Our case report highlights this patient's clinical presentation, workup and treatment, as part of a review for the risk factors and guidelines recommendations for management of an acute PVT.
https://ift.tt/2vDoViy
Appendiceal schwannoma: a rare cause of perforated appendicitis
Description
An 82-year-old woman presented to the emergency department with an acute abdomen. CT imaging revealed a proximal appendiceal mass with distal appendicitis. She underwent a laparoscopic appendicectomy with partial caecectomy and subsequent histopathology confirmed an appendiceal schwannoma.
The woman presented with a 1-day history of acute abdominal pain localised to the lower quadrants, worse on mobilisation, loss of appetite and fever. She denied any previous abdominal pain, nausea or vomiting, bowel or bladder symptoms. There was no history of weight loss, generalised fatigue or other symptoms of chronic anaemia. She had been well in the preceding weeks. Her medical history was significant for a cerebrovascular accident, hypertension and hypercholesterolaemia. She had never had previous abdominal surgery.
On examination the patient had a temperature of 37.7°C. There were no signs of haemodynamic instability. Her abdomen was rigid with severe tenderness on palpation, worse in the right lower quadrant....
https://ift.tt/2n9NEY7
Iliac bone tuberculosis with bicompartmental abscess
Description
A 39-year-old man presented with insidious onset back pain and groin pain for 2 weeks, and limp for 7 days to orthopaedic outpatient department. He had anorexia for the past fortnight and had noticed weight loss of about 7 kg, though he remained afebrile. On examination, he had a pseudoflexion deformity of the right hip and tenderness in the right iliac fossa. An X-ray of the pelvis was done which showed an ill-defined lytic lesion in the anterior half of the right iliac blade with minimal periosteal reactions (figure 1). His laboratory investigation showed a high haemoglobin of 12 g/dL, erythrocyte sedimentation rate of 64 mm fall at the end of first hour, a raised total lymphocyte count of 13x109/L with lymphocytosis 40%. His renal, liver and nutritional parameters were within normal range (albumin >3500 mg/dL, absolute lymphocyte count >1500/mm3). X-ray of the dorsolumbosacral region and chest was unremarkable. An MRI was done which...
https://ift.tt/2vBk1CJ
Sensory ganglionopathy associated with drug-induced hypersensitivity syndrome caused by mexiletine
Although various causes are reported for sensory ganglionopathy, drug-induced hypersensitivity syndrome (DIHS) has not been considered a possibility. We describe a 70-year-old woman, previously administered mexiletine hydrochloride for 4 weeks, who presented with systemic oedematous erythema and subacute progressive gait disturbance. Evaluation revealed lymphadenopathy with atypical lymphocytosis and eosinophilia, and human herpesvirus 6 (HHV-6) reactivation. Neurological examination indicated the almost complete loss of joint positional sense in her extremities; her tendon reflex was lost and there was marked pseudoathetosis and Romberg's sign. Skin biopsy revealed spongiosis with lymphocyte infiltration. Based on these findings, we diagnosed acute sensory ganglionopathy secondary to DIHS. Although her DIHS-induced symptoms subsided after methylprednisolone treatment, partial remission of sensory ganglionopathy occurred, even after subsequent intravenous immunoglobulin therapy. This case suggests the possibility that reactivation of HHV-6 may be involved in the pathomechanism of sensory ganglionopathy.
https://ift.tt/2n9NHmL
Inflammatory myofibroblastic tumour mimicking a vocal cord polyp
Description
A 9-year-old child presented with the complaint of voice change of 8 months in duration, which was gradually progressive, and a recent-onset noisy breathing at night noticed by the parents. There were no signs of airway distress or feeding issues on presentation, and the growth of the child was appropriate for her age.
On indirect laryngoscopic examination, a smooth, large polypoidal mass was seen arising from the anterior commissure, partially obscuring the laryngeal airway. Bilateral vocal cords were mobile. The initial impression was that of a benign vocal cord polyp (figure 1).
Figure 1
Laryngoscopic image showing smooth polypoidal mass arising from the anterior commissure.
The rest of the clinical examination was normal.
The patient was then planned for microlaryngoscopic laser-assisted excision of the polyp under general anaesthesia. Intraoperatively, the mass was engaged using a suspension laryngoscope and was seen to arise from the anterior commissure and found to be firm on palpation....
https://ift.tt/2vBjUXP
Functional Multichannel Poly(Propylene Fumarate)‐Collagen Scaffold with Collagen‐Binding Neurotrophic Factor 3 Promotes Neural Regeneration After Transected Spinal Cord Injury
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2I4M41G
Quantum Dot–Dye Conjugates for Biosensing, Imaging, and Therapy
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2Jj1wwD
Ampli: A Construction Set for Paperfluidic Systems
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2wORaif
Amplifying Apoptosis Homing Nanoplatform for Tumor Theranostics
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2L0uyOM
About Chemical Strategies to Fabricate Cell‐Instructive Biointerfaces with Static and Dynamic Complexity
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2JIPTLq
Inkjet–Spray Hybrid Printing for 3D Freeform Fabrication of Multilayered Hydrogel Structures
Advanced Healthcare Materials, Volume 7, Issue 14, July 25, 2018.
