Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers, Vol. 9, Pages 118: EML4-ALK Variants: Biological and Molecular Properties, and the Implications for Patients

Cancers doi: 10.3390/cancers9090118

Authors: Sarah Sabir Sharon Yeoh George Jackson Richard Bayliss

Since the discovery of the fusion between EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase), EML4-ALK, in lung adenocarcinomas in 2007, and the subsequent identification of at least 15 different variants in lung cancers, there has been a revolution in molecular-targeted therapy that has transformed the outlook for these patients. Our recent focus has been on understanding how and why the expression of particular variants can affect biological and molecular properties of cancer cells, as well as identifying the key signalling pathways triggered, as a result. In the clinical setting, this understanding led to the discovery that the type of variant influences the response of patients to ALK therapy. Here, we discuss what we know so far about the EML4-ALK variants in molecular signalling pathways and what questions remain to be answered. In the longer term, this analysis may uncover ways to specifically treat patients for a better outcome.

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Launch of new Atlas of Colposcopy

The Section of Early Detection and Prevention of the International Agency for Research of Cancer (IARC) is pleased to announce the launch of a new atlas of colposcopy. The Atlas of Colposcopy: Principles and Practice is a digital tool to train students, nurses, and gynaecologists, particularly in developing countries, where resources are limited. The atlas, which is freely available on the website of the IARC Screening Group, offers a wide range of digital resources to help those involved in diagnosing or treating cervical cancer or precancerous lesions. The tool includes videos, case studies, and quizzes.

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Editorial Board / Contents / Imprint

Breast Care 2017;12:201-206

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Added Value of Digital Breast Tomosynthesis Combined with Digital Mammography According to Reader Agreement: Changes in BI-RADS Rate and Follow-Up Management

Background: The aim of this study was to evaluate the added value of digital breast tomosynthesis (DBT) when combined with digital mammography (DM) in BI-RADS assessment and follow-up management. Methods: From February 2014 to January 2015, 214 patients underwent DM and DBT, acquired with a Siemens Mammomat Inspiration unit. 2 expert readers independently reviewed the studies in 2 steps: DM and DM+DBT, according to BI-RADS rate. Patients with BI-RADS 0, 3, 4, and 5 were recalled for work-up. Inter-reader agreement for BI-RADS rate and work-up rate were evaluated using Cohen's kappa. Results: Inter-reader agreement (#x03BA; value) for BI-RADS classification was 0.58 for DM and 0.8 for DM+DBT. DM+DBT increased the number of BI-RADS 1, 2, 4, 5 and reduced the number of BI-RADS 0 and 3 for both readers compared to DM alone. Regarding work-up rate agreement, #x03BA; was poor for DM and substantial (0.7) for DM+DBT. DM+DBT also reduced the work-up rate for both Reader 1 and Reader 2. Conclusion: DM+DBT increased the number of negative and benign cases (BI-RADS 1 and 2) and suspicious and malignant cases (BI-RADS 4 and 5), while it reduced the number of BI-RADS 0 and 3. DM+DBT also improved inter-reader agreement and reduced the overall recall for additional imaging or short-interval follow-up.
Breast Care 2017;12:218-222

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Advanced Imaging for Precision Medicine in Breast Cancer: From Morphology to Function

Breast Care 2017;12:208-210

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Dynamic Contrast-Enhanced Magnetic Resonance Imaging in the Assessment of Inflammatory Breast Cancer Prior to and After Neoadjuvant Treatment

Background: The aim of this study was to describe the dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) features of inflammatory breast cancer (IBC) and to assess the value of DCE-MRI for the prediction of pathological complete response (pCR). Methods: Image analysis was performed in 15 patients with IBC (cT4d) and 12 patients with non-IBC (cT2), and included the assessment of BIRADS characteristics, skin alterations, enhancement characteristics, and changes post chemotherapy. Sensitivity and specificity of DCE-MRI for the presence of residual disease were obtained. Pearson's correlation coefficients were calculated comparing the (preoperative) tumor size with the histological size. Results: Skin thickening/enhancement (80%) and non-mass-like enhancement (66.7%) occurred more often in IBC (16.7 vs. 8.3% in non-IBC). In 2 of 3 cases of IBC, pCR was correctly predicted (sensitivity 92%, specificity 67%), compared to 3 of 5 cases in non-IBC (sensitivity 86%, specificity 40%). Lower peak enhancement might be associated with a higher likelihood of pCR in IBC. No other parameters predicted eventual pCR. In IBC, no correlation between preoperative tumor size and histological size was found (r = 0.22, p = 0.50), whereas in non-IBC, size estimations were more accurate (r = 0.75, p = 0.03). Conclusion: IBC is characterized on MRI by skin changes and non-mass-like enhancement. Radiological complete response seems indicative of pCR in IBC and non-IBC. Size estimation of residual disease in IBC appears to be inaccurate.
Breast Care 2017;12:224-229

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Results of Short-Term Follow-Up in BI-RADS 3 and 4a Breast Lesions with a Histological Diagnosis of Fibroadenoma at Percutaneous Needle Biopsy

Objective: To evaluate the usefulness of short-term (6 months) follow-up in patients with Breast Imaging Report and Data System (BI-RADS) 3 and 4a lesions, after a diagnosis of fibroadenoma at an image-guided biopsy. Patients and Methods: The data of 318 women with 349 biopsy-proven fibroadenomas, a 6-month follow-up, and a follow-up of ≥ 24 months were retrospectively reviewed. Information on clinical history, lesion characteristics on ultrasound (US), mammography, and magnetic resonance imaging (MRI), BI-RADS classification, and follow-up was collected. The false-negative (FN) rate and the negative predictive value (NPV) for the biopsy were calculated. Results: 43 patients (13.5%) presented with a palpable nodule; 18 (5.7%) had a history of breast cancer. There were 334 lesions visible on US (95.7%), 57 on US and mammography (16.3%), and 15 on mammography only (4.3%); 37 lesions were first detected on MRI. All lesions were stable at 6 months. After an at least 1-year follow-up, 4 lesions changed their features and were excised. Histology showed 1 invasive lobular cancer, 1 ductal carcinoma in situ, 1 phyllodes tumor, and 1 papilloma. The FN rate of the needle biopsy was 1.1% and the NPV was 98.9%. Conclusion: For lesions initially described as BI-RADS 3 and 4a with a histological diagnosis of fibroadenoma after biopsy, short-term follow-up can be avoided.
Breast Care 2017;12:238-242

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Quality of life after thyroidectomy in patients with nontoxic nodular goiter: A prospective cohort study

Abstract

Background

Using the thoroughly validated Thyroid-Related Quality-of-Life Patient-Reported Outcome (ThyPRO) questionnaire, the purpose of this study was to investigate changes in disease-specific quality of life (QOL) after surgical treatment in patients with benign nontoxic multinodular goiters.

Method

Patients with goiters scheduled for thyroid surgery (n = 106) and individuals from the general population (n = 739) were studied. The ThyPRO data before, 3 months, and 6 months after surgery were compared with normative scores from the general population using a linear mixed model and t tests.

Results

Before surgery, patients with goiters experienced poorer scores on all scales compared to the general population. After surgery, moderate to large improvements were seen in goiter symptoms, tiredness, anxiety, and overall QOL. After surgery, all scales returned to values equal to the general population. The degree of anxiety was, in fact, lower than in the general population.

Conclusion

Thyroid surgery leads to significant benefit among patients with benign nontoxic goiters by restoring QOL equal to that in the general population.

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Quality of life after thyroidectomy in patients with nontoxic nodular goiter: A prospective cohort study

Abstract

Background

Using the thoroughly validated Thyroid-Related Quality-of-Life Patient-Reported Outcome (ThyPRO) questionnaire, the purpose of this study was to investigate changes in disease-specific quality of life (QOL) after surgical treatment in patients with benign nontoxic multinodular goiters.

