Oligodendrocyte- and Neuron-Specific Nogo-A Restrict Dendritic Branching and Spine Density in the Adult Mouse Motor Cortex

Abstract

Nogo-A has been well described as a myelin-associated inhibitor of neurite outgrowth and functional neuroregeneration after central nervous system (CNS) injury. Recently, a new role of Nogo-A has been identified as a negative regulator of synaptic plasticity in the uninjured adult CNS. Nogo-A is present in neurons and oligodendrocytes. However, it is yet unclear which of these two pools regulate synaptic plasticity. To address this question we used newly generated mouse lines in which Nogo-A is specifically knocked out in (1) oligodendrocytes (oligoNogo-A KO) or (2) neurons (neuroNogo-A KO). We show that both oligodendrocyte- and neuron-specific Nogo-A KO mice have enhanced dendritic branching and spine densities in layer 2/3 cortical pyramidal neurons. These effects are compartmentalized: neuronal Nogo-A affects proximal dendrites whereas oligodendrocytic Nogo-A affects distal regions. Finally, we used two-photon laser scanning microscopy to measure the spine turnover rate of adult mouse motor cortex layer 5 cells and find that both Nogo-A KO mouse lines show enhanced spine remodeling after 4 days. Our results suggest relevant control functions of glial as well as neuronal Nogo-A for synaptic plasticity and open new possibilities for more selective and targeted plasticity enhancing strategies.

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Localization and distribution of gonadal proteins in the oviparous lizard Sceloporus aeneus (Squamata: Phrynosomatidae)

Publication date: Available online 14 May 2017
Source:Acta Histochemica
Author(s): Antonio-Rubio Nivia Rocio, Villagrán-SantaCruz Maricela, Moreno-Mendoza Norma
Among vertebrates, several specific proteins are involved in the function and development of gonads. Several genes such as SOX9, FOXL2, DDX4, IFITM3, and DPPA3, are active during embryonic differentiation and maintain their expression in adult tissues, playing important roles in the function and development of the line cell, where these are produced. Among reptiles, molecular mechanisms for sex differentiation have been analyzed in turtles, crocodiles, and some lizards, while in adult stages such studies are scarce. The aim of this study was to locate and analyze the distribution of important gonadal proteins in adult and embryonic ovaries and testes of the oviparous lizard Sceloporus aeneus (Squamata: Phrynosomatidae). Adult specimens and embryos of the lizard S. aeneus were collected in Milpa Alta, a suburb located Southwest of Mexico City. Expression of gonadal proteins was analyzed using immunofluorescent staining and confocal microscopy. Our results showed that SOX9 is located in Sertoli cells of embryonic and adult testes. FOXL2 is expressed in follicular cells of adult ovaries. DDX4 and IFITM3 are located in germ line cells as well as in follicular cells of adult ovaries. DPPA3 was observed in somatic and germ line cells of adult and embryonic gonads. Our observations show that important molecules of vertebrate ovaries and testes are conserved in S. aeneus and it is suggested that these may have a similar role during gonadal development and function.



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Editorial Board ((ofc))

Publication date: May 2017
Source:Acta Histochemica, Volume 119, Issue 4





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What We Know About Stage II and III Colon Cancer: It’s Still Not Enough

Abstract

The introduction of oxaliplatin as adjuvant treatment for stage III colon cancer in 2004 has been the last practice changing progress in adjuvant treatment for patients with early colon cancer. Since then, many prognostic and predictive biomarkers have been studied, but only DNA mismatch repair status has been validated as having an important prognostic value. Accordingly, TNM and clinical-pathological patterns, such as pT4 lesions and lymph node sampling <12 nodes, are the main factors that guide physicians' choice regarding adjuvant treatment. More recently, many biomarkers showed promising results: POLE, ErbB2, CDX2, SMAD4, BRAF and KRAS. In addition to these, immune-contexture, molecular classification, and gene signatures could become new ways to better classify colon cancer patients with more discriminatory power than TNM. The aim of this review is to report the state-of-the-art of prognostic and predictive factors in the adjuvant setting and which of these could modify clinical practice and maybe replace TNM classification.

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Therapeutic effect of microneedling and autologous platelet-rich plasma in the treatment of atrophic scars: A randomized study

Summary

Background

New treatments and techniques were being added over the last few years to treat atrophic scars with variable results and adverse effects.

Aim of the work

The aim of this study was to evaluate and compare the therapeutic efficacy and safety of microneedling, autologous platelet-rich plasma, and combination of both procedures in the treatment of atrophic scars.

Patients and methods

This study included 90 patients with atrophic scars and were classified randomly into three groups: I: 28 patients treated with microneedling, one session every 4 weeks; II: 34 patients treated with intradermal injection of platelet-rich plasma, one session every 2 weeks; and III: 28 patients treated with alternative sessions of each microneedling and platelet-rich plasma, 2 weeks between each session, for a maximum of six sessions.

Results

There was a statistically significant improvement in the appearance of atrophic scars, with reduction in the scores associated with the clinical evaluation scale for atrophic scarring in all groups, but the improvement was more obvious in group III.

Conclusions

Although a single treatment may give good results, combination between skin needling and platelet-rich plasma is more effective, safe with less number of sessions in all types of atrophic scars.

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The effect of autologous activated platelet-rich plasma injection on female pattern hair loss: A randomized placebo-controlled study

Summary

Background

Hair is an essential part of a woman's appearance and attractiveness. This is reflected in the predominantly psychological morbidity that can be associated with female pattern hair loss. Platelet-rich plasma(PRP) has been used in numerous fields of medicine. Recently, PRP has received growing attention as a potential therapeutic tool for hair loss.

Objective

To evaluate the efficacy and safety of autologous platelet-rich plasma in the treatment of female pattern hair loss.

Materials and methods

Thirty female patients with female pattern hair loss were randomly assigned to receive autologous PRP injection into a selected area, and another area was injected with normal saline as a placebo. Sessions were performed weekly for a maximum total of four sessions. Patients were followed up 6 months after the end of last session. The outcome was assessed both subjectively and objectively.

Results

There was a statistical significant difference between PRP and placebo areas (P<.005) regarding both hair density and hair thickness as measured by a folliscope. The hair pull test became negative in PRP-injected areas in 25 patients (83%) with average number of three hairs. Global pictures showed a significant improvement in hair volume and quality together with a high overall patient satisfaction in PRP-injected sites, and these results were maintained during the 6-month follow- up.

Conclusion

Platelet-rich plasma injections can be regarded as an alternative for the treatment of female pattern hair loss with minimal morbidity and a low cost-to-benefit ratio.

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Incubatory environment of the scalp impacts pre-emergent hair to affect post-emergent hair cuticle integrity

Summary

Objectives

To determine whether the oxidative stress transmitted to newly grown hair from an unhealthy scalp has physical consequences to the cuticular condition and function.

Methods

A uniquely designed 24-week clinical study included 8 weeks of pretreatment with a cosmetic shampoo and 16 weeks of treatment with either a potentiated zinc pyrithione (ZPT) antidandruff shampoo or a placebo cosmetic shampoo. This clinical design allowed the growth and acquisition of hair samples under conditions of varying but known scalp health as a result of treating a dandruff/seborrheic dermatitis (D/SD) population. Two complementary methods were used to characterize the integrity of the cuticular surface. Hair surface hydrophobicity was assessed by quantifying water wetting force using a Wilhelmy balance method. Surface structure and porosity were assessed using dynamic vapor sorption (DVS) to gravimetrically quantify water sorption.

Results

Chemical oxidative stress to pre-emergent hair has been shown to have negative consequences to hair surface structure. Compared to a placebo shampoo control, use of a potentiated ZPT shampoo improved scalp health and significantly improved the following attributes associated with healthy hair: hair surface hydrophobicity (surface energy) and cuticular moisture barrier effectiveness (dynamic vapor sorption).

Conclusions

Pre-emergent hair can be negatively impacted by the oxidative stress that occurs with an unhealthy scalp, possibly due to metabolic activity of resident microbes. Manifestations of the oxidative stress include altered cuticle surface properties that are responsible for its protective function; these effects are similar in type to those observed by bleaching post-emergent hair. These alterations have the potential to make the hair, once emerged from the scalp, more susceptible to the cumulative physical and chemical insults responsible for hair feel and look, fiber integrity, and overall retention.

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Management of Massive Hemoptysis with Oren Friedman

http://sfaki.blogspot.com/2017/05/management-of-massive-hemoptysis-with.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Mismatch repair cancer syndrome (MMRCS) : Multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity.

http://sfaki.blogspot.com/2017/05/mismatch-repair-cancer-syndrome-mmrcs.html

Haematologica. 2010 May; 95(5): 699–701.

doi:  10.3324/haematol.2009.021626

PMCID: PMC2864372

Constitutional mismatch repair-deficiency syndrome

Katharina Wimmer1 and Christian P. Kratz2

1 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

2 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA. E-mail: ta.ca.dem-i@remmiw.anirahtak

Katharina Wimmer, PhD, is Associate Professor at the Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck. She is supervising the onco-genetic laboratory for the diagnostics of cancer predisposition syndromes which are also her main research interest. Christian P. Kratz, M.D. is an investigator in the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health. His research focuses on individuals with inherited cancer predispositions.