https://ift.tt/2I84MJS
Hydrogel Encapsulation Facilitates Rapid‐Cooling Cryopreservation of Stem Cell‐Laden Core–Shell Microcapsules as Cell–Biomaterial Constructs
Advanced Healthcare Materials, July 2018.
https://ift.tt/2M3grvx
Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications
Advanced Healthcare Materials, July 2018.
https://ift.tt/2ObUrfu
Droplet Microarray Based on Patterned Superhydrophobic Surfaces Prevents Stem Cell Differentiation and Enables High‐Throughput Stem Cell Screening
Advanced Healthcare Materials, July 2018.
https://ift.tt/2M3gkjB
Biomechanical Regulation of Mesenchymal Stem Cells for Cardiovascular Tissue Engineering
Advanced Healthcare Materials, July 2018.
https://ift.tt/2MjzeQa
Phase II trial of capecitabine plus oxaliplatin (CAPOX) as perioperative therapy for locally advanced rectal cancer
Abstract
Purpose
The standard strategy for locally advanced lower rectal cancer is chemoradiotherapy followed by total mesorectal excision (TME) in Western countries and TME followed by adjuvant chemotherapy without preoperative treatment in Japan.
Methods
This phase II trial evaluated the efficacy of a preoperative CAPOX chemotherapy regimen without radiation therapy for patients with locally advanced rectal cancer. The primary endpoint was 2-year disease-free survival.
Results
The trial enrolled 45 patients from 9 institutions between 2012 and 2014. The mean age was 63.5 (29–74) years; 31 patients were male. Most patients (n = 41) received preoperative chemotherapy (CTx), and the preoperative CTx completion rate was 95.2%. R0 resection after CTx was performed in 41 patients. The pathological complete response rate was 7.3% (3/41). After surgery, 35 patients (85.3%) received adjuvant CTx, and 22 of 35 completed the protocol treatment. The follow-up period ranged from 0.71 to 4.68 years (median 2.86 years). There was recurrence in 13 of 40 patients who underwent R0 resection, and the 2-year disease-free survival rate and overall survival rate were 71.6 and 92.7%, respectively.
Conclusions
Here we report the completion rates for neoadjuvant CTx and adjuvant CTx, the pathological complete response rate, and the mid-term prognosis. The results indicate that CAPOX followed by TME may be a safe treatment strategy for locally advanced rectal cancer.
https://ift.tt/2AFgbhU
Long-term outcome of high risk patients with myelodysplastic syndromes or secondary acute myeloid leukemia receiving intensive chemotherapy
Abstract
Intensive chemotherapy (IC) used to be a common treatment approach for patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia after MDS (sAML). We conducted a retrospective analysis of 299 patients, including a matched pair analysis comparing 96 patients receiving IC with 96 patients not undergoing IC, in order to evaluate the impact of IC on overall survival (OS) and to identify factors that influence remission rates and OS. Complete remission (CR) after first induction chemotherapy was reached in 50% of patients. Parameters influencing the probability of achieving CR were blast count in the bone marrow (< 30%), age < 65 years, presence of Auer rods, duration of antecedent MDS shorter than 6 months, and timing of IC in relation to first diagnosis. The difference in survival time was not significantly better for patients receiving IC (median OS 12.7 months vs. 7 months). Parameters favorably influencing survival were the presence of Auer rods, age below 60 years, blast count below 30%, IC given shortly after first diagnosis, and achievement of CR. On multivariate analysis, achieving CR, presence of Auer rods, and percentage of blasts below or above 30% significantly influenced median survival. Relapse occurred in 63% of patients after a median of 9.9 months with a median survival of 7.6 months. Considering the high relapse rate and short survival, we conclude that intensive chemotherapy is not promising for high-risk MDS or sAML.
https://ift.tt/2vCG7F9
Neuromuscular Complications of Programmed Cell Death-1 (PD-1) Inhibitors
Abstract
Purpose of Review
In recent years, immune checkpoint inhibitors have been increasingly used in patients with metastatic cancers with favorable oncological outcomes; however, there have also been increasing number of cancer survivors who have developed immune-related adverse events. Little is known about PD-1 inhibitor-associated neuromuscular complications.
Recent Findings
Neuromuscular disorders are the most common neurological complication reported in PD-1 inhibitor-treated patients. Myasthenia gravis, immune-mediated myopathies, and Guillain-Barre syndrome are among commonly reported immune-related neuromuscular complications. HyperCKemia occurs frequently in patients with PD-1 inhibitor-associated myasthenia gravis, indicating coexisting myopathies or myocarditis. Oculobulbar weakness is a unique and common presentation of PD-1 inhibitor-associated immune-mediated myopathies with or without concomitant myasthenia gravis. High-dose steroid monotherapy may be associated with clinical deterioration in some patients with PD-1 inhibitor-associated myasthenia gravis, immune-mediated myopathies, or Guillain-Barre syndrome.