Method

Patients with goiters scheduled for thyroid surgery (n = 106) and individuals from the general population (n = 739) were studied. The ThyPRO data before, 3 months, and 6 months after surgery were compared with normative scores from the general population using a linear mixed model and t tests.

Results

Before surgery, patients with goiters experienced poorer scores on all scales compared to the general population. After surgery, moderate to large improvements were seen in goiter symptoms, tiredness, anxiety, and overall QOL. After surgery, all scales returned to values equal to the general population. The degree of anxiety was, in fact, lower than in the general population.

Conclusion

Thyroid surgery leads to significant benefit among patients with benign nontoxic goiters by restoring QOL equal to that in the general population.

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Global Medical Device Technology market Trends and forecasts

Global Medical Device Technology market by type, by End User, by region -Industry Analysis, Size, Share, Growth, Trends and forecasts According to the report "Global Medical Device Technologies market", published by Market Data Forecast, the global market is projected to reach USD 634.5 billion by 2021, at a CAGR of 5.6% from 2016 to 2021. For full report refer to http://ift.tt/2gIHuhD ..

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3,6-Dihydroxyflavone regulates microRNA-34a through DNA methylation

Breast cancer is the common cancer in China. In previous study, we determined that 3,6-dihydroxyflavone (3,6-DHF) increases miR-34a significantly in breast carcinogenesis, but the mechanism remains unclear.

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Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy

Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fc-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab), and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor-seeking immune cells. Mol Cancer Ther; 16(9); 1887–97. ©2017 AACR.

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Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient–derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validated by immunoblots, was significantly inhibited by the drug combination in several myeloma cell lines. Furthermore, 88% of the 34 genes downregulated have MYC-binding sites in their promoters, and the drug combination cooperatively reduced MYC half-life by 55% and increased degradation. Cells with MYC mutations were refractory to the combination. Thus, integrative approaches to understand drug synergy identified a clinically actionable strategy to inhibit MYC/E2F activity and tumor cell growth in vivo. Mol Cancer Ther; 16(9); 2008–21. ©2017 AACR.

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ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell–originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843–54. ©2017 AACR.

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Metformin Synergizes with BCL-XL/BCL-2 Inhibitor ABT-263 to Induce Apoptosis Specifically in p53-Defective Cancer Cells

p53 deficiency, a frequent event in multiple kinds of malignancies, decreases the sensitivity of diverse targeted chemotherapeutics including the BCL-XL/BCL-2 inhibitor ABT-263. Loss of p53 function can activate mTOR complex 1 (mTORC1), which may make it a vulnerable target. Metformin has shown anti-neoplastic efficiency partially through suppressing mTORC1. However, it remains unknown whether mTORC1 activation confers ABT-263 resistance and whether metformin can overcome it in the p53-defective contexts. In this study, we for the first time demonstrated that metformin and ABT-263 synergistically elicited remarkable apoptosis through orchestrating the proapoptotic machineries in various p53-defective cancer cells. Mechanistic studies revealed that metformin sensitized ABT-263 via attenuating mTORC1-mediated cap-dependent translation of MCL-1 and survivin and weakening internal ribosome entry site (IRES)-dependent translation of XIAP. Meanwhile, ABT-263 sensitized metformin through disrupting the BCL-XL/BIM complex. However, metformin and ABT-263 had no synergistic killing effect in p53 wild-type (p53-WT) cancer cells because the cotreatment dramatically induced the senescence-associated secretory phenotype (SASP) in the presence of wild type p53, and SASP could aberrantly activate the AKT/ERK–mTORC1–4EBP1–MCL-1/survivin signaling axis. Blocking the axis using corresponding kinase inhibitors or neutralizing antibodies against different SASP components sensitized the cotreatment effect of metformin and ABT-263 in p53-WT cancer cells. The in vivo experiments showed that metformin and ABT-263 synergistically inhibited the growth of p53-defective (but not p53-WT) cancer cells in tumor xenograft nude mice. These results suggest that the combination of metformin and ABT-263 may be a novel targeted therapeutic strategy for p53-defective cancers. Mol Cancer Ther; 16(9); 1806–18. ©2017 AACR.

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Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells

Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by ¹⁴C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance. Mol Cancer Ther; 16(9); 1819–30. ©2017 AACR.

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Antitumor Synergism and Enhanced Survival with a Tumor Vasculature-Targeted Enzyme Prodrug System, Rapamycin, and Cyclophosphamide

Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with Annexin A1 or Annexin A5. Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart nonnative methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of nontoxic selenomethionine. The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of nonnative proteins and/or DNA required with other enzyme prodrug systems. The enzyme fusion exhibits strong and stable in vitro binding with dissociation constants in the nanomolar range for both human and mouse breast cancer cells and in a cell model of tumor vascular endothelium. Daily administration of the therapy suppressed growth of highly aggressive triple-negative murine 4T1 mammary tumors in immunocompetent BALB/cJ mice and MDA-MB-231 tumors in SCID mice. Treatment did not result in the occurrence of negative side effects or the elicitation of neutralizing antibodies. On the basis of the vasculature-targeted nature of the therapy, combinations with rapamycin and cyclophosphamide were evaluated. Rapamycin, an mTOR inhibitor, reduces the prosurvival signaling of cells in a hypoxic environment potentially exacerbated by a vasculature-targeted therapy. IHC revealed, unsurprisingly, a significant hypoxic response (increase in hypoxia-inducible factor 1 α subunit, HIF1A) in the enzyme prodrug–treated tumors and a dramatic reduction of HIF1A upon rapamycin treatment. Cyclophosphamide, an immunomodulator at low doses, was combined with the enzyme prodrug therapy and rapamycin; this combination synergistically reduced tumor volumes, inhibited metastatic progression, and enhanced survival. Mol Cancer Ther; 16(9); 1855–65. ©2017 AACR.

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IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma

Inflammation mediated by activation of JAK/STAT signaling is a major cause of chemotherapy resistance in cancer. We studied the impact of selectively blocking the IL6 receptor (IL6R) as a strategy to inhibit IL6-induced STAT activation and to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). To do this, STAT activation was investigated in tumors arising spontaneously in LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1Cre (KPC) mice. Plasma from patients with PDAC was assessed for its ability to activate STAT3/SOCS3 in human monocytes using immunofluorescence microscopy and quantitative gene expression assays. KPC mice and syngeneic mice (wild type and IL6^–/–) implanted with KPC-derived cell lines were treated with an IL6R-blocking antibody (anti-IL6R). The impact of treatment on tumor growth in KPC mice and mice with KPC-derived tumor implants was monitored using ultrasonography and calipers, respectively. Tumors were analyzed by IHC to detect changes in STAT activation, tumor viability, and proliferation. We found that STAT3 was the most activated STAT protein in PDAC tumors from KPC mice. Plasma from patients with advanced PDAC stimulated STAT3/SOCS3 activation in human monocytes. In mice, anti-IL6R antibodies targeted Ly6C^hi monocytes, inhibited STAT3 activation in tumor cells, and decreased tumor cell proliferation in vivo. IL6R blockade in combination with chemotherapy induced tumor cell apoptosis, tumor regressions, and improved overall survival. Overall, we show that IL6 signaling drives STAT3 activation in tumor cells and mediates chemoresistance in PDAC. Thus, disrupting IL6 signaling using anti-IL6R antibodies holds promise for improving chemotherapy efficacy in PDAC. Mol Cancer Ther; 16(9); 1898–908. ©2017 AACR.