Author information ▼ Copyright and License information ►

See "Constitutional mismatch repair deficiency and childhood leukemia/lymphoma – report on a novel biallelic MSH6 mutation" on page 841.

This article has been cited by other articles in PMC.

The mismatch repair (MMR) machinery contributes to genome integrity and the MLH1, MSH2, MSH6 and PMS2 genes play a crucial role in this process. MMR corrects single base-pair mismatches and small insertion-deletion loops that arise during replication. Moreover, the MMR system is involved in the cellular response to a variety of agents that damage DNA1 and in immunoglobulin class switch recombination.2 Heterozygous germline mutations in MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome (LS), an autosomal dominant cancer syndrome associated with hereditary non-polyposis colorectal cancer (HNPCC), endometrium carcinoma and other malignancies, occurring on average in the fourth and fifth decade of life. Notably, LS associated tumors display somatic loss of the remaining wild type MLH1, MSH2, MSH6 or PMS2 allele and evidence of microsatellite instability (for review see 3).

In contrast to individuals with LS who harbor a heterozygous mutant MMR gene allele, rare cases with biallelic deleterious germline mutations in MMR genes leading to constitutional mismatch repair-deficiency (CMMR-D) have been recognized since 1999.4,5 This cancer syndrome is characterized by a broad spectrum of early-onset malignancies and a phenotype that resembles neurofibromatosis type 1. In this issue of Haematologica, Ripperger and colleagues report on a patient with CMMR-D caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. In addition, they review 26 leukemia and/or lymphoma cases reported previously.6

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The clinical presentation and tumor spectrum of CMMR-D

Our knowledge of the CMMR-D syndrome originates primarily from the medical literature; consequently, potential publication bias must be kept in mind as we interpret these reports. Table 1 summarizes the malignancies observed in 89 reported6–11 and 3 unreported cases of CMMR-D. Neoplasms can be divided into four groups: (1) hematologic malignancies (reviewed in 6); (2) brain tumors; (3) LS-associated tumors; and (4) other malignancies. Notably, 31 out of the known 92 CMMR-D patients developed more than one malignancy, and in 19 cases the second or third neoplasm was an LS-associated tumor.

Table 1.

List of malignancies in 92 CMMR-D patients.

In some cases of CMMR-D, areas of skin hypo-pigmentation have been reported.12–15 However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.9,13 Interestingly, several reports stress that CALMs in patients with CMMR-D differ from typical NF1-associated CALMs in that they vary in their degree of pigmentation, have irregular borders, and may display a segmental distribution. Other features of NF1 found in CMMR-D patients include skinfold freckling, Lisch nodules, neurofibromas and tibial pseudarthrosis. Hence, it is not surprising that a number of CMMR-D cases were initially diagnosed as having NF1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development. The identification of a truncating NF1 mutation in the blood of one patient16 and data supporting the notion that the NF1 gene is a mutational target of MMR deficiency17 are in line with this assumption. However, extensive mutation analysis in other CMMR-D patients has not confirmed this theory (see 8,12,18 and papers cited therein).

Péron et al.2 have shown in 3 CMMR-D patients that constitutional PMS2 deficiency leads to impaired immunoglobulin class switch recombination characterized by increased serum IgM concomitant with decrease or absence of IgG2, IgG4, and IgA. Of note, one CMMR-D patient initially presented with a primary immunodeficiency,2 and patients with biallelic MSH2 and MSH6 mutations also show IgG2 and/or IgA deficiency 15,19,20. It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.

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Genotype-phenotype correlation of CMMR-D

A review of the literature suggests that the clinical features in patients with biallelic germline mutations of MLH1 or MSH2 differ from those with biallelic germline mutations of MSH6 or PMS2 (Table 2). Hematologic malignancies appear to occur more frequently in patients with MLH1 or MSH2 mutations than in patients with mutations of MSH6 or PMS2. In contrast, the latter group appears to have a higher prevalence of brain tumors. Furthermore, tumors tend to develop earlier in MLH1 or MSH2 mutation carriers than in patients with a mutation of MSH6 or PMS2. Patients with biallelic mutations in MSH6 or PMS2 are more likely to survive their first tumors and develop a second malignancy. Overall, the prevalence of LS-associated tumors is higher in patients with biallelic MSH6 or PMS2 mutations than in biallelic MLH1 or MSH2 mutation-positive individuals (Table 2). These factors facilitate the clinical diagnosis of CMMR-D in patients with mutations of MSH6 or PMS2 and may at least partly explain the preponderance of PMS2 mutations in published cases.

Table 2.

Differences in the overall tumor spectrum and age of malignancy onset between carriers of biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively.

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Strategies for clinical and subsequent molecular diagnosis of CMMR-D

In view of the wide tumor spectrum that overlaps with Lynch and Turcot syndrome but also includes hematologic malignancies and embryonic tumors such as neuroblastoma, Wilms tumor and rhabdomyosarcoma (Table 1), CMMR-D should be considered in the differential diagnosis in all patients with malignancies (except clearly NF1-associated tumors) who show one or more of the following features: (1) CALMs and/or other signs of NF1 and/or hypo-pigmented skin lesions; (2) consanguineous parents; (3) family history of LS-associated tumors; (4) second malignancy; and (5) sibling with childhood cancer. It is important to note that especially in patients with PMS2 mutations, the family history will often not fulfill the Amsterdam or revised Bethesda criteria for LS.

Typically, confirmation of the diagnosis involves the analysis of microsatellite instability (MSI) and/or immunohistochemistry (IHC), followed by mutation analysis. MSI analysis follows current protocols used for LS-screening; however, this analysis may be unreliable in CMMR-D related brain tumors.7,11,21 IHC is a useful technique employed in patients with CMMR-D associated neoplasms including brain tumors and guides subsequent mutation analysis in the four MMR-genes. In general, a truncating mutation in PMS2 or MSH6 will result in isolated loss of these proteins, whereas a mutation in MLH1 or MSH2 will lead to concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, since MLH1 and MSH2 are the obligatory partners in the formation of MLH1/PMS2 and MSH2/MSH6 heterodimers. Notably, in the case of an underlying missense mutation, IHC may show normal results. As CMMR-D patients constitutively lack the expression of one of the MMR genes, IHC detects loss in both neoplastic and non-neoplastic tissues. Conveniently, expression loss of one of the MMR genes can be demonstrated in blood lymphocytes (e.g. by Western blot 2). Similarly, it has been shown that MSI can be determined in normal non-neoplastic tissue of CMMR-D patients by analyzing DNA samples that are diluted to approximately 0–3 genome equivalents per PCR-reaction.22 Nonetheless, standardized procedures for the detection of MMR expression loss and MSI in non-neoplastic tissue from CMMR-D patients have not been developed to date. The diagnosis of CMMR-D should be confirmed by gene-specific mutation analysis. Reliable methods for all four MMR genes including PMS2 are now available.12 Mutation analysis will facilitate identification and surveillance of heterozygous and homozygous individuals in the wider family, and allow for informed decision-making about prenatal or pre-implantation genetic diagnosis.

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Treatment and surveillance of the patient and counseling of relatives

Genetic counseling should be offered to the parents prior to testing of the affected child, and should include information on the potential 25% recurrence risk and on the clinical consequences of a possible heterozygous mutation in both parents. Predictive testing following the established interdisciplinary counseling guidelines should be offered to all family members once a mutation has been identified. Heterozygous family members should be followed according to current LS-guidelines.23

Because of the wide spectrum of malignancies in CMMR-D patients, defining recommendations for surveillance of affected patients remains a challenge. Early diagnosis of CMMR-D and subsequent cancer screening at regular intervals may increase the likelihood of detecting associated cancers, such as colon cancer or brain tumors, at an operable stage. In theory, this screening could include regular exams such as: (1) clinical evaluation; (2) blood tests with full blood count and carcinoembryonic antigen (CEA); (3) magnetic resonance imaging of the brain; (4) endoscopic examination of the gastrointestinal tract; and (5) endometrial sampling and transvaginal ultrasound for endometrial and ovarian cancer. However, these recommendations rest only on clinical judgment and do not represent a standard of care. To date there is no available evidence to support any of these recommendations or to provide guidance on the optimal frequency of such tests. Likewise, there is currently no information available regarding the optimal treatment of CMMR-D patients. Several reports stress that careful attention should be given to the possibly increased cyto-toxicity and reduced efficacy of chemotherapeutic agents due to constitutionally impaired mutation repair, and the high risk of a second malignancy 6,8,14,15.

Reports such as the article by Ripperger and colleagues are valuable in increasing awareness and knowledge of the syndrome in the clinical community. Nevertheless, systematic studies are needed in order to better define the phenotype of MMR-D. Data related to cancer screening, treatment and outcome should be collected and evaluated systematically to provide a basis for recommendations on how to manage patients with CMMR-D.

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Footnotes

( Related Original Article on page 841)

We thank Drs. Anne Durandy and Johannes Zschocke for their helpful comments on the manuscript. Dr. Kratz's work was supported by the Intramural Research Program of the US National Cancer Institute.

No potential conflict of interest relevant to this article was reported.

