Absence or mislocalization of DNAH5 is a characteristic marker for motile ciliary abnormality in nasal polyps

Objective

Motile cilia impairment is a common condition in patients with chronically inflamed airways, such as is seen in nasal polyps (NPs). The mechanism underlying this pathogenic condition is complex and not fully understood.

Methods

We investigated the presence and localization of dynein axonemal heavy chain 5 (DNAH5) in motile cilia using immunofluorescence staining in paraffin-embedded nasal biopsies from NPs (n = 120) and inferior turbinate mucosa (n = 35) of healthy controls. We also performed single-cell staining on cytospin samples (NP = 5, control = 5). Three patterns of DNAH5 localization are defined, including pattern A (presence throughout the axoneme), pattern B (undetectable in the distal part of the axoneme), and pattern C (completely missing throughout the entire axoneme). We developed a semiquantitative scoring system for which 0 = (pattern A > 70%); 1 = (patterns A + B > 70%); and 2 = (pattern C ≥ 30%) in each high-power field (5 fields per sample).

Results

Based on our DNAH5 scoring system, the median (1st and 3rd quartile) score was 0.3 (0.2 and 0.4) for samples from controls, and 1.1 (0.6 and 1.6) for samples from NPs in paraffin specimens (P < 0.001). The DNAH5 score had a significant positive relationship with the Lund-Mackay computed tomography score (r = 0.329, P = 0.005) and was higher in patients with eosinophilic NPs (P = 0.006). For cytospin samples, the mean percentage of patterns A, B, and C were 74%, 14%, and 12% in controls, and 48%, 20%, and 32% in NPs, respectively.

Conclusion

Our results suggest that the absence or mislocalization of DNAH5 from motile cilia is a common and potentially important pathological phenomenon in chronically inflamed airway epithelium.

Level of Evidence

NA. Laryngoscope, 2017

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Absence or mislocalization of DNAH5 is a characteristic marker for motile ciliary abnormality in nasal polyps

Objective

Motile cilia impairment is a common condition in patients with chronically inflamed airways, such as is seen in nasal polyps (NPs). The mechanism underlying this pathogenic condition is complex and not fully understood.

Methods

We investigated the presence and localization of dynein axonemal heavy chain 5 (DNAH5) in motile cilia using immunofluorescence staining in paraffin-embedded nasal biopsies from NPs (n = 120) and inferior turbinate mucosa (n = 35) of healthy controls. We also performed single-cell staining on cytospin samples (NP = 5, control = 5). Three patterns of DNAH5 localization are defined, including pattern A (presence throughout the axoneme), pattern B (undetectable in the distal part of the axoneme), and pattern C (completely missing throughout the entire axoneme). We developed a semiquantitative scoring system for which 0 = (pattern A > 70%); 1 = (patterns A + B > 70%); and 2 = (pattern C ≥ 30%) in each high-power field (5 fields per sample).

Results

Based on our DNAH5 scoring system, the median (1st and 3rd quartile) score was 0.3 (0.2 and 0.4) for samples from controls, and 1.1 (0.6 and 1.6) for samples from NPs in paraffin specimens (P < 0.001). The DNAH5 score had a significant positive relationship with the Lund-Mackay computed tomography score (r = 0.329, P = 0.005) and was higher in patients with eosinophilic NPs (P = 0.006). For cytospin samples, the mean percentage of patterns A, B, and C were 74%, 14%, and 12% in controls, and 48%, 20%, and 32% in NPs, respectively.

Conclusion

Our results suggest that the absence or mislocalization of DNAH5 from motile cilia is a common and potentially important pathological phenomenon in chronically inflamed airway epithelium.

Level of Evidence

NA. Laryngoscope, 2017

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Hypoparatyroidism: what is the best calcium carbonate supplementation intake form?

Publication date: Available online 15 November 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Loraine Gollino, Maria Fernanda Giovanetti Biagioni, Nathalia Regina Sabatini, José Vicente Tagliarini, José Eduardo Corrente, Sérgio Alberto Rupp de Paiva, Gláucia Maria Ferreira da Silva Mazeto
IntroductionIn hypoparathyroidism, calcium supplementation using calcium carbonate is necessary for the hypocalcemia control. The best calcium carbonate intake form is unknown, be it associated with feeding, juice or in fasting.ObjectiveThe objective was to evaluate the calcium, phosphorus and Calcium×Phosphorus product serum levels of hypoparathyroidism women after total thyroidectomy, following calcium carbonate intake in three different forms.MethodsA crossover study was carried out with patients presenting definitive hypoparathyroidism, assessed in different situations (fasting, with water, orange juice, breakfast with a one-week washout). Through the review of clinical data records of tertiary hospital patients from 1994 to 2010, 12 adult women (18 50 years old) were identified and diagnosed with definitive post-thyroidectomy hypoparathyroidism. The laboratory results of calcium and phosphorus serum levels dosed before and every 30min were assessed, for 5h, after calcium carbonate intake (elementary calcium 500mg).ResultsThe maximum peak average values for calcium, phosphorus and Calcium×Phosphorus product were 8.63mg/dL (water), 8.77mg/dL (orange juice) and 8.95mg/dL (breakfast); 4.04mg/dL (water), 4.03mg/dL (orange juice) and 4.12mg/dL (breakfast); 34.3mg²/dL² (water), 35.8mg²/dL² (orange juice) and 34.5mg²/dL² (breakfast), respectively, and the area under the curve 2433mg/dLmin (water), 2577mg/dLmin (orange juice) and 2506mg/dLmin (breakfast), 1203mg/dLmin (water), 1052mg/dLmin (orange juice) and 1128mg/dLmin (breakfast), respectively. There was no significant difference among the three different tests (p>0.05).ConclusionThe calcium, phosphorus and Calcium×Phosphorus product serum levels evolved in a similar fashion in the three calcium carbonate intake forms.