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Herpes Simplex Virus Glycoprotein D Targets a Specific Dendritic Cell Subset and Improves the Performance of Vaccines to Human Papillomavirus-Associated Tumors

Cervical cancer is a major public health problem and one of the leading causes of cancer deaths in women. Virtually all cases of cervical cancer, as well as a growing share of anal and head/neck tumors, are associated with human papillomavirus (HPV) infection. Despite the effectiveness, the available prophylactic vaccines do not benefit women with cervical lesions or cancer. Therefore, the search of new immunotherapeutic approaches to treat HPV-induced tumors is still a priority. The present study characterizes a therapeutic antitumor vaccine based on the genetic fusion of the Herpes simplex virus-1 (HSV-1) glycoprotein D (gD) with the E7 oncoprotein from HPV-16 (gDE7). Two subcutaneous doses of gDE7, admixed with poly (I:C), conferred complete and long-lasting therapeutic antitumor protection on mice previously challenged with tumor cells expressing the HPV-16 oncoproteins. The vaccine induced multifunctional E7-specific CD8⁺ T cells with cytotoxic activity and effector memory phenotype (CD44⁺ CD62L^low). In addition, gDE7 admixed with poly (I:C) vaccination controlled the expansion of tumor-induced regulatory T cells and myeloid-derived suppressor cells. More importantly, gDE7 activated mouse CD11c⁺ CD8α⁺ and human BDCA3⁺ dendritic cells (DC), specialized in antigen cross-presentation to CD8⁺ T cells, under in vitro conditions. These results indicated that the activation of a specific DC population, mediated by gD, improved the antigen-specific immune responses and the therapeutic performance induced by antitumor vaccines. These results open perspectives for the clinical testing of gDE7-based vaccines under the concept of active immunization as a tool for the therapeutic control of cancer. Mol Cancer Ther; 16(9); 1922–33. ©2017 AACR.

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mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL

Elevated activity of mTOR is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high-risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph⁺ and Ph-like B-ALL models. Surprisingly, inhibiting mTOR complex 1 (mTORC1) protected B-ALL cells from killing by methotrexate and 6-mercaptopurine, two antimetabolite drugs used in maintenance chemotherapy. The cytoprotective effects correlated with decreased cell-cycle progression and were recapitulated using cell-cycle inhibitors, palbociclib or aphidicolin. Dasatinib, a tyrosine kinase inhibitor currently used in Ph⁺ patients, inhibits ABL kinase upstream of mTOR. Dasatinib resistance is mainly caused by ABL kinase mutations, but is also observed in a subset of ABL unmutated cases. We identified dasatinib-resistant Ph+ cell lines and patient samples in which dasatinib can effectively reduce ABL kinase activity and mTORC1 signaling without causing cell death. In these cases, dasatinib protected leukemia cells from killing by 6-mercaptopurine. Using xenograft models, we observed that mTOR inhibition or dasatinib increased the numbers of leukemia cells that emerge after cessation of chemotherapy treatment. These results demonstrate that inhibitors targeting mTOR or upstream signaling nodes should be used with caution when combined with chemotherapeutic agents that rely on cell-cycle progression to kill B-ALL cells. Mol Cancer Ther; 16(9); 1942–53. ©2017 AACR.

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Wnt/{beta}-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin–mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1. In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo. Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered Kit^V558/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954–66. ©2017 AACR.

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Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis

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Increased risk of influenza among vaccinated adults who are obese

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Perivascular adipose tissue: epiphenomenon or local risk factor?

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High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance

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Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner

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Joint effect of maternal plasma homocysteine and prepregnancy obesity on child blood pressure: a prospective birth cohort study

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Role of aquaporin-7 in ghrelin- and GLP-1-induced improvement of pancreatic β-cell function after sleeve gastrectomy in obese rats

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Adiposity and grip strength as long-term predictors of objectively measured physical activity in 93 015 adults: the UK Biobank study

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Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis

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Metabolite profiling of obese individuals before and after a one year weight loss program

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rs9939609 FTO genotype associations with FTO methylation level influences body mass and telomere length in an Australian rural population

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Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: relationship with metabolic outcomes

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Maternal cytokine status may prime the metabolic profile and increase risk of obesity in children

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Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery

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Arterial stiffening, insulin resistance and acanthosis nigricans in a community sample of adolescents with obesity

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International Endodontic Journal 50th Anniversary Editorial

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Issue Information

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An unusual combination of discreet subaortic membrane, aortopulmonary window, severe aortic insufficiency and rheumatic mitral regurgitation

Abstract

We report a 15-year-old female patient with an unusual combination of discreet subaortic membrane, aortopulmonary window, severe aortic insufficiency and rheumatic mitral regurgitation.

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Hughes-Stovin syndrome—a rare entity with combination of venous thrombosis and multiple pulmonary arterial aneurysms

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3D printed TCP-based scaffold incorporating VEGF-loaded PLGA microspheres for craniofacial tissue engineering

Publication date: Available online 4 September 2017
Source:Dental Materials
Author(s): F. Fahimipour, M. Rasoulianboroujeni, E. Dashtimoghadam, K. Khoshroo, M. Tahriri, F. Bastami, D. Lobner, L. Tayebi
ObjectiveVascularization is a critical process during bone regeneration/repair and the lack of tissue vascularization is recognized as a major challenge in applying bone tissue engineering methods for cranial and maxillofacial surgeries. The aim of our study is to fabricate a vascular endothelial growth factor (VEGF)-loaded gelatin/alginate/β-TCP composite scaffold by 3D printing method using a computer-assisted design (CAD) model.MethodsThe paste, composed of (VEGF-loaded PLGA)-containing gelatin/alginate/β-TCP in water, was loaded into standard Nordson cartridges and promptly employed for printing the scaffolds. Rheological characterization of various gelatin/alginate/β-TCP formulations led to an optimized paste as a printable bioink at room temperature.ResultsThe in vitro release kinetics of the loaded VEGF revealed that the designed scaffolds fulfill the bioavailability of VEGF required for vascularization in the early stages of tissue regeneration. The results were confirmed by two times increment of proliferation of human umbilical vein endothelial cells (HUVECs) seeded on the scaffolds after 10 days. The compressive modulus of the scaffolds, 98±11MPa, was found to be in the range of cancellous bone suggesting their potential application for craniofacial tissue engineering. Osteoblast culture on the scaffolds showed that the construct supports cell viability, adhesion and proliferation. It was found that the ALP activity increased over 50% using VEGF-loaded scaffolds after 2 weeks of culture.SignificanceThe 3D printed gelatin/alginate/β-TCP scaffold with slow releasing of VEGF can be considered as a potential candidate for regeneration of craniofacial defects.



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Targeting histone-acetyltransferase Tip60 inhibits intestinal allergy

Abstract

Background

The over production of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body.

Objectives

This study tests a hypothesis that HAT Tat-interactive protein 60 (Tip60) plays an important role in the initiation of IgE-mediated allergy.

Methods

The effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE-mediated allergic inflammation.

Results

High levels of Tip60 were observed in the peripheral B cells of patients with FA. Tip60 was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6) and nuclear factor-κB at the locus of Iε promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa.

Conclusions

Tip60 plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti-allergy drug.

This article is protected by copyright. All rights reserved.

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Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report

Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroi...

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Selection and characterization of DNA aptamers for detection of glutamate dehydrogenase from Clostridium difficile

Publication date: Available online 4 September 2017
Source:Biochimie
Author(s): Meng Liu, Qingxin Yin, John D. Brennan, Yingfu Li
Rapid and accurate diagnosis of Clostridium difficile infections (CDI) is crucial for patient treatment, infection control and epidemiological monitoring. As an important antigen, glutamate dehydrogenase (GDH) has been proposed as a preliminary screening test target for CDI. However, current assays based on GDH activity or GDH immunoassays have suboptimal sensitivity and specificity. Herein, we described the selection and characterization of single-stranded DNA aptamers that specifically targeted GDH. After 10 rounds of selection, high-throughput sequencing was used to identify enriched aptamer candidates. Of 10 candidates, three aptamers for GDH were identified. Gel shift assays showed that these aptamers exhibited low nanomolar affinities. One aptamer was optimized based on structural analysis and further engineered into a structure-switching fluorescence signaling aptamer, wherein desorption from reduced graphene oxide (RGO) upon binding of GDH led to an increase in fluorescence emission. This method allowed for quantitative detection of GDH with a detection limit of 1 nM, providing great potential for its further application in CDI diagnosis.