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References

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2. Peron S, Metin A, Gardes P, Alyanakian MA, Sheridan E, Kratz CP, et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med. 2008;205(11):2465–72. [PMC free article] [PubMed]

3. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174–9. [PubMed]

4. Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59(2):290–3. [PubMed]

5. Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, et al. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59(2):294–7. [PubMed]

6. Ripperger T, Beger C, Rahner N, Sykora KW, Bockmeyer CL, Lehmann U, et al. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma - report on a novel biallelic MSH6 mutation. Haematologica. 2009 Dec 16; [Epub ahead of print] [PMC free article] [PubMed]

7. Giunti L, Cetica V, Ricci U, Giglio S, Sardi I, Paglierani M, et al. Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome. Eur J Hum Genet. 2009;17(7):919–27. [PMC free article] [PubMed]

8. Peters A, Born H, Ettinger R, Levonian P, Jedele KB. Compound heterozygosity for MSH6 mutations in a pediatric lymphoma patient. J Pediatr Hematol Oncol. 2009;31(2):113–5. [PubMed]

9. Sjursen W, Bjornevoll I, Engebretsen LF, Fjelland K, Halvorsen T, Myrvold HE. A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts. Fam Cancer. 2009;8(3):179–86. [PubMed]

10. Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, et al. Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Fam Cancer. 2009;8(3):187–94. [PubMed]

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12. Etzler J, Peyrl A, Zatkova A, Schildhaus HU, Ficek A, Merkelbach-Bruse S, et al. RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Human Mut. 2008;29(2):299–305. [PubMed]

13. Rahner N, Hoefler G, Hogenauer C, Lackner C, Steinke V, Sengteller M, et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. Am J Med Genet A. 2008;146A(10):1314–9. [PubMed]

14. Scott RH, Homfray T, Huxter NL, Mitton SG, Nash R, Potter MN, et al. Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet. 2007;44(7):e83. [PMC free article] [PubMed]

15. Scott RH, Mansour S, Pritchard-Jones K, Kumar D, MacSweeney F, Rahman N. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol. 2007;4(2):130–4. [PubMed]

16. Alotaibi H, Ricciardone MD, Ozturk M. Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia. Mutat Res. 2008;637(1–2):209–14. [PubMed]

17. Wang Q, Montmain G, Ruano E, Upadhyaya M, Dudley S, Liskay RM, et al. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet. 2003;112(2):117–23. [PubMed]

18. Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, et al. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007;28(11):1084–90. [PubMed]

19. Ostergaard JR, Sunde L, Okkels H. Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am J Med Genet A. 2005;139:96–105. discussion 96. [PubMed]

20. Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, et al. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-aulait spots. Cancer Res. 2002;62(2):359–62. [PubMed]

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23. Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) J Med Genet. 2007;44(6):353–62. [PMC free article] [PubMed]

Articles from Haematologica are provided here courtesy of Ferrata Storti Foundation

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Technology: Nucleic acid detection — it's elementary with SHERLOCK!

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The evolutionary significance of polyploidy

Polyploidy occurs frequently but is usually detrimental to survival; thus, few polyploids survive in the long term. Here, evidence linking the short-term evolutionary success of polyploids to environmental upheaval is reviewed and possible longer-term evolutionary benefits of polyploidy are discussed.

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Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: If you are planning a pregnancy, currently pregnant, or in the postpartum period, it's important to stay up to date on the latest guidelines on thyroid disease and pregnancy. Read More….

We welcome your feedback and suggestions. Let us know what you want to see in this publication.

Feedback & Suggestions

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

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Variant in a common odorant-binding protein gene is associated with bitter sensitivity in people

Publication date: 30 June 2017
Source:Behavioural Brain Research, Volume 329
Author(s): Iole Tomassini Barbarossa, M. Hakan Ozdener, Melania, Latisha Love-Gregory, Makedonka Mitreva, Nada A. Abumrad, M. Yanina Pepino
Deeper understanding of signaling mechanisms underlying bitterness perception in people is essential for designing novel and effective bitter blockers, which could enhance nutrition and compliance with orally administered bitter-tasting drugs. Here we show that variability in a human odorant-binding protein gene, OBPIIa, associates with individual differences in bitterness perception of fat (oleic acid) and of a prototypical bitter stimulus, 6-n-propylthiouracil (PROP), suggesting a novel olfactory role in the modulation of bitterness sensitivity.



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Studies on diagnostic biomarkers and therapeutic mechanism of Alzheimer's disease through metabolomics and hippocampal proteomics

Publication date: 15 July 2017
Source:European Journal of Pharmaceutical Sciences, Volume 105
Author(s): Weiwei Lin, Jianmei Zhang, Yanmeng Liu, Ruijun Wu, Haisong Yang, Xiaobo Hu, Xiaomei Ling
Alzheimer's disease (AD) is the main cause of dementia, but precise diagnosis and treatment are not sufficient so far. The purpose of this study is to develop biomarkers and therapeutic targets for diagnosis and better understanding of AD. As a result, lysophosphatidylcholine and intermediates of sphingolipid metabolism including sphinganine-1-phosphate, sphingosine-1-phosphate, sphingomyelin, and sphingosine in plasma were annotated as potential biomarkers by using UPLC-Q-TOF-MS and UHPLC-Q-Exactive-MS. Besides, glutathione S-transferases (GSTs) including GstA3, Gstm1, Gstm5, Gstm3, Gstk1 and Gstp1 were significantly enhanced in AD hippocampus by using label free nano-LC-MS/MS. Thus, pathogenesis of AD was involved with increasing of choline, decreasing of ACh, enhancement of GSTs and increasing of glutamate which led to oxidative stress and excitotoxity. Effects of donepezil and a natural medicine were evaluated through metabolomics and proteomics. In summary, proteomic and metabolomic analysis on constructed AD rat model were performed through rapid, sensitive and high resolution LC-MS methods to reveal candidate biomarkers. The data suggested that GSTs have great value as therapeutic targets. This study provided valuable information for the diagnosis mechanism and drug discovery of AD.

Graphical abstract

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“Ziziphus oxyphylla”: Ethnobotanical, ethnopharmacological and phytochemical review

Publication date: July 2017
Source:Biomedicine & Pharmacotherapy, Volume 91
Author(s): Rizwan Ahmad, Niyaz Ahmad, Atta Abbas Naqvi
Ethnopharmacological relevanceZiziphus oxyphylla (ZO) is distributed mainly in tropic and warm temperate regions in the world. Pakistan owns six (06) indigenous species of genus Ziziphus out of which ZO is widely used for traditional treatment of different ailments such as diabetes, jaundice and liver diseases.Aim of the studyThe present review aims to provide in-depth and comprehensive literature overview, regarding botanical, chemical and biological characteristics of the plant alongwith phytochemical isolation and mechanistic studies to support its folklore and traditional uses.Materials and methodsThe literature search and relevant information were collected through authentic resources using data bases such as Google Scholar, PubMed, Web of Science, Scopus and Science Direct, peer reviewed articles, books and thesis.Results and discussionThe phytochemical characterization as well as color tests confirmed the presence of diverse chemical groups presents in the plant such as alkaloids, flavonoids, phenolic compounds and tannins. In-vivo and in-vitro pharmacological activities for the crude extracts and its fractions revealed potent antinociceptive, anti-inflammatory, antipyretic, antioxidant, antibacterial as well as acetyl choline esterase and lipoxygenase inhibitory activity. Majority of the isolated compounds belonged to class of Cyclopeptide alkaloids for which the genus is already very famous. Compounds from alkaloids and flavonoids chemical class were isolated and evaluated with a role as antioxidant, antidiabetic, anti-glycation and advanced glycation end products inhibitors. No toxicity was observed during cytotoxicity (MRC-5 cell lines), insecticidal and brine shrimp lethality studies.ConclusionThe review article supports the folklore uses of this plant in the aforementioned diseases. The plant due to its diverse biological nature may be further studied for mechanistic studies, its anticancer effects as well as its potency and toxicity studies for safe use in human beings.

Graphical abstract

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Signature of the Sleeper Cell: A Biomarker of HIV Latency Revealed

Publication date: Available online 13 May 2017
Source:Trends in Immunology
Author(s): Satish K. Pillai, Steven G. Deeks
HIV establishes a reservoir in latently infected T cells, and this reservoir has long hampered curative approaches. A recent study by Descours et al. identifies CD32a as a marker of latently infected T cells, potentially opening the way to the development of strategies that directly target this critical HIV reservoir.