Summary
PD-1 inhibitor-associated neuromuscular complications have some characteristic features compared to their idiopathic counterparts. Although steroid monotherapy is commonly used in non-neuromuscular autoimmune disorders triggered by anti-PD-1 therapy, this may lead to unfavorable outcomes in some patients with PD-1 inhibitor-associated neuromuscular complications.
https://ift.tt/2vgw2OT
Transanal Total Mesorectal Excision for Treatment of Carcinoma in the Middle or Lower Third Rectum: the Technical Feasibility of the Procedure, Pathological Results, and Clinical Outcome
Abstract
We are trying to illustrate operative, short-term, and pathological outcomes of transanal total mesorectal excision (TaTME) as a surgical procedure for patients who are suffering cancer in the lower or middle rectum. This study included 25 consecutive patients who underwent TaTME for the mid and low cancer rectum. The primary outcome measures included frequency of postoperative (PO) bleeding, leakage, ileus, days to regain bowel function, days for Foley's removal, and erectile function. The secondary outcome measures included operation time, status of resection margins, number, the quality of TME, and duration PO hospital stay. No recorded intraoperative complications. The mean hospital stay was 6.9 ± 2.6 days. The mean duration need for urinary catheter removal and flatus passage were 2.4 ± 2.1 and 1.5 + 0.9 days, respectively. The mean IPSS was returned to normal 12 months after surgery. The mean distal margin distance was 1.9 ± 1.1. Circumferential margin distance was > 1 mm in 23 (92%) patients. The mesorectum was complete in 22 (88%) patients. The survival rate was 88% over 3 years. TaTME could be considered as a safe, feasible, and effective surgical modality for patients who had mid and lower rectal tumors with an excellent pathological outcome.
https://ift.tt/2OauH33
Novel Therapies in Acute Lymphoblastic Leukemia
Abstract
Purpose of Review
Treatment options for patients with acute lymphoblastic leukemia (ALL) beyond standard chemotherapy have grown significantly in recent years. In this review, we highlight new targeted therapies in ALL, with an emphasis on immunotherapy.
Recent Findings
Major advances include antibody-based therapies, such as naked monoclonal antibodies, antibody-drug conjugates and bispecific T cell engaging (BiTE) antibodies, as well as adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells. Apart from the above immunotherapeutic approaches, other targeted therapies are being employed in Philadelphia chromosome-positive (Ph+) ALL, Philadelphia-like (Ph-like) ALL, and T cell ALL.
Summary
These new treatment strategies are changing the treatment landscape of ALL and challenging the current standard of care. Clinical trials will hopefully help determine how to best incorporate these novel therapies into existing treatment algorithms.
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Apatinib reverses alectinib resistance by targeting vascular endothelial growth factor receptor 2 and attenuating the oncogenic signaling pathway in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene-positive lung cancer cell lines
Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. https://ift.tt/1hexVwJ Correspondence to Shaozhang Zhou, Second Department of Chemotherapy, Affiliated Cancer Hospital, Guangxi Medical University, 71 Heti road, Nanning, Guangxi, 530021, Peoples's Republic of China Tel: +86 077 1533 4955; fax: +86 077 1530 0613; e-mail: zhoushaozhang@qq.com Received January 17, 2018 Accepted June 20, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1–CH3 fusion protein
Abstract
Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1–CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3+ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC.
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Increased antitumor activities of glypican-3-specific chimeric antigen receptor-modified T cells by coexpression of a soluble PD1–CH3 fusion protein
Abstract
Our recent clinical study demonstrated that glypican-3 (GPC3)-specific chimeric antigen receptor-modified T (CAR-T) cells are a promising treatment for hepatocellular carcinoma (HCC). However, the interaction of programmed cell death 1 (PD-1) and PD-L1-mediated T-cell inhibition is involved in immune evasion in a wide range of solid tumors, including HCC. To overcome this problem, we introduced a fusion protein composed of a PD-1 extracellular domain and CH3 from IgG4 into GPC3-specific CAR-T cells (GPC3-28Z) to block the PD-1/PD-L1 pathway. GPC3-specific CAR-T cells carrying the PD-1–CH3 fusion protein (sPD1) specifically recognized and lysed GPC3-positive HCC cells. The proliferation capacity of GPC3-28Z-sPD1 T cells after weekly stimulation with target cells was much higher than that of control GPC3-28Z T cells. Additionally, the coexpression of sPD1 could protect CAR-T cells from exhaustion when incubated with target cells, as phosphorylated AKT and Bcl-xL expression levels were higher in GPC3-28Z-sPD1 T cells than in GPC3-28Z cells. Importantly, in two HCC tumor xenograft models, GPC3-28Z-sPD1 T cells displayed a significantly higher tumor suppression capacity than GPC3-28Z T cells. In addition, an increased number of CD3+ T cells in the circulation and tumors and increased granzyme B levels and decreased Ki67 expression levels in the tumors were observed in the mice treated with GPC3-28Z-sPD1 T cells. Together, these data indicated that GPC3-specific CAR-T cells carrying sPD1 show promise as a treatment for patients with HCC.
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