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Role of Densitometric Criteria in Evaluation of Effectiveness of Antiangiogenic Therapies in Metastatic Colorectal Cancer: An Italian Clinical Experience

Background/Aim: To evaluate the role of densitometric criterion using the Choi Criteria in the assessment of the response to antiangiogenic treatments of metastatic colorectal cancer (mCRC) compared to the RECIST criteria. Patients and Methods: Fifty-four patients (mean age=50.6 years) affected by advanced colorectal cancer and with hepatic and possibly peritoneal and pulmonary metastases, that can be treated with bevacizumab, were prospectively evaluated by computerized tomography (CT) scan. Metastases were also evaluated by CT in one-dimensional form according to RECIST. Results: Results show that in 58% of analyzed cases, stable disease according to RECIST coincided with stable disease according to the CHOI criteria, whereas in 42% of analyzed cases disease progression according to RECIST corresponded to stable disease or even partial response according to CHOI criteria. Conclusion: By using the densitometric criterion with CHOI criteria, the evaluation of the response to antiangiogenic treatment of mCRC is partially different compared to RECIST criteria.

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Lidocaine Stimulates the Function of Natural Killer Cells in Different Experimental Settings

Background: One of the functions of natural killer (NK) cells is to eliminate cancer cells. The cytolytic activity of NK cells is tightly regulated by inhibitory and activation receptors located in the surface membrane. Lidocaine stimulates the function of NK cells at clinically relevant concentrations. It remains unknown whether this effect of lidocaine has an impact on the expression of surface receptors of NK cells, can uniformly stimulate across different cancer cell lines, and enhances the function of cells obtained during oncological surgery. Materials and Methods: NK cells from healthy donors and 43 patients who had undergone surgery for cancer were isolated. The function of NK cells was measured by lactate dehydrogenase release assay. NK cells were incubated with clinically relevant concentrations of lidocaine. By flow cytometry, we determined the impact of lidocaine on the expression of galactosylgalactosylxylosylprotein3-beta-glucuronosytranferase 1, marker of cell maturation (CD57), killer cell lectin like receptor A, inhibitory (NKG2A) receptors and killer cell lectin like receptor D, activation (NKG2D) receptors of NK cells. Differences in expression at p<0.05 were considered statistically significant. Results: Lidocaine increased the expression of NKG2D receptors and stimulated the function of NK cells against ovarian, pancreatic and ovarian cancer cell lines. Lidocaine also increased the cytolytic activity of NK cells from patients who underwent oncological surgery, except for those who had orthopedic procedures. Conclusion: Lidocaine showed an important stimulatory activity on NK cells. Our findings suggest that lidocaine might be used perioperatively to minimize the impact of surgery on NK cells.

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MRI and Ultrasound Fusion Imaging for Cervical Cancer

Background: Evaluating locoregional extension of cervical cancer is a key step in patient management. This study evaluated the feasibility of fusion imaging – a combination of magnetic resonance imaging (MRI) with real-time high-resolution ultrasound (US) – to diagnose cervical cancer and its extension. Patients and Methods: This prospective bi-center study included 13 women who underwent a 1.5-T MRI protocol including at least one T2-weighted plane. The results of imaging fusion were then compared with US and MRI results alone. Results: Cervical cancer was detected as a hyperechogenic hypervascularized lesion. Parametrial extension was detected by exploration of the stromal ring and the use of color Doppler mode in fusion imaging, and characterized by visualization of a vascular bridge. Conclusion: Fusion imaging could be used as a complementary technique for MRI to enhance diagnostic performance for cervical cancer lesions. While MRI remains the reference, real-time fusion imaging could improve its characterization and detect parametrial infiltration.

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Physical Needs of Long-term Cancer Patients

The enormous success in the therapeutic area of oncology has allowed achieving a number of long-term survival patients unthinkable until a few decades ago. The number of cancer survivors in the world has, in fact, almost tripled in the last decade alone. Anticancer therapies, including those of the latest generation, aimed at targeting also the chronicity of the disease, are not free from side-effects, especially when used in the long term. This scenario should lead to development of follow-up programs with the purpose of assessing long-term effects related to cancer treatments, in addition to the early detection of any relapse or a second tumor. Oncologists who take care of cancer survivors cannot ignore these effects; it is, therefore, essential to start a program of prevention and treatment of these sequelae, to meet patients' health needs.

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Study on the Validity of Pancreaticoduodenectomy in the Elderly

Aim: Pancreaticoduodenectomy (PD) is still the only curative treatment for periampullary cancer. Confirming the outcomes of PD in elderly patients is important as the aging population continues to grow. Patients and Methods: We analyzed 340 patients with periampullary cancer who underwent PD, dividing them into three groups by age: group A: aged 64 years or younger, n=115; group B: 65-74 years, n=144; and group C: 75 years or older, n=81. Results: Group C had a significantly higher 60-day mortality of 6.3% (p=0.04), the lowest 5-year overall survival rate of 9.9% (p=0.02), and there was no impact of staging of the Union for International Cancer Control classification on overall survival of patients with pancreatic cancer. Independent prognostic factors of group C in the multivariate analysis were pancreatic cancer and reoperation. Conclusion: For elderly patients aged 75 years or over, caution should be exercised in selecting PD for patients with pancreatic cancer.

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Deepening a Simple Question: Can MSCs Be Used to Treat Cancer?

In cancer, mesenchymal stem/stromal cells (MSCs) have been considered as vehicles for targeted delivery of drugs due to their inherent tropism toward primary and metastatic tumors. However, it is still unclear whether MSCs could be therapeutically explored without significant harm, since a great amound of evidence indicates that MSCs are able to exert both tumor-suppressive and pro-oncogenic effects. Here, we discuss how MSCs might adopt a pro- or anti-inflammatory profile in response to changes within the tumor microenvironment and how these features may lead to opposite outcomes in tumor development. Additionally, we address how differences in experimental design might impact interpretation and consistency of the current literature in this specific field. Finally, we point-out critical issues to be addressed at a pre-clinical stage, regarding safety and therapeutic effectiveness of MSCs application in cancer treatment.

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Flattening Filter Free vs. Flattened Beams for Lung Stereotactic Body Radiation Therapy

Background/Aim: To assess the clinical impact of high dose rate stereotactic body radiation therapy (SBRT) in patients with lung neoplastic lesions. Patients and Methods: From January 2014 to June 2016, a single-center retrospective analysis was performed including all patients treated by either flattening filter free (FFF) beams or flattening filter beams (FF) three-dimensional (3D) SBRT for lung neoplastic lesions. Results: A total of 99 SBRT were performed on 75 patients. Among these, 29 SBRT were performed using a FFF technique while 70 other SBRT were done using a FF technique. Median follow-up time was 12.9 months. Overall, no difference between the two groups was found except for the mean beam on time which was reduced by 3.3 to 0.9 minutes in the FFF group (p<0.001). Conclusion: We report a low toxicity rate and a shortened beam on time in patients treated with 3D FFF SBRT for lung neoplastic lesions.

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Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants

One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models.

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The Local Recurrence of Breast Cancer with Squamous Metaplasia and Obvious Histological Heterogeneity

Case Report: We herein report a case of local recurrence of breast cancer with squamous metaplasia and obvious intratumoral and intertumoral heterogeneity. A 39-year-old female patient was diagnosed with T3N2M0 stage IIIB right breast cancer and underwent right total mastectomy and axillar lymph node dissection. At four years after surgery, she became aware of chest wall pain and diagnostic imaging revealed recurrence in the lung, right thoracic wall and sternum. The recurrent lesions remained stable for 18 months with endocrine therapy. Thereafter, the lesion in the right thoracic wall suddenly became enlarged. Moreover, liver metastasis was confirmed on FDG-PET/CT. She underwent right thoracic wall tumor resection. A biopsy was simultaneously performed to obtain a specimen from the site of liver metastasis. Postoperatively, the right chest wall mass showed obvious intratumoral heterogeneity; squamous differentiation with aggressive features and a papillotubular component similar to the primary tumor. The metastatic liver tumor showed similar pathological features to the primary tumor. Conclusion: Intratumoral and intertumoral heterogeneity within primary tumors and associated metastatic sites may contribute to treatment failure and drug resistance.