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Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder

Publication date: June 2017
Source:Research in Developmental Disabilities, Volume 65
Author(s): Emi Murata, Ikuko Mohri, Kumi Kato-Nishimura, Jiro Iimura, Makoto Ogawa, Masaya Tachibana, Yuko Ohno, Masako Taniike
Background and objectiveObstructive sleep apnea (OSA) may affect daily cognitive functioning in children. The aims of our study were two-fold. The first aim was to detect, using the Child Behavior Checklist (CBCL), whether adenotonsillectomy (AT) for the treatment of OSA improved the behavior of children with autism spectrum disorder (ASD). The second aim was to identify characteristics for behavioral improvement following the treatment of OSA in these children with ASD.MethodsThe behaviors of ASD children aged 5–14 years diagnosed as having OSA (n=30) were evaluated using CBCL before and after AT. CBCL evaluation of ASD children without OSA at two time points with the same interval served as a control (n=24). We statistically examined the two groups. In addition, we conducted a paired t-test to assess changes in CBCL Tscores between the improved group and unchanged/deteriorated group to identify characteristics that may affect behavioral changes following OSA treatment.ResultsAfter AT, T-scores of the CBCL scales were significantly improved in the OSA group, but no change was observed in the control. A paired t-test revealed that the improved group had significantly higher scores on the CBCL pre-AT than the unchanged/deteriorated group in ASD children with OSA after OSA treatment.ConclusionsBehavioral problems were significantly improved following AT in ASD children with OSA. Early detection and treatment of children with OSA is essential to prevent behavioral problems and to support mental development.



http://ift.tt/2pzOn8B

Acquisition of Who-question Comprehension in German Children with Hearing Loss

Publication date: Available online 13 May 2017
Source:Journal of Communication Disorders
Author(s): Eva Wimmer, Monika Rothweiler, Martina Penke
For children with sensorineural hearing loss the ability to understand wh-questions might be particularly challenging because they often have only restricted access to spoken language input during optimal periods of language acquisition. In previous research it has been suggested that this restricted input during critical stages in language acquisition might lead to syntactic deficits that persist into adolescence. In this study we want to pursue this issue by investigating the comprehension of wh-questions in German children with bilateral sensorineural hearing loss. We report results of a who-question comprehension task in a group of 21 3- to 4-year-old German hard-of-hearing children compared to a group of age-matched children with normal hearing. The group data and individual performance patterns suggest that the syntactic comprehension difficulties observed in some, but not all, of the children with hearing loss reflect a delay in the acquisition of who-question comprehension rather than a persistent syntactic deficit. Follow-up data elicited from a subgroup of children confirmed this supposition.



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Heart murmur detection based on Wavelet Transformation and a synergy between Artificial Neural Network and modified Neighbor Annealing methods

Publication date: Available online 13 May 2017
Source:Artificial Intelligence in Medicine
Author(s): Gholamhossein Eslamizadeh, Ramin Barati
Early recognition of heart disease plays a vital role in saving lives. Heart murmurs are one of the common heart problems. In this study, Artificial Neural Network (ANN) is trained with Modified Neighbor Annealing (MNA) to classify heart cycles into normal and murmur classes. Heart cycles are separated from heart sounds using wavelet transformer. The network inputs are features extracted from individual heart cycles, and two classification outputs. Classification accuracy of the proposed model is compared with five multilayer perceptron trained with Levenberg-Marquardt, Extreme-learning-machine, back-propagation, simulated-annealing, and neighbor-annealing algorithms. It is also compared with a Self-Organizing Map (SOM) ANN. The proposed model is trained and tested using real heart sounds available in the Pascal database to show the applicability of the proposed scheme. Also, a device to record real heart sounds has been developed and used for comparison purposes too. Based on the results of this study, MNA can be used to produce considerable results as a heart cycle classifier.



http://ift.tt/2rfxT21

Epigenetics and immunotherapy: The current state of play

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Jennifer Dunn, Sudha Rao
Cancer cells employ a number of mechanisms to escape immunosurveillance and facilitate tumour progression. The recent explosion of interest in immunotherapy, especially immune checkpoint blockade, is a result of discoveries about the fundamental ligand-receptor interactions that occur between immune and cancer cells within the tumour microenvironment. Distinct ligands expressed by cancer cells engage with cell surface receptors on immune cells, triggering inhibitory pathways (such as PD-1/PD-L1) that render immune cells immunologically tolerant. Importantly, recent studies on the role of epigenetics in immune evasion have exposed a key role for epigenetic modulators in augmenting the tumour microenvironment and restoring immune recognition and immunogenicity. Epigenetic drugs such as DNA methyltransferase and histone deacetylase inhibitors can reverse immune suppression via several mechanisms such as enhancing expression of tumour-associated antigens, components of the antigen processing and presenting machinery pathways, immune checkpoint inhibitors, chemokines, and other immune-related genes. These discoveries have established a highly promising basis for studies using combined epigenetic and immunotherapeutic agents as anti-cancer therapies. In this review, we discuss the exciting role of epigenetic immunomodulation in tumour immune escape, emphasising its significance in priming and sensitising the host immune system to immunotherapies through mechanisms such as the activation of the viral defence pathway. With this background in mind, we highlight the promise of combined epigenetic therapy and immunotherapy, focusing on immune checkpoint blockade, to improve outcomes for patients with many different cancer types.



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Molecular cloning and characterization of DNGR-1 in rhesus macaques

Publication date: July 2017
Source:Molecular Immunology, Volume 87
Author(s): Wen-Rong Yao, Lei Yu, Dong Li, Gui-Bo Yang
DC, NK lectin group receptor-1 (DNGR-1), also known as C-type lectin domain family 9 member A (CLEC9A), is a promising target for immunological therapeutics and vaccination against tumors and viruses. However, little is known about its property in rhesus macaques. In this study, we cloned rhesus macaque DNGR-1 cDNA, and found that its coding region could encode a 241-amino acid polypeptide with 91.7% sequence identity and similar antigenicity to that of humans. Both free and cell surface rhesus macaque DNGR-1 expressed in vitro could bind to apoptotic/dead cells induced by serum deprivation or freeze-thaw, and to pyroptotic cells stimulated with PMA and LPS. We also demonstrated that rhesus macaque DNGR-1 mRNA was present in all the examined tissues, with the highest in lymph nodes, spleen, blood, and thymus. The expression of DNGR-1 that is highly similar to that of humans warranted the usefulness of rhesus macaques in testing human therapeutics and vaccines targeting DNGR-1, especially those for HIV/AIDS.



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Application of metabolomics in sarcoma: from biomarkers to therapeutic targets

Publication date: Available online 13 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Li Min, Edwin Choy, Chongqi Tu, Francis Hornicek, Zhenfeng Duan




http://ift.tt/2rfedva

A novel pathogenic variant in the FZD6 gene causes recessive nail dysplasia in a large Iranian kindred

Publication date: Available online 13 May 2017
Source:Journal of Dermatological Science
Author(s): Javad Mohammadi-asl, Mohammad Reza Pourreza, Aliasgar Mohammadi, Ameneh Eskandari, Sima Mozafar-Jalali, Mohammad Amin Tabatabaiefar
BackgroundNail disorder nonsyndromic congenital (NDNC) is a very rare clinically and genetically heterogeneous disease inherited both in recessive or dominant modes. FZD6 is a component of Wnt-FZD signaling pathway in which recessive loss-of-function variants in the corresponding genes could lead to nail anomalies.ObjectiveA large multiplex family with NDNC was referred for genetic counselling. Thorough genetic evaluation was performed.MethodsPCR-Sanger sequencing was carried out for the coding exons and exon-intron boundaries of the FZD6 gene. Co-segregation analysis, in silico evaluation and computational protein modeling was accomplished.ResultsA homozygous 1bp deletion variant, c.1859delC (p.Ser620Cysfs*75), leading to a truncating protein was found in the patient. Parents were heterozygous for the variant. The variant was found to be co-segreagting with the phenotype in the family. Computational analysis and protein modeling revealed its pathogenic consequence by disturbing the cytoplasmic domain structure and signaling through loss of phosphorylation residues. The variant met the criteria of being pathogenic according to the ACMG guideline.ConclusionsThis is the first report of the genetic diagnosis of NDNC in Iran. We also report a novel pathogenic variant. The study of the FZD6 gene is recommended as the first step in the diagnostic routing of the autosomal recessive NDNC patients with enlarged nails.



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Fluorogenic Kinetic Assay for High-Throughput Discovery of Stereoselective Ketoreductases Relevant to Pharmaceutical Synthesis

Publication date: Available online 13 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yen-Chi Thai, Anna Szekrenyi, Yuyin Qi, Gary W. Black, Simon J. Charnock, Wolf-Dieter Fessner
Enantiomerically pure 1-(6-methoxynaphth-2-yl) and 1-(6-(dimethylamino)naphth-2-yl) carbinols are fluorogenic substrates for aldo/keto reductase (KRED) enzymes, which allow the highly sensitive and reliable determination of activity and kinetic constants of known and unknown enzymes, as well as an immediate enantioselectivity typing. Because of its simplicity in microtiter plate format, the assay qualifies for the discovery of novel KREDs of yet unknown specificity among this vast enzyme superfamily. The suitability of this approach for enzyme typing is illustrated by an exemplary screening of a large collection of short-chain dehydrogenase/reductase (SDR) enzymes arrayed from a metagenomic approach. We believe that this assay format should match well the pharmaceutical industry's demand for acetophenone-type substrates and the continuing interest in new enzymes with broad substrate promiscuity for the synthesis of chiral, non-racemic carbinols.

Graphical abstract

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Application of In-vitro Screening Methods on Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitors

Publication date: Available online 13 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yue Wu, Zhensheng Jiang, Qidong You, Xiaojin Zhang
Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-α (HIF-α), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-α, which may lead to the degradation of HIF-α and eventually cause disenabling the expression of erythropoietin. Therefore, it is valid to improve anemia by inhibiting HIF-PHD2. In-vitro screening plays a vital role in searching for novel small molecule HIF-PHD2 inhibitors, thus, this review classified in-vitro screening methods which are used to hit novel HIF-PHD2 inhibitors.