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Fluoride Induces Apoptosis in Mammalian Cells: In Vitro and In Vivo Studies

Apoptosis is genetically programmed cell death, an irreversible process of cell senescence with characteristic features different from other cellular mechanisms of death such as necrosis. In the last years, apoptosis has been extensively studied in the scientific literature, because it has been established that apoptosis plays a crucial role following the time course of chronic degenerative diseases, such as cancer. Thus, several researchers have strugged to detect what chemical agents are able to inter fere with the apoptotic process. Thus, the purpose of this literature review is to assess if fluoride induces apoptosis in mammalian cells using in vivo and in vitro test systems. Certain mammalian cell types such as oral cells, blood and brain were exetensively investigated; the results showed that fluoride is able to induce apoptosis in both intrinsinc and extrinsic pathways. Moreover, other cells types have been poorly investigated such as bone, kidney and reproductive cells with conflicting results so far. Therefore, this area needs further investigation for the safety of human populations exposed to fluoride in a chronic way, as for example in developing countries.

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Thrombocytosis Portends Adverse Prognosis in Colorectal Cancer: A Meta-Analysis of 5,619 Patients in 16 Individual Studies

Aim: The current study aimed to determine the prognostic significance of thrombocytosis in patients with colorectal cancer (CRC) by a meta-analysis of the literature. Patients and Methods: The meta-analysis followed the 2009 guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature review was conducted from PubMed and Web of Science for articles published up to May 15, 2015. Sixteen studies with a total of 5,619 patients met the inclusion criteria. Hazard ratios and 95% confidence intervals were retrieved from the original articles, calculated from the published Kaplan–Meier survival curves, or the corresponding authors were contacted for additional information. Heterogeneity was assessed using the I² statistic and Chi-square tests. Publication bias was assessed by Begg's funnel plot, Egger's linear regression test and trim-and-fill method. Sensitivity analysis was performed to validate the reliability. Results: Thrombocytosis is associated with shorter overall, disease-free and cancer-specific survival. Overall survival is reduced in patients with thrombocytosis regardless of their clinical tumor stage, and ethnicity. Shortened disease-free survival is associated with elevated platelet count in the non-specific stage (I-IV), localized tumor (stage I-III), and in the Asian patient population. Thrombocytosis is further associated with reduced cancer-specific survival in the non-specific stage and in Asian patients. Finally, thrombocytosis is significantly related to female patients, colon tumor location, T3-4 stage, lymph node positivity, metastasis, undifferentiated histology and lymphatic involvement. Conclusion: Thrombocytosis portends adverse prognosis in CRC, and may serve as a clinically useful marker to facilitate risk stratification and guide postoperative management.

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Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density

Background/Aim: Gefitinib is a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and has been approved for the treatment of non-small cell lung cancers (NSCLCs) with EGFR mutations. Here we demonstrated that gefitinib induced a significantly enhanced biological activity of succinate-tetrazolium reductase (STR) in mitochondria and mitochondrial membrane potential in HCC827 cells (EGFR mutation NSCLCs, sensitive to gefitinib) at a high cell density. Materials and Methods: We assessed the biological activity (STR, mitochondrial membrane potential, expression level of Bcl-2 family proteins) of gefitinib on NSCLCs at different cell densities. Results: The 3D cell culture experiments showed the enhanced mitochondrial biological activity in clustered cell culture treated with gefitinib. Interestingly, the expression levels of Bcl-x_L and Bax, were affected by the cellular number and gefitinib treatment. We also found that gefitinib prevented additive anticancer activity in the combinational treatment with doxorubicin, which induces mitochondria-dependent apoptotic cell death. Conclusion: Our results indicate that gefitinib may work as a mitochondrial protector against combinational treatment with mitochondria-dependent anticancer agents in high-cell-density.

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Metastatic Microcystic Adnexal Carcinoma with DNA Sequencing Results and Response to Systemic Antineoplastic Chemotherapy

Microcystic adnexal carcinoma (MAC) is a rare cutaneous malignancy. Due to its rarity, the molecular characteristics and treatment for metastatic MAC remain undefined. Here we present, as far as we are aware, the first case of metastatic MAC with DNA sequencing results indicating a mutation in TP53 and chromosomal losses in cyclin dependent kinase inhibitor 2A (CDKN2A) and cyclin dependent kinase inhibitor 2B (CDKN2B). In addition, this is the first case of metastatic MAC with a documented objective response to systemic antineoplastic chemotherapy (carboplatin and paclitaxel) confirmed by positron emission tomography/computed tomography. Our case increases the very limited medical knowledge of this rare disease.

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Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells

Background: Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Materials and Methods: Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Results: Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Conclusion: Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application.

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Prognostic Significance of Serum CEA for Non-small Cell Lung Cancer Patients Receiving Stereotactic Body Radiotherapy

Background/Aim: To examine the prognostic significance of serum carcinoembryonic antigen (CEA) for stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Patients and Methods: In total, 129 stage I NSCLC patients were analyzed and divided into two groups: CEA-High (CEA>5 ng/ml) and CEA-Low (CEA≤5 ng/ml). Results: Median follow-up time was 38 months. Overall survival was not significantly different between CEA-High (n=47) and CEA-Low (n=82) patients (57% vs. 63% at 3 years; p=0.39), although progression-free survival (PFS) was significantly worse in CEA-High patients (31% vs. 51% at 3 years; p=0.01). Larger tumor size and high CEA level were independent prognostic factors for worse PFS. Failure pattern analysis showed that regional node or distant recurrence was more common in CEA-High patients (47%) than in CEA-Low patients (29%). Conclusion: Patients with CEA-High stage I NSCLC have a higher risk of regional or systemic relapse and should be followed-up carefully.

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Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2

Background: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO). Materials and Methods: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2. Results: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity. Conclusion: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.

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Comparing the Efficacy of DeVIC Therapy and High-dose Methotrexate Monotherapy with Whole-brain Radiation Therapy for Newly-diagnosed Primary Central Nervous System Lymphoma: A Single Institution Study

Background/Aim: In the current study, we aimed to compare DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin) chemotherapy with high-dose methotrexate (HD-MTX) monotherapy plus whole-brain radiation therapy (WBRT) for newly-diagnosed primary central nervous system lymphoma (PCNSL), in terms of their efficacies and tolerability. Patients and Methods: A total of 21 consecutive patients with PCNSL were treated with DeVIC therapy and WBRT, between 2002 and 2010. From 2010 to 2014, 14 consecutive patients with PCNSL were treated with HD-MTX followed by WBRT. Results: Overall response rates of complete and partial response for initial chemotherapy were significantly better with DeVIC therapy (95.2%) than with HD-MTX monotherapy (50%). Furthermore, one-year and two-year progression-free survival (PFS) rates were better in the DeVIC cohort than in the HD-MTX cohort. DeVIC therapy yielded higher early response rates, longer PFS, and manageable adverse events, and may be potentially better for the treatment of cases that are refractory to MTX-based therapy. Conclusion: Our retrospective clinical study revealed that DeVIC therapy is comparable with that of HD-MTX monotherapy plus WBRT, for newly diagnosed PCNSL.

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Effective Metabolic Targeting of Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models with Recombinant Methioninase

Background: Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino--mercaptomethane lyase [EC 4.4.1.11]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo. Materials and Methods: Human osteosarcoma cell lines 143B, HOS and SOSN2 were tested in vitro for survival during a 72-h exposure to rMETase using the WST-8 assay. Half-maximal inhibitory concentrations were calculated for in vitro efficacy experiments. 143B cells were orthotopically transplanted into the tibia of nude mice. Mouse models were randomized into the following groups 1 week after transplantation: Group 1, untreated control; Group 2, cisplatinum (CDDP) [intraperitoneal (i.p.) injection at 6 mg/kg weekly, for 3 weeks], positive control; Group 3, rMETase, 100 units/mouse i.p. daily, for 21 days. Tumor sizes and body weight were measured with calipers and a digital balance once per week, respectively. Results: rMETase significantly inhibited osteosarcoma cell growth, in a dose-dependent manner, in vitro. Both CDDP and rMETase treatment significantly inhibited tumor volume compared to untreated control mice at 5 weeks after initiation. Tumor volumes were as follows: Group 1, untreated, control: 1808.2 ± 344 mm³; Group 2, CDDP: 1102.2 ± 316 mm³, p=0.0008 compared to untreated control; Group 3, rMETase: 884.8 ± 361 mm³, p=0.0001 compared to untreated control. There were no animal deaths in any group. The body weight of mice was not significantly different between any group. Conclusion: rMETase showed promising efficacy against osteosarcoma, a recalcitrant tumor type. Future studies will investigate the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of osteosarcoma as a bridge to testing rMETase in the clinic.

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Surgical Strategy for T1 Duodenal or Ampullary Carcinoma According to the Depth of Tumor Invasion

Aim: To investigate the utility of local resection (LR) for T1 duodenal carcinoma and T1 ampullary carcinoma. Patients and Methods: Between June 2002 and November 2014, a total of 64 patients with pathological T1 (pT1) ampullary carcinoma (25 patients) and pT1 duodenal carcinoma (39 patients) were treated. Of these, 33 patients underwent local resection (LR group), while the other 31 patients underwent pancreatoduodenectomy (PD group). Results: The LR group had 31 patients with pT1a and 2 patients with pT1b. PD group had 18 patients with pT1a and 13 patients with pT1b. One patient with pT1b duodenal carcinoma (20.0%) and one patient with pT1b ampullary carcinoma (10.0%) developed lymph node metastasis, while none of the patients with pT1a disease developed metastases. Conclusion: LR may be considered in the patients preoperatively diagnosed with T1a duodenal carcinoma and T1a ampullary carcinoma.

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Probing the Molecular Mechanisms Governing the Oncolytic Activity of Paeonia suffruticosa on Triple-negative Breast Cancer Cells In Vitro

Background/Aim: Extracts of Paeonia suffruticosa are traditionally used in Chinese medicine to increase blood flow. Recently, this extract has been shown to possess anti-tumor and anti-inflammatory properties, though this mechanism remains unknown. In the current work, we prepared extracts of P. suffruticosa and analyzed their effects on MDA-MB-231 triple-negative breast cancer cells. Materials and Methods: Varying concentrations of an aqueous extract of P. suffruticosa was administered to MDA-MB-231. An MTS assay was used to determine the cell viability. Cytokine production was investigated through enzyme-linked immunosorbent assay (ELISA). Caspase-Glo assays were performed to measure caspase 3/7, 8 and 9 to analyze anti-apoptotic effects. Results: MTS assay for cell viability revealed that the extract increased viability at low concentrations (0.6 mg/ml) and decreased viability observed at concentrations ≥2.5 mg/ml (p<0.01). ELISA for IL-6, IL-2, and TNF-alpha revealed a biphasic dose-response inversely related to viability (p<0.05). IL-24 expression also increased at 2.5 mg/ml and 4.0 mg/ml (p<0.05). Bax levels remained relatively constant while Bcl-2 decreased significantly in all concentrations (p<0.01). Small decreases in Fas ligand levels was observed in parallel with a lack of increase in caspase-8 activity. Most notable was that while 4mg/ml of P. suffruticosa extract reduced MDA-MB-231 viability by >60% (p<0.01), the same concentration reduced the viability of non-transformed HaCat cells by ~8% (p>0.05), suggesting a selective oncolytic effect. Conclusion: P. suffruticosa extract has the ability to modulate the production of several tumor suppressive cytokines, induce intrinsic apoptosis and has the capability of reducing cancer burden while sparing healthy tissue.

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Accuracy of computer-assisted mandibular reconstructions using patient-specific implants in combination with CAD/CAM fabricated transfer keys

Computer-assisted surgery with intraoperative navigation as well as preoperative virtual planning of the surgery is becoming more and more common in clinical practice for craniomaxillofacial surgery (Chen et al., 2016).

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Changes in consumption of added sugars from age 13 to 30 years: a systematic review and meta-analysis of longitudinal studies

Summary

Added sugar intake during adolescence has been associated with weight gain and cardiometabolic risk factors. Moreover, dietary habits may persist into adulthood, increasing chronic disease risk in later life. This systematic review investigated changes in intake of added sugars between the ages of 13 and 30 years.

Literature databases were searched for longitudinal studies of diet during adolescence or early adulthood. Retrieved articles were screened for studies including multiple measures of intake of sugars or sugary foods from cohort participants between the ages of 13 and 30. Data were analysed using random-effects meta-analysis, by the three main nutrient and food group categories identified (PROSPERO: CRD42015030126).

Twenty-four papers reported longitudinal data on intake of added sugar or sucrose (n = 6), sugar-sweetened beverages (SSBs) (n = 20) and/or confectionery (n = 9). Meta-analysis showed a non-significant per year of age decrease in added sugar or sucrose intake (−0.15% total energy intake (95%CI −0.41; 0.12)), a decrease in confectionery consumption (−0.20 servings/week (95%CI −0.41; −0.001)) and a non-significant decrease in SSB consumption (−0.15 servings/week (95%CI −0.32; 0.02)). Taken together, the overall decrease in added sugar intake observed from adolescence to early adulthood may suggest opportunities for intervention to further improve dietary choices within this age range.

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Practical Management of Cancer Cachexia

Abstract

In cancer patients, delivery of palliative care during anticancer treatment (i.e., concurrent care) leads to enhanced clinical outcome. Nutrition therapy is part of palliative care and, therefore, should be prescribed to prevent or treat cachexia. Effective nutrition therapy is based on a thorough assessment of weight loss history, eating behaviour, changes in appetite, and the presence of nutrition impact symptoms. By identifying a patient's needs, the delivery of nutritional care (i.e., counselling, supplements, enteral or parenteral nutrition according to the "maximal use of supportive therapy" approach) has greater likelihood to be highly effective. However, a careful monitoring programme, which includes periodical check of body weight, energy and protein intake, quality of life, ensures constant adaptation of nutritional care to the changing needs of cancer patients. Nutrition therapy is becoming a key component of cancer patients management. In this new role, nutrition therapy is key in allowing cancer patients to receive and complete treatments and in improving quality of life. Whether these effects also translate into longer survival remains to be demonstrated but preliminary results are encouraging.

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ESMO 2017: 3-year outcomes favour laparoscopic surgery for oesophageal cancer

Patients requiring surgery for oesophageal cancer fare better after undergoing a hybrid minimally invasive oesophagectomy (HMIO) compared to an open oesophagectomy (OO), according to long-term results of the MIRO trial to be presented at the ESMO 2017...

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Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy

Abstract

Purpose

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.

Methods

We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).

Results

Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048–0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22–0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14–0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58, p = 0.19).

Conclusion

These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

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Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer

Abstract

Background

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center.

Patients and Methods

Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS.

Results

Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection.

Conclusion

The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

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Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer

Abstract

Background

Visceral fat accumulation and muscle depletion have been identified as poor prognostic factors for various cancers. However, the significance of visceral adiposity and sarcopenic visceral obesity on outcomes after resection of pancreatic cancer remains unclear.