Graphical abstract

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External pelvic and vaginal irradiation vs. vaginal irradiation alone as postoperative therapy in women with early stage uterine serous carcinoma: Results of a National Cancer Database analysis

Publication date: Available online 13 May 2017
Source:Brachytherapy
Author(s): Ankit Modh, Charlotte Burmeister, Adnan R. Munkarah, Mohamed A. Elshaikh
PurposeAdjuvant treatment in early stage uterine serous carcinoma (USC) usually consists of chemotherapy with vaginal brachytherapy (VB), pelvic external beam radiation therapy (EBRT), or combination. We compared survival outcomes across these various radiation treatment modalities using the National Cancer Database.Methods and MaterialsThe National Cancer Database was queried for adult females with histologically confirmed International Federation of Gynecology and Obstetrics 1988 Stage I–II USC diagnosed from 2003 to 2013 treated definitively with hysterectomy, adjuvant chemotherapy, and radiation therapy. χ² tests were used to assess differences by radiation type (VB, pelvic EBRT, and EBRT + VB) and various clinical variables. Kaplan–Meier and log-rank test methods were used to evaluate survival outcomes. Risk factors related to overall survival were identified by univariate and multivariate analysis.ResultsWe identified 1336 patients with USC who met our inclusion criteria. Most patients were treated with VB (66%) compared with EBRT (21%) or combination EBRT + VB (13%). The proportion of patients who received EBRT (including EBRT + VB) was higher for those who did not have a lymph node dissection or with fewer dissected lymph nodes. Patients treated with VB alone had longer 5-year survival rates (84% [95% confidence interval: 80, 90]) than those treated with EBRT (75% [95% confidence interval: 69, 80]) (p < 0.001). On multivariate analysis, the presence of lymphovascular space invasion (hazard ratio, 2.48; p < 0.001) and the absence of a lymph node dissection (hazard ratio, 2.24; p = 0.047) were independent predictors of overall survival.ConclusionsThis large hospital-based study suggests that VB alone may be sufficient for adjuvant radiation treatment in women with USC treated with adjuvant chemotherapy and who underwent an adequate surgical staging.



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Synthesis of a ternary Ag/RGO/ZnO nanocomposite via microwave irradiation and its application for the degradation of Rhodamine B under visible light

Abstract

Reduced graphene oxide supporting plasmonic photocatalyst (Ag) on ZnO has been synthesized via a facile two-step microwave synthesis using RGO/ZnO and AgNO₃. First step involves fabrication of RGO/ZnO via microwave irradiation. The nanocomposites were characterized by X-ray diffraction analysis, transmission electron microscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy. Ag/RGO/ZnO shows enhanced photoactivity under visible light for the degradation of Rhodamine B. Enhanced charge separation and migration have been assigned using UV-vis diffuse reflectance spectra, photoluminescence spectra, electrochemical impedance spectra, and TCSPC analysis. The improved photoactivity of Ag/RGO/ZnO can be ascribed to the prolonged lifetime of photogenerated electron–hole pairs and effective interfacial hybridization between RGO and Ag with ZnO nanoparticles. Ag nanoparticles can absorb visible light via surface plasmon resonance to enhance photocatalytic activity.

http://ift.tt/2pyzR0W

Light absorption of biomass burning and vehicle emission-sourced carbonaceous aerosols of the Tibetan Plateau

Abstract

Carbonaceous aerosols over the Tibetan Plateau originate primarily from biomass burning and vehicle emissions (BB and VEs, respectively). The light absorption characteristics of these carbonaceous aerosols are closely correlated with the burning conditions and represent key factors that influence climate forcing. In this study, the light absorption characteristics of elemental carbon (EC) and water-soluble organic carbon (WSOC) in PM_2.5 (fine particulate matter smaller than 2.5 μm) generated from BB and VEs were investigated over the Tibetan Plateau (TP). The results showed that the organic carbon (OC)/EC ratios from BB- and VE-sourced PM_2.5 were 17.62 ± 10.19 and 1.19 ± 0.36, respectively. These values were higher than the ratios in other regions, which was primarily because of the diminished amount of oxygen over the TP. The mass absorption cross section of EC (MAC_EC) at 632 nm for the BB-sourced PM_2.5 (6.10 ± 1.21 m².g⁻¹) was lower than that of the VE-sourced PM_2.5 (8.10 ± 0.98 m².g⁻¹), indicating that the EC content of the BB-sourced PM_2.5 was overestimated because of the high OC/EC ratio. The respective absorption per mass (α/ρ) values at 365 nm for the VE- and BB-sourced PM_2.5 were 0.71 ± 0.17 m².g⁻¹ and 0.91 ± 0.18 m².g⁻¹. The α/ρ value of the VEs was loaded between that of gasoline and diesel emissions, indicating that the VE-sourced PM_2.5 originated from both types of emissions. Because OC and WSOC accounts for most of the carbonaceous aerosols at remote area of the TP, the radiative forcing contributed by the WSOC should be high, and requires further investigation.

http://ift.tt/2qjuTSU

Clinical and Pathological Characteristic of Metastatic Malignant Mesothelioma Initially Diagnosed by Lymph Node Biopsy

Publication date: Available online 13 May 2017
Source:Pathology - Research and Practice
Author(s): Xiang-Lan Zhu, Li-Min Gao, Fen Li, Wei-ping Liu, Wen-Yan Zhang, Gan-Di Li, Xiu-Hui Zhang, Min Chen, Xiao-Yu Liu, Sha Zhao
BackgroundIt is a great challenge for pathologists to initially diagnose metastatic malignant mesothelioma (MM) by the lymph node biopsy without any history of primary MM. Because the onset of MM is hidden and the metastatic MM in lymph node is relatively uncommon. Besides, morphologic and immuohistochemestry features of MM are similar to other tumors.MethodsIn order to improve the initial diagnositic accuracy of metastatic MM from LN biopsy and to reduce or avoid the possibility of missed diagnosis or misdiagnosis, we had collected the clinical and pathological data of the metastatic MM cases in our department, and summarized the characteristics of morphological, immunohistochemical and fluorescence in situ hybridization (FISH) results.ResultsSeven patients (4 males and 3 females) with 21–73 year-old had been included in our study. Six cases showed serous cavity effusion, serosal thickening and systemic multiple lymph node enlargement. The "moderate, nice" tumor cells were arranged in variable patterns. Mitosis was hardly to be found and necrosis was absent. Four immunohistochemical staining panels and FISH detection had been used for diagnosis and differential diagnosis of MM. All cases expressed broad-spectrum epithelial markers and at least 2 mesothelial-cell-origin markers. None were positive for specific-tissue-origin markers, and all cases were diagnosed of malignancy according to immunohistochemical markers and detection of pl6 gene deletion.ConclusionIt is necessary for us to keep our awareness of metastatic MM in lymph node. Correct diagnosis of MM metastasis by lymph node biopsy were based on detailed understanding of the clinical manifestation and the image data, careful observation of morphologic characteristics, and properly using immunohistochemical markers or FISH detection if necessary for diagnosis and differential diagnosis.



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Prognostic value of putative cancer stem cell markers (CD24, CD44, CD133, and ALDH1) in human papillary thyroid carcinoma

Publication date: Available online 13 May 2017
Source:Pathology - Research and Practice
Author(s): Sang-Ah Han, Jae Hoon Jang, Kyu Yeoun Won, Sung-Jig Lim, Jeong-Yoon Song
We hypothesized that cancer stem cells (CSCs) are responsible for the poor outcome and aggressive clinicopathological factors. We surveyed the expression of selected CSC markers that are specifically expressed in thyroid papillary carcinoma (PTC). A total of 80 patients with PTC from 2011 to 2012 were enrolled. We selected CD24, CD44, CD133, and dehydrogenase 1 (ALDH1), as they have been suggested to be candidate CSC markers. Expression of these markers was investigated by immunohistochemical (IHC) staining. IHC staining for CD24, CD44, CD133 and ALDH1 was evaluated according to staining intensity and proportion. The intensity and proportion scores were multiplied together for a total score, which was either 0–2 (negative) or 3–7 (positive). IHC for CD133 in PTC was positive in 49 (61.3%) patients, and CD24 was positive in 28 (35.0%). Seventy-eight (97.5%) patients were CD44 positive and 79 (98.8%) were ALDH1 positive. When we assessed the relationship between CSC markers and clinicopathological factors in PTC, CD24 expression was inversely correlated with multifocality (p=0.045; odds ratio [OR], 0.370; 95% confidence interval [CI], 0.138–0.991) and CD44 expression was significantly correlated with a BRAF mutation (p=0.001; OR, 7.091; 95% CI, 4.101–12.262). However, CD133 and ALDH1 were not associated with any of the clinicopathological parameters. CD24 expression was inversely correlated with multifocality, and CD44 expression was significantly correlated with a BRAF mutation. Therefore, CD24 and CD44 are related to clinicopathological aggressive features and important for determining surgical extent in patients with PTC.



http://ift.tt/2retfkG

3D printing and modelling of customized implants and surgical guides for non-human primates

Publication date: Available online 13 May 2017
Source:Journal of Neuroscience Methods
Author(s): Xing Chen, Jessy K. Possel, Catherine Wacongne, Anne F. van Ham, P. Christiaan Klink, Pieter R. Roelfsema
BackgroundPrimate neurobiologists use chronically implanted devices such as pedestals for head stabilization and chambers to gain access to the brain and study its activity. Such implants are skull-mounted, and made from a hard, durable material, such as titanium.New methodHere we present a low-cost method of creating customized 3D-printed cranial implants that are tailored to the anatomy of individual animals. We performed pre-surgical computed tomography (CT) and magnetic resonance (MR) scans to generate three-dimensional (3D) models of the skull and brain. We then used 3D modeling software to design implantable head posts, chambers, and a pedestal anchorage base, as well as craniotomy guides to aid us during surgery. Prototypes were made from plastic or resin, while implants were 3D-printed in titanium. The implants underwent post-processing and received a coating of osteocompatible material to promote bone integration.ResultsTheir tailored fit greatly facilitated surgical implantation, and eliminated the gap between the implant and the bone. To date, our implants remain robust and well-integrated with the skull.Comparison with existing method(s)Commercial-off-the-shelf solutions typically come with a uniform, flat base, preventing them from sitting flush against the curved surface of the skull. This leaves gaps for fluid and tissue ingress, increasing the risk of microbial infection and tissue inflammation, as well as implant loss.ConclusionsThe use of 3D printing technology enabled us to quickly and affordably create unique, complex designs, avoiding the constraints levied by traditional production methods, thereby boosting experimental success and improving the wellbeing of the animals.