Methods

A retrospective analysis of 301 patients who underwent resection for localized pancreatic cancer between 2004 and 2015 was performed. The extent of visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] and visceral obesity [visceral fat area (VFA)] were measured on preoperative computed tomography images, together with skeletal muscle index (SMI) and muscle attenuation (MA). The impacts of these body composition parameters on outcomes after pancreatic resection were investigated.

Results

The overall survival (OS) and recurrence-free survival (RFS) rates in patients with high VSR were significantly lower than those in patients with low VSR (P = 0.001, P = 0.007, respectively). There were no differences in OS and RFS between high VFA and low VFA group; however, when analyzed together with sarcopenic factors, OS and RFS rates of the patients with sarcopenic visceral obesity were significantly lower compared with those of the others. Multivariate analyses revealed that high VSR was an independent risk factor for mortality (hazard ratio (HR) 1.58, P = 0.009) and recurrence (HR 1.41, P = 0.026) together with low SMI, low MA, high CA19-9, microvascular invasion, and nodal metastasis.

Conclusions

Visceral adiposity and sarcopenic visceral obesity, as well as low muscle mass and quality, were closely associated with mortality and recurrence after resection of pancreatic cancer.

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Issue Information

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Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy

Abstract

Purpose

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.

Methods

We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).

Results

Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048–0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22–0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14–0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58, p = 0.19).

Conclusion

These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

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Prognostic Value of the Age-Adjusted Charlson Comorbidity Index (ACCI) on Short- and Long-Term Outcome in Patients with Advanced Primary Epithelial Ovarian Cancer

Abstract

Background

We evaluated the prognostic impact of the age-adjusted Charlson Comorbidity Index (ACCI) on both postoperative morbidity and overall survival (OS) in patients with advanced epithelial ovarian cancer (EOC) treated at a tertiary gynecologic cancer center.

Patients and Methods

Exploratory analysis of our prospectively documented tumor registry was performed. Data of all consecutive patients with stage IIIB–IV ovarian cancer who underwent primary cytoreductive surgery (PDS) from January 2000 to June 2016 were analyzed. Patients were divided into three groups, based on their ACCI: low (0–1), intermediate (2–3), and high (≥4), and postoperative surgical complications were graded according to the Clavien–Dindo classification (CDC). The Fisher's exact test, log-rank test, and Cox regression models were used to investigate the predictive value of the ACCI on postoperative complications and OS.

Results

Overall, 793 consecutive patients were identified; 328 (41.4%) patients were categorized as low ACCI, 342 (43.1%) as intermediate ACCI, and 123 (15.5%) as high ACCI. A high ACCI was significantly associated with severe postoperative complications (CDC 3–5; odds ratio 3.27, 95% confidence interval 1.97–5.43, p < 0.001). Median OS for patients with a low, intermediate, or high ACCI was 50, 40, and 23 months, respectively (p < 0.001), and the ACCI remained a significant prognostic factor for OS in multivariate analysis (p = 0.001). The same impact was observed in a sensitivity analysis including only those patients with complete tumor resection.

Conclusion

The ACCI is associated with perioperative morbidity in patients undergoing PDS for EOC, and also has a prognostic impact on OS. The potential role of the ACCI as a selection criteria for different therapy strategies is currently under investigation in the ongoing, prospective, multicenter AGO-OVAR 19 trial.

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Visceral Adiposity and Sarcopenic Visceral Obesity are Associated with Poor Prognosis After Resection of Pancreatic Cancer

Abstract

Background

Visceral fat accumulation and muscle depletion have been identified as poor prognostic factors for various cancers. However, the significance of visceral adiposity and sarcopenic visceral obesity on outcomes after resection of pancreatic cancer remains unclear.

Methods

A retrospective analysis of 301 patients who underwent resection for localized pancreatic cancer between 2004 and 2015 was performed. The extent of visceral adiposity [visceral to subcutaneous adipose tissue area ratio (VSR)] and visceral obesity [visceral fat area (VFA)] were measured on preoperative computed tomography images, together with skeletal muscle index (SMI) and muscle attenuation (MA). The impacts of these body composition parameters on outcomes after pancreatic resection were investigated.

Results

The overall survival (OS) and recurrence-free survival (RFS) rates in patients with high VSR were significantly lower than those in patients with low VSR (P = 0.001, P = 0.007, respectively). There were no differences in OS and RFS between high VFA and low VFA group; however, when analyzed together with sarcopenic factors, OS and RFS rates of the patients with sarcopenic visceral obesity were significantly lower compared with those of the others. Multivariate analyses revealed that high VSR was an independent risk factor for mortality (hazard ratio (HR) 1.58, P = 0.009) and recurrence (HR 1.41, P = 0.026) together with low SMI, low MA, high CA19-9, microvascular invasion, and nodal metastasis.

Conclusions

Visceral adiposity and sarcopenic visceral obesity, as well as low muscle mass and quality, were closely associated with mortality and recurrence after resection of pancreatic cancer.

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Toward Universal Forward Genetics: Using a Draft Genome Sequence of the Nematode Oscheius tipulae To Identify Mutations Affecting Vulva Development

Fabrice Besnard<br />Aug 1, 2017; 206:1747-1761<br />Methods, technology and resources

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LIN-41 and OMA Ribonucleoprotein Complexes Mediate a Translational Repression-to-Activation Switch Controlling Oocyte Meiotic Maturation and the Oocyte-to-Embryo Transition in Caenorhabditis elegans

Tatsuya Tsukamoto<br />Aug 1, 2017; 206:2007-2039<br />Developmental and behavioral genetics

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A Unified Characterization of Population Structure and Relatedness

Bruce S. Weir<br />Aug 1, 2017; 206:2085-2103<br />Population and evolutionary genetics

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A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans

Víctor González-Huici
Aug 1, 2017; 206:1853-1864
Genome integrity and transmission

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Caenorhabditis elegans CES-1 Snail Represses pig-1 MELK Expression To Control Asymmetric Cell Division

Hai Wei<br />Aug 1, 2017; 206:2069-2084<br />Developmental and behavioral genetics

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Heat-Induced Calcium Leakage Causes Mitochondrial Damage in Caenorhabditis elegans Body-Wall Muscles

Kenta Momma<br />Aug 1, 2017; 206:1985-1994<br />Developmental and behavioral genetics

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Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection

Chuan Cao<br />Aug 1, 2017; 206:2159-2173<br />Population and evolutionary genetics

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Networks Underpinning Symbiosis Revealed Through Cross-Species eQTL Mapping

Yuelong Guo<br />Aug 1, 2017; 206:2175-2184<br />Genetics of complex traits

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Discovering Complete Quasispecies in Bacterial Genomes

Frederic Bertels<br />Aug 1, 2017; 206:2149-2157<br />Population and evolutionary genetics

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Canalization by Selection of de Novo Induced Mutations

Laura Fanti<br />Aug 1, 2017; 206:1995-2006<br />Developmental and behavioral genetics

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Evolving Mistranslating tRNAs Through a Phenotypically Ambivalent Intermediate in Saccharomyces cerevisiae

Matthew D. Berg<br />Aug 1, 2017; 206:1865-1879<br />Gene expression

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Polycomb and Trithorax Group Genes in Drosophila

Judith A. Kassis<br />Aug 1, 2017; 206:1699-1725<br />Gene expression

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The Draft Genome and Transcriptome of Panagrellus redivivus Are Shaped by the Harsh Demands of a Free-Living Lifestyle

Jagan Srinivasan<br />Apr 1, 2013; 193:1279-1295<br />Genome and systems biology

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Statistical Design and Analysis of RNA Sequencing Data

Paul L. Auer<br />Jun 1, 2010; 185:405-416<br />Methods, technology and resources

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Construction of Transgenic Drosophila by Using the Site-Specific Integrase From Phage {phi}C31

Amy C. Groth<br />Apr 1, 2004; 166:1775-1782<br />INVESTIGATIONS

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Labor Day: It's About Time

The first Monday in September is a federal holiday in the United States. It marks Labor Day—a tribute to contributions made by American workers to the growth and development of the country (or...