Graphical abstract

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Chondroitin Sulfate-Functionalized Polyamidoamine as a Tumor-targeted Carrier for miR-34a Delivery

Publication date: Available online 13 May 2017
Source:Acta Biomaterialia
Author(s): Wenqi Chen, Yong Liu, Xiao Liang, Yu Huang, Quanshun Li
Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4 h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy.Statement of SignificanceThe cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors.

Graphical abstract

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Photothermal and photodynamic activity of polymeric nanoparticles based on α-tocopheryl succinate-RAFT block copolymers conjugated to IR-780.

Publication date: Available online 13 May 2017
Source:Acta Biomaterialia
Author(s): Raquel Palao-Suay, Francisco M. Martin-Saavedra, María Rosa Aguilar, Clara Escudero Duch, Sergio Martín-Saldaña, Francisco J. Parra-Ruiz, Nathan A. Rohner, Susan N. Thomas, Nuria Vilaboa, Julio San Román
The aim of this work was the generation of a multifunctional nanopolymeric system that incorporates IR-780 dye, a near-infrared (NIR) imaging probe that exhibits photothermal and photodynamic properties; and a derivate of α-tocopheryl succinate (α-TOS), a mitochondria-targeted anticancer compound. IR-780 was conjugated to the hydrophilic segment of copolymer PEG-b-polyMTOS, based on poly(ethylene glycol) (PEG) and a methacrylic derivative of α-tocopheryl succinate (MTOS), to generate IR-NP, self-assembled nanoparticles (NPs) in aqueous media which exhibit a hydrophilic shell and a hydrophobic core. During assembly, the hydrophobic core of IR-NP could encapsulate additional IR-780 to generate derived subspecies carrying different amount of probe (IR-NP-eIR). Evaluation of photo-inducible properties of IR-NP and IR-NP-eIR were thoroughly assessed in vitro. Developed nanotheranostic particles showed distinct fluorescence and photothermal behavior after excitation by a laser light emitting at 808 nm. Treatment of MDA-MB-453 cells with IR-NP or IR-NP-eIR resulted in an efficient internalization of the IR-780 dye, while subsequent NIR-laser irradiation led to a severe decrease in cell viability. Photocytoxicity conducted by IR-NP, which could not be attributed to the generation of lethal hyperthermia, responded to an increase in the levels of intracellular reactive oxygen species (ROS). Therefore, the fluorescence imaging and inducible phototoxicity capabilities of NPs derived from IR-780-PEG-b-polyMTOS copolymer confer high value to these nanotheranostics tools in clinical cancer research.State of significanceMultifunctional polymeric nanoparticles (NPs) that combine imaging and therapeutic properties are highly valuable in cancer treatment. In this paper we describe the development of NPs that are fluorescent in the near-infrared (NIR). This is important for their visualization in living tissues that present low absorption and low autofluorescence in this wavelength region (between 700 and 1000 nm). Moreover, NPs present photothermal and photodynamic properties when NIR irradiated: the NPs produce an efficient increment of temperature and increase the intracellular reactive oxygen species (ROS) when laser irradiated at 808 nm. These tuneable photoinduced properties make the NPs highly cytotoxic after NIR irradiation and provides a new tool for highly precise cancer treatment.

Graphical abstract

http://ift.tt/2qgMBrJ

Visible light-switched cytosol release of siRNA by amphiphilic fullerene derivative to enhance RNAi efficacy in vitro and in vivo

Publication date: Available online 13 May 2017
Source:Acta Biomaterialia
Author(s): Jing Wang, Lifei Xie, Tao Wang, Fengxin Wu, Jie Meng, Jian Liu, Haiyan Xu
Cationic macromolecules are attractive for use as small interfering RNA (siRNA) carriers due to their performance in non-immunological reactions, customization during synthesis, and low costs compared to viral carriers. However, their low transfection efficiency substantially hinders their application in both clinical practices and academic research, which is mostly attributable to the low capacity of siRNA/cationic macromolecule complexes to escape lysosomes. To address this challenge, we designed an amphiphilic fullerene derivative (C60-Dex-NH2) for efficient and controllable siRNA delivery.To synthesize C60-Dex-NH2, terminally aminated dextran was conjugated to C60. The conjugate was further cationized by covalently introducing ethylenediamine to the dextran. The physicochemical characteristics of C60-Dex-NH2 was examined with elemental analyses, gel permeation chromatography, solid-state nuclear magnetic resonance (¹³C, HPDEC), agarose gel electrophoresis, and dynamic light scattering. The cytotoxicity, cellular uptake, intracellular distribution, and in vitro RNA interference (RNAi) of siRNA/C60-Dex-NH2 complex was evaluated in the human breast cancer cell line MDA-MB-231. The RNAi efficiencies mediated by C60-Dex-NH2in vivo was evaluated in subcutaneous tumor-bearing mice.The results showed that C60-Dex-NH2 has a specific amphiphilic skeleton and could form micelle-like aggregate structures in water, which could prevent siRNA from destroying by reactive oxygen species (ROS). When exposed to visible light, C60-Dex-NH2 could trigger controllable ROS generation which could destroy the lysosome membrane, promote the lysosomal escape, and enhance the gene silencing efficiency of siRNA in vitro and in vivo. The gene silencing efficiency could reach a maximum of 53% in the MDA-MB-231-EGFP cells and 69% in the 4T1-GFP-Luc2 tumor-bearing mice.Statement of SignificanceWe designed a novel photosensitive amphiphilic carrier (C60-Dex-NH2) for efficient and controllable siRNA delivery, which can be used in gene therapy.We showed that C60-Dex-NH2 could destroy lysosome membrane via controllable generation of ROS when exposed to light, which can help siRNA to escape from lysosome before degradation. This can enhance the gene silencing efficiency significantly and provides a useful way to regulate RNAi efficiency by light. One advantage for C60-Dex-NH2 system is C60 has broad absorbance spectrum and can be activated by weak visible light; Furthermore, C60-Dex-NH2has a specific amphiphilic structure, which may prevent siRNA from degrading and allows C60-Dex-NH2 to embed into the lipid membrane of lysosome to improve the ROS induced lysosomal disturbance after internalization.

Graphical abstract

http://ift.tt/2qgN3pR

A geometrically adjustable receive array for imaging marmoset cohorts

Publication date: 1 August 2017
Source:NeuroImage, Volume 156
Author(s): Kyle M. Gilbert, Joseph S. Gati, L. Martyn Klassen, Peter Zeman, David J. Schaeffer, Stefan Everling, Ravi S. Menon
The common marmoset (Callithrix jacchus) is an increasingly popular animal model for translational neuroscience studies, during which anatomical and functional MRI can be useful investigative tools. To attain the requisite SNR for high-resolution acquisitions, the radiofrequency coil must be optimized for the marmoset; however, relatively few custom coils have been developed that maximize SNR and are compatible with accelerated acquisitions. For the study of large populations of animals, the heterogeneity in animal size reduces the effectiveness of a "one size fits all" approach to coil sizing and makes coils tailored to individual animals cost and time prohibitive. The approach taken in this study was to create an 8-channel phased-array receive coil that was adjustable to the width of the marmoset head, thereby negating the need for tailored coils while still maintaining high SNR. Two marmosets of different size were imaged on a 9.4-T small-animal scanner. Consistent SNR was achieved in the periphery of the brain between head sizes. When compared to a 15-channel, "one size fits all" receive coil, the adjustable coil achieved 57% higher SNR in the superior frontal and parietal cortices and 29% higher SNR in the centre of the brain. The mean geometry factor of the adjustable coil was less than 1.2 for a 2-fold reduction factor in the left-right and anterior-posterior directions. Geometry factors were compared to the 15-channel coil to guide future designs. The adjustable coil was shown to be a practical means for anatomical and echo-planar imaging of marmoset cohorts.

Graphical abstract

http://ift.tt/2r62mTA

Cosmetics, Vol. 4, Pages 14: Meta Analysis of Skin Microbiome: New Link between Skin Microbiota Diversity and Skin Health with Proposal to Use This as a Future Mechanism to Determine Whether Cosmetic Products Damage the Skin

There is a skin allergy epidemic in the western world, and the rate of deterioration has increased significantly in the past 5–10 years. It is probable that there are many environmental contributing factors, yet some studies have linked it primarily to the rise in the use of synthetic chemical ingredients in modern cosmetics. Our challenge, therefore, was to find a mechanism to determine the effect these substances have on skin health, and whether they really are a primary cause of long term damage to the skin. The first problem is the lack of any definitive way to measure skin health. Motivated by the overwhelming evidence for a link between deficient gut flora and ill health, we decided to look at whether our skin microbiota could similarly be used as an indicator of skin health. Our research illustrates how microbiota diversity alone can predict whether skin is healthy or not, after we revealed a complete lack of conclusive findings linking the presence or abundance of particular species of microbe to skin problems. This phenomenon is replicated throughout nature, where high biodiversity always leads to healthy ecosystems. 'Caveman' skin, untouched by modern civilisation, was far different to "western" skin and displayed unprecedented levels of bacterial diversity. The less exposed communities were to western practices, the higher the skin diversity, which is clear evidence of an environmental factor in the developed world damaging skin. For the first time we propose benchmark values of diversity against which we can measure skin to determine how healthy it is. This gives us the ability to be able to predict which people are more likely to be prone to skin ailments, and start to test whether cosmetic ingredients and products are a main cause of the skin allergy epidemic.

http://ift.tt/2pyekW7

Determination of avermectins by the internal standard recovery correction - high performance liquid chromatography - quantitative Nuclear Magnetic Resonance method

Publication date: 1 September 2017
Source:Talanta, Volume 172
Author(s): Wei Zhang, Ting Huang, Hongmei Li, Xinhua Dai, Can Quan, Yajuan He
Quantitative Nuclear Magnetic Resonance (qNMR) is widely used to determine the purity of organic compounds. For the compounds with lower purity especially molecular weight more than 500, qNMR is at risk of error for the purity, because the impurity peaks are likely to be incompletely separated from the peak of major component. In this study, an offline ISRC-HPLC-qNMR (internal standard recovery correction - high performance liquid chromatography - qNMR) was developed to overcome this problem. It is accurate by excluding the influence of impurity; it is low-cost by using common mobile phase; and it extends the applicable scope of qNMR. In this method, a mix solution of the sample and an internal standard was separated by HPLC with common mobile phases, and only the eluents of the analyte and the internal standard were collected in the same tube. After evaporation and re-dissolution, it was determined by qNMR. A recovery correction factor was determined by comparison of the solutions before and after these procedures. After correction, the mass fraction of analyte was constant and it was accurate and precise, even though the sample loss varied during these procedures, or even in bad resolution of HPLC. Avermectin B1a with the purity of ~93% and the molecular weight of 873 was analyzed. Moreover, the homologues of avermectin B1a were determined based on the identification and quantitative analysis by tandem mass spectrometry and HPLC, and the results were consistent with the results of traditional mass balance method. The result showed that the method could be widely used for the organic compounds, and could further promote qNMR to become a primary method in the international metrological systems.

Graphical abstract

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Pre-operative Evaluation of Axillary Lymph Node Status in Patients with Suspected Breast Cancer Using Shear Wave Elastography

Publication date: Available online 13 May 2017
Source:Ultrasound in Medicine & Biology
Author(s): Ji Hyun Youk, Eun Ju Son, Jeong-Ah Kim, Hye Mi Gweon
The aim of this study was to evaluate shear wave elastography (SWE) for pre-operative evaluation of axillary lymph node (LN) status in patients with suspected breast cancer. A total of 130 axillary LNs in 130 patients who underwent SWE before fine-needle aspiration, core biopsy or surgery were analyzed. On gray-scale images, long and short axes, shape (elliptical or round), border (sharp or unsharp) and cortical thickening (concentric, eccentric or no fatty hilum) of LNs were assessed. On SWE, mean, maximum, minimum, standard deviation and the lesion-to-fat ratio (Eratio) values of elasticity were collected. Gray-scale and SWE features were compared statistically between metastatic and benign LNs using the χ²-test and independent t-test. Diagnostic performance of each feature was evaluated using the area under the receiver operating characteristic curve (AUC). Logistic regression analysis was used to determine gray-scale or SWE features independently associated with metastatic LNs. Of the 130 LNs, 65 (50%) were metastatic and 65 (50%) were benign after surgery. Metastatic LNs were significantly larger (p = 0.018); had higher elasticity indexes at SWE (p < 0.0001); and had higher proportions of round shape (p = 0.033), unsharp border (p = 0.048) and eccentric cortical thickening or no fatty hilum (p = 0.005) compared with benign LNs. On multivariate analysis, Eratio was independently associated with metastatic LNs (odds ratio = 3.312, p = 0.008). Eratio had the highest AUC among gray-scale (0.582–0.719) and SWE (0.900–0.950) variables. SWE had good diagnostic performance in metastatic axillary LNs, and Eratio was independently associated with metastatic LNs.



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siRNA Targeting Net1 Reduces the Angiogenesis and Tumor Growth of in vivo Cervical Squamous Cell Carcinoma through VEGF down-regulation

Publication date: Available online 13 May 2017
Source:Human Pathology
Author(s): Yuting Zhang, Pei Xia, Wenhui Zhang, Min Yan, Xiujuan Xiong, Weiwei Yu, Enlin Song
Net1, a guanine nucleotide exchange factor, is implicated in cancer cell invasion through activation of RhoA. However, there is still no report on the association between Net1 and cancer angiogenesis. The current study was designed to explore the roles of Net1 in the angiogenesis of cervical squamous cell carcinoma (CSCC) and further observe the effects of Net1 siRNA on the tumor growth. Net1 was overexpressed in CSCC samples (n=80), correlated to the cancer microvessel density (MVD, r=0.223, P=.026) and related to aggressive clinical behaviors, including depth of cervical wall invasion (P=.041), parametrial involvement (P=.037), lymph node metastasis (P=.021) and vascular invasion (P=.018). Human umbilical vein endothelial cells (HUVECs) treated with supernatant of SiHa cells with Net1 siRNA showed significantly decreased ability of proliferation (0.75±0.038 vs 1.0±0.015, P<.001), migration (39.3±6.5 vs 66.0±10.1, P=.019) and tube formation (13.5±3.05 vs 21.7±2.89, P=.030) compared to those HUVECs treated with normal SiHa cells supernatant. Net1 siRNA of SiHa decreased VEGF expression level (0.60±0.026 vs 0.78±0.031, P=.02). Furthermore, Net1 siRNA significantly reduced tumor growth (P=.037) and MVD (5.8±0.43 vs 3.4±0.55, P=.012) and decreased the expression level of VEGF (0.31±0.002 vs 0.39±0.004, P<.001) in CSCC. In conclusion, Net1 promotes the angiogenesis of CSCC, and siRNA targeting Net1 can effectively reduce the angiogenesis and thus inhibit the tumor growth of CSCC in vivo.



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CO2: Editorial Board/Subscription info.

Publication date: June 2017
Source:Progress in Neurobiology, Volume 153





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A method to predict PM2.5 resulting from compliance with national ambient air quality standards

Publication date: August 2017
Source:Atmospheric Environment, Volume 162
Author(s): James T. Kelly, Adam Reff, Brett Gantt
Area-wide composite monitor time series of daily PM2.5 (particulate matter with aerodynamic diameter < 2.5 μm) that correspond to just meeting U.S. National Ambient Air Quality Standards (NAAQS) have been used in risk assessments conducted during periodic reviews of PM NAAQS by U.S. EPA. Such time series were developed by adjusting ambient PM2.5 over an area according to a prescribed spatial pattern. A new technique for this purpose based on photochemical grid modeling for the continental U.S. is demonstrated here. The method uses a spatial prediction model to impute missing data and PM2.5 relative response factors based on simulations with reductions in anthropogenic emissions of primary PM2.5 and PM2.5 precursors (i.e., NOx and SO2). Case study results indicate that relatively urban sites are generally more responsive to primary PM2.5 reductions, while outlying sites are more responsive to NOx and SO2 reductions. The method enables the sensitivity of outcomes to be examined by quickly implementing PM2.5 adjustments based on different combinations of primary PM2.5 and NOx and SO2 emission reductions for areas of the U.S.



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Novel method for the depletion of cariogenic bacteria using dextranomer microspheres

Summary

Streptococcus mutans is recognized as one of the key contributors to the dysbiotic state that results in dental caries. While existing treatment strategies reduce the incidence of tooth decay, they also eliminate both the cariogenic and beneficial microbes. Here we introduce a novel treatment alternative using Sephadex, cross-linked dextranomer microspheres (DMs), typically used for gel filtration chromatography. In addition DM beads can be used for affinity purification of glucosyltransferases (GTFs) from S. mutans. In this study we take advantage of the native pathogenic mechanisms used by S. mutans to adhere, form a biofilm and induce dental caries through the expression of surface associated GTFs. We demonstrate that planktonic and biofilm grown (adhered to hydroxy apatite coated pegs to mimic the tooth surface) S. mutans, specifically and competitively attach to DMs. Further investigation demonstrated that DMs are a specific affinity resin for S. mutans and other cariogenic/pathogenic oral streptococci, whereas other commensal and probiotic strains failed to readily adhere to DMs. Using antimicrobial cargo loaded into the DM lumen, we demonstrate that when in co-culture with non-binding to even modest binding commensal species, S. mutans was selectively killed. This proof of concept study introduces a novel means to safely and effectively reduce the pool of S. mutans and other pathogenic streptococci in the oral cavity with limited disturbance of the necessary commensal (healthy) microbiota when compared to current oral healthcare products.