-- Read more on ScientificAmerican.com

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Labor Day: It's About Time

The first Monday in September is a federal holiday in the United States. It marks Labor Day—a tribute to contributions made by American workers to the growth and development of the country (or...

-- Read more on ScientificAmerican.com

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Anatomy of the Transverse Mesocolon Based on Embryology for Laparoscopic Complete Mesocolic Excision of Right-Sided Colon Cancer

Abstract

Background

To treat colon cancer via complete mesocolic excision (CME) with central vascular ligation (CVL), dissection along the embryologic fusion planes is required. However, this surgery is difficult, especially for right-sided colon cancer, because the anatomy and embryology of the transverse mesocolon are not familiar to gastrointestinal surgeons.

Methods

In this video article, the anatomic details of the transverse mesocolon based on embryology are illustrated with a focus on the venous anatomy. Dissection of the transverse mesocolon along the embryologic planes using a cranial approach during laparoscopic right hemicolectomy also is presented.

Results

During the development of the primitive gastrointestinal tract, the transverse mesocolon locates between the terminal portion of the midgut and the beginning of the hindgut. After 270° counterclockwise rotation of the primary intestinal loop, the transverse mesocolon fuses with the frontal surface of the duodenum and pancreas. Simultaneously, the greater omentum hangs down from the greater curvature of the stomach in front of the transverse colon and fuses with the transverse mesocolon. Moreover, the drainage vein of the right colon sometimes joins the right gastroepiploic vein, and the gastrocolic trunk is formed. Anatomic complexity of the transverse mesocolon is caused by rotation and fusion of the gastrointestinal tract during embryologic development.

Conclusions

Knowledge concerning these embryologic peculiarities of the transverse mesocolon should be useful in the performance of laparoscopic CME with CVL for right-sided colon cancer.

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Anatomy of the Transverse Mesocolon Based on Embryology for Laparoscopic Complete Mesocolic Excision of Right-Sided Colon Cancer

Abstract

Background

To treat colon cancer via complete mesocolic excision (CME) with central vascular ligation (CVL), dissection along the embryologic fusion planes is required. However, this surgery is difficult, especially for right-sided colon cancer, because the anatomy and embryology of the transverse mesocolon are not familiar to gastrointestinal surgeons.

Methods

In this video article, the anatomic details of the transverse mesocolon based on embryology are illustrated with a focus on the venous anatomy. Dissection of the transverse mesocolon along the embryologic planes using a cranial approach during laparoscopic right hemicolectomy also is presented.

Results

During the development of the primitive gastrointestinal tract, the transverse mesocolon locates between the terminal portion of the midgut and the beginning of the hindgut. After 270° counterclockwise rotation of the primary intestinal loop, the transverse mesocolon fuses with the frontal surface of the duodenum and pancreas. Simultaneously, the greater omentum hangs down from the greater curvature of the stomach in front of the transverse colon and fuses with the transverse mesocolon. Moreover, the drainage vein of the right colon sometimes joins the right gastroepiploic vein, and the gastrocolic trunk is formed. Anatomic complexity of the transverse mesocolon is caused by rotation and fusion of the gastrointestinal tract during embryologic development.

Conclusions

Knowledge concerning these embryologic peculiarities of the transverse mesocolon should be useful in the performance of laparoscopic CME with CVL for right-sided colon cancer.

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The structure, splicing, synteny and expression of lamprey COE genes and the evolution of the COE gene family in chordates

Abstract

COE genes encode transcription factors that have been found in all metazoans examined to date. They possess a distinctive domain structure that includes a DNA-binding domain (DBD), an IPT/TIG domain and a helix-loop-helix (HLH) domain. An intriguing feature of the COE HLH domain is that in jawed vertebrates it is composed of three helices, compared to two in invertebrates. We report the isolation and expression of two COE genes from the brook lamprey Lampetra planeri and compare these to COE genes from the lampreys Lethenteron japonicum and Petromyzon marinus. Molecular phylogenetic analyses do not resolve the relationship of lamprey COE genes to jawed vertebrate paralogues, though synteny mapping shows that they all derive from duplication of a common ancestral genomic region. All lamprey genes encode conserved DBD, IPT/TIG and HLH domains; however, the HLH domain of lamprey COE-A genes encodes only two helices while COE-B encodes three helices. We also identified COE-B splice variants encoding either two or three helices in the HLH domain, along with other COE-A and COE-B splice variants affecting the DBD and C-terminal transactivation regions. In situ hybridisation revealed expression in the lamprey nervous system including the brain, spinal cord and cranial sensory ganglia. We also detected expression of both genes in mesenchyme in the pharyngeal arches and underlying the notochord. This allows us to establish the primitive vertebrate expression pattern for COE genes and compare this to that of invertebrate chordates and other animals to develop a model for COE gene evolution in chordates.

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Dental and oropharyngeal lesions in rats with chronic acid reflux esophagitis

In this study, we evaluated pathological changes in the tooth and pharynx of GERD rats to elucidate the association between gastric acid reflux and oral and pharyngeal diseases.

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Dental and oropharyngeal lesions in rats with chronic acid reflux esophagitis

In this study, we evaluated pathological changes in the tooth and pharynx of GERD rats to elucidate the association between gastric acid reflux and oral and pharyngeal diseases.

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Reproducibility of the dynamics of facial expressions in unilateral facial palsy

The aim of this study was to assess the reproducibility of non-verbal facial expressions in unilateral facial paralysis using dynamic four-dimensional (4D) imaging. The Di4D system was used to record five facial expressions of 20 adult patients. The system captured 60 three-dimensional (3D) images per second; each facial expression took 3–4seconds which was recorded in real time. Thus a set of 180 3D facial images was generated for each expression. The procedure was repeated after 30min to assess the reproducibility of the expressions.

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Secondary surgical management of osteoradionecrosis using three-dimensional isodose curve visualization: a report of three cases

Osteoradionecrosis is defined as bone death secondary to radiotherapy. There is a relationship between the radiation dose received and the occurrence of osteoradionecrosis of the jaws, with the risk increasing above a dose of 60Gy. In cases of class III mandibular osteoradionecrosis, a segmental resection can be indicated. Current practice is to completely remove the affected bone up to the point where the bone looks healthy and is bleeding. Exact resection planning and the use of guided surgery based on imaging of the bone changes have not been reported so far.

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Understand and identify the differences between #fatigue, #anorexia + #cachexia on our India #palliativecare Course… https://t.co/SJWyZdqqGi

Understand and identify the differences between #fatigue, #anorexia + #cachexia on our India #palliativecare Course… https://t.co/SJWyZdqqGi

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Alcohol Consumption and Breast Cancer Risk in Younger Women According to Family History of Breast Cancer and Folate Intake

Abstract

To evaluate the association between alcohol consumption and breast cancer risk in younger women, overall and by family history of breast cancer and folate intake, we prospectively followed 93,835 US women aged 27–44 years in Nurses' Health Study II who had alcohol consumption data in 1991. Alcohol consumption and folate intake were measured by food frequency questionnaire every 4 years. We documented 2,866 incident cases of invasive breast cancer between 1991 and 2011. Alcohol consumption was not associated with breast cancer risk overall (for intake of ≥10 g/day vs. nondrinking, multivariate hazard ratio = 1.07, 95% confidence interval: 0.94, 1.22). When the association was stratified by family history and folate intake, a positive association between alcohol consumption and breast cancer was found among women with a family history and folate intake less than 400 μg/day (multivariate hazard ratio = 1.82, 95% confidence interval: 1.06, 3.12; P-trend = 0.08). Alcohol consumption was not associated with breast cancer in other categories of family history and folate intake (P-interaction = 0.55). In conclusion, in this population of younger women, higher alcohol consumption was associated with increased risk of breast cancer among those with both a family history of breast cancer and lower folate intake.

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