This article is protected by copyright. All rights reserved.

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Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre

Publication date: July 2017
Source:European Journal of Cancer, Volume 79
Author(s): Margarida Matias, Gwénaël Le Teuff, Laurence Albiges, Annalisa Guida, Caroline Brard, Giulia Bacciarelo, Yohann Loriot, Christophe Massard, Nathalie Lassau, Karim Fizazi, Bernard Escudier
BackgroundAxitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials.MethodsA prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored.ResultsOne-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in 38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n = 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF.ConclusionEfficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy.



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Squamous cell carcinoma of the pancreas: A systematic review and pooled survival analysis

Publication date: July 2017
Source:European Journal of Cancer, Volume 79
Author(s): Ioannis Ntanasis-Stathopoulos, Diamantis I. Tsilimigras, Despoina Georgiadou, Prodromos Kanavidis, Olga Riccioni, Charitini Salla, Theodora Psaltopoulou, Theodoros N. Sergentanis
The diagnosis and treatment of squamous cell carcinoma of the pancreas pose dilemmas in the clinical practice. The present study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eligible articles were sought in MEDLINE up to 30th April 2016. A pooled Cox regression analysis was performed to evaluate factors potentially associated with overall survival (OS) and relapse-free survival (RFS). Fifty-four cases of pure squamous cell pancreatic carcinomas were identified in total. The mean age was 61.9 years, and most patients were males (61.1%). The median OS was 7 months. Resectability (p = 0.003) and more recent publication year (p < 0.001) were associated with better OS, as was low/intermediate tumour grade (p = 0.032) with RFS. Despite its poor prognosis, survival rates of pancreatic squamous cell carcinoma seem improved during the recent years; resectability and low/intermediate grade emerged as favourable prognostic factors. Collaborative epidemiological studies are deemed necessary to further validate the results stemming from the published case reports of this rare entity.



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Scholar : These new articles for AIDS Care are available online

The online platform for Taylor & Francis Online content New for AIDS Care and online now on Taylor & Francis Online: Original Articles Minority stress model components and affective well-being in a sample of sexual orientation minority adults living with HIV/AIDS Robert J. Cramer, Alixandra C. Burks, Martin Plöderl & Praveen Durgampudi Pages: 1-7 | DOI: 10.1080/09540121.2017.1327650 Free access World Diabetes Day research collection – Eyes on Diabetes. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Inadequate target volume delineation and local–regional recurrence after intensity-modulated radiotherapy for human papillomavirus-positive oropharynx cancer

Publication date: Available online 13 May 2017
Source:Radiotherapy and Oncology
Author(s): Allen M. Chen, Robert Chin, Philip Beron, Taeko Yoshizaki, Argin G. Mikaeilian, Minsong Cao
PurposeTo perform a spatial analysis of local–regional recurrences, in relation to quantitative dose distribution, among patients treated by intensity-modulated radiotherapy (IMRT) for human papillomavirus (HPV)-positive oropharyngeal cancer.Methods and materialsThe records of 107 consecutive patients who presented for consideration of re-irradiation for local–regional recurrent disease occurring in a previously irradiated field were reviewed. The original IMRT plans were retrieved for those with HPV-positive disease originating from the oropharynx, and deformable image registration was used to fuse the magnetic resonance imaging (MRI) and positron emission tomography (PET) scans obtained at recurrence to the pre-treatment planning computed tomography (CT) dataset. The recurrent tumor volume (Vrecur) was subsequently identified on axial imaging, and the dose of radiation received by Vrecur was then calculated and analyzed using dose–volume histograms.ResultsA total of 83 recurrent lesions occurring in 50 oropharyngeal cancer patients were HPV-positive and met inclusion criteria. Using PET-defined Vrecur, thirty-three lesions were classified as in-field recurrences (40%), 35 were marginal misses (41%), and 15 were true misses (18%). Using the MRI-defined Vrecur, thirty-seven lesions were classified as in-field recurrences (45%), 32 were marginal misses (39%), and 14 were true misses (17%).ConclusionA significant proportion of local–regional recurrences from HPV-positive oropharyngeal cancer represented geographical misses which possibly could have been prevented with more meticulous attention to IMRT planning. This finding has important implications with respect to ongoing attempts to de-escalate radiation dose for this disease. Our data highlight the importance of robust quality assurance with careful review of target volumes prior to the initiation of IMRT.



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Identification of somatic TERT promoter mutations in familial non-medullary thyroid carcinomas (FNMTC)

Abstract

Objective

The genes causing Familial Non-Medullary Thyroid Carcinoma (FNMTC) identified to date are only involved in a small fraction of the families. Recently, somatic mutations in TERT promoter region and in EIF1AX gene were reported in thyroid tumours of undefined familial status. The aim of the present study was to investigate the role of TERT and EIF1AX mutations in familial thyroid tumours.

Design

The promoter region of TERT was sequenced in leukocyte DNA of the probands from 75 FNMTC families. In tumours from 54 familial cases, we assessed somatic TERT promoter, RAS and BRAF hotspot mutations, and the whole EIF1AX gene.

Results

No potentially pathogenic germline variants were identified in TERT in the 75 FNMTC families' probands. In the 54 carcinomas, we identified five cases (9%) with hotspot somatic TERT promoter mutations. BRAF mutations were found in 41% of the tumours. All TERT positive samples were also positive for BRAF p.Val600Glu and this co-occurrence was found to be statistically significant (P=0.008). RAS mutations were detected in four tumours wild-type for TERT (7%). Evaluation of tumour mutation data together with the patients' clinicopathological features revealed a significant correlation between TERT plus BRAF mutations and advanced tumour stage (T4) (P=0.020). No mutations were identified in EIF1AX.

Conclusions

The results of this study suggest that TERT promoter and EIF1AX mutations are not frequently involved in FNMTC aetiology. However, we show for the first time that TERT alterations are associated with familial thyroid tumour progression. Our data also suggest that TERT mutations are more often found in concomitance with BRAF mutations in advanced stages of FNMTC.

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DNA-assisted upconversion nanoplatform for imaging-guided synergistic therapy and laser-switchable drug detoxification

Publication date: August 2017
Source:Biomaterials, Volume 136
Author(s): Luoyuan Li, Panlong Hao, Peng Wei, Limin Fu, Xicheng Ai, Jianping Zhang, Jing Zhou
The side effects of chemotherapy bring significant physical and psychological suffering to patients. To solve this urgent medical problem, Yb³⁺ and Er³⁺ co-doped NaLuF4 upconversion nanoparticles (UCNPs) were constructed for upconversion luminescence (UCL)-labeled diagnosis under 980 nm laser irradiation. The UCNPs were then modified layer by layer with polypyrrole and a special programming DNA segment as photothermal conversion agents and controllable drug carriers, respectively. The nanoplatform was successfully used for imaging-guided synergistic therapy (photothermal therapy and chemotherapy) at a safe power density (300 mW cm⁻²), and DNA-assisted detoxification at lower temperature in cancer cells when the laser off. The synergistic therapy of the nanoplatform achieved a higher therapeutic index (∼85%) than chemotherapy only (∼44%) and photothermal therapy only (∼25%) in vitro. In vivo experiments also suggested that the nanoplatform had a higher therapeutic effect and lower side effects. The toxicity study was also evaluated, indicating the nanoplatform is low toxic to living system. This multifunctional upconversion nanoplatform provided an innovative method for imaging-guided photothermal-chemotherapy and laser-switchable drug detoxification.



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Tailoring nanostructured lipid carriers for the delivery of protein antigens: Physicochemical properties versus immunogenicity studies

Publication date: August 2017
Source:Biomaterials, Volume 136
Author(s): Thomas Courant, Emilie Bayon, Hei Lanne Reynaud-Dougier, Christian Villiers, Mathilde Menneteau, Patrice N. Marche, Fabrice P. Navarro
New vaccine formulations are still highly anticipated in the near-future to face incoming health challenges, such as emergence or reemergence of severe infectious diseases, immunosenescence associated with elderly or the spread of pathogens resistant to antibiotics. In particular, new nanoparticle-based adjuvants are promising for sub-unit vaccines in order to elicit potent and long lasting immune responses with a better control on their safety. In this context, an innovative delivery system of protein antigens has been designed based on the chemical grafting of the antigen onto the shell of Nanostructured Lipid Carriers (NLC). By using the well-known ovalbumin (OVA) as model of protein antigen, we have compared the immunogenicity properties in mice of different formulations of NLC grafted with OVA, by studying the influence of two main parameters: the size (80 nm versus 120 nm) and the surface charge (anionic versus cationic). We have shown that all mice immunized with OVA delivered through NLC produced much higher antibody titers for all tested formulations as compared to that immunized with OVA or OVA formulated in Complete Freund Adjuvant (CFA, positive control). More interestingly, the 80 nm anionic lipid particles were the most efficient antigen carrier for eliciting higher humoral immune response, as well as cellular immune response characterized by a strong secretion of gamma interferon (IFN-γ). These results associated with the demonstrated non-immunogenicity of the NLC carrier by itself open new avenues for the design of smart sub-unit vaccines containing properly engineered lipid nanoparticles which could stimulate or orient the immune system in a specific way.



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Editorial board

Publication date: August 2017
Source:Biomaterials, Volume 135





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