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Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance

Publication date: Available online 16 November 2017
Source:Cancer Cell
Author(s): Shipra Shukla, Joanna Cyrta, Devan A. Murphy, Edward G. Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Dan Li, Elissa W.P. Wong, Andrea Sboner, Himisha Beltran, Juan Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P. Koche, Anuradha Gopalan, Deyou Zheng, Mark A. Rubin, Howard I. Scher, Ping Chi, Yu Chen
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.

Teaser

Shukla et al. identify an aberrantly expressed gastrointestinal-lineage transcriptome governed by HNF4G and HNF1A in ∼30% of castration-resistant prostate cancer. HNF4G is a pioneer factor for this transcriptional program and its ectopic expression at physiologic levels reduces sensitivity to hormone deprivation.


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Stress-Activated NRF2-MDM2 Cascade Controls Neoplastic Progression in Pancreas

Publication date: Available online 16 November 2017
Source:Cancer Cell
Author(s): Jelena Todoric, Laura Antonucci, Giuseppe Di Caro, Ning Li, Xuefeng Wu, Nikki K. Lytle, Debanjan Dhar, Sourav Banerjee, Johan B. Fagman, Cecille D. Browne, Atsushi Umemura, Mark A. Valasek, Hannes Kessler, David Tarin, Michael Goggins, Tannishtha Reya, Maria Diaz-Meco, Jorge Moscat, Michael Karin
Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras^G12D acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice. p62 accumulation promotes neoplastic progression by controlling the NRF2-mediated induction of MDM2, which acts through p53-dependent and -independent mechanisms to abrogate checkpoints that prevent conversion of differentiated acinar cells to proliferative ductal progenitors. MDM2 targeting may be useful for preventing PDAC development in high-risk individuals.

Graphical abstract

Teaser

Todoric et al. demonstrate that pancreatitis-induced accumulation of the autophagy substrate p62/SQSTM1 in the context of oncogenic KRAS promotes progression to pancreatic ductal adenocarcinoma. This p62 function relies on NRF2-driven induction of MDM2 and both p53 dependent and independent activity of MDM2.


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Properties of oriented carbon fiber/polyamide 12 composite parts fabricated by fused deposition modeling

Publication date: 5 February 2018
Source:Materials & Design, Volume 139
Author(s): Guangxin Liao, Zhixiang Li, Yuchuan Cheng, Dingding Xu, Dingchun Zhu, Shenglong Jiang, Jianjun Guo, Xinde Chen, Gaojie Xu, Yuejin Zhu
This paper reports the thermal and mechanical properties of carbon fiber (CF) reinforced polyamide 12 (PA12) composites for fused deposition modeling (FDM) process. The printable filaments of carbon fiber/PA12 composites with different mass fraction were fabricated and applied in FDM. The results indicate that the tensile strength and flexural strength of 10 wt% CF/PA12 composites are enhanced by 102.2% and 251.1% respectively. The laser-flash diffusivity analysis measurements exhibit remarkable improvements on thermal conductivity (λ) of carbon fiber/PA12 composites. Moreover, the carbon fiber/PA12 composites mechanical properties are greatly improved. Our work presents a kind of anisotropic high performance composite for FDM.

Graphical abstract

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Safety of intraperitoneal Mitomycin C versus intraperitoneal oxaliplatin in patients with peritoneal carcinomatosis of colorectal cancer undergoing cytoreductive surgery and HIPEC

Publication date: Available online 15 November 2017
Source:European Journal of Surgical Oncology
Author(s): W.J. van Eden, N.F.M. Kok, K. Woensdregt, A.D.R. Huitema, H. Boot, A.G.J. Aalbers
BackgroundColorectal peritoneal carcinomatosis (PC) is commonly treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). There is an ongoing international debate about which intraperitoneal chemotherapeutic agent is preferred, Mitomycin C (MMC) or oxaliplatin. We questioned whether the type of chemotherapeutic agent influenced postoperative complication rates or short-term survival.MethodsIn this retrospective cohort study patients with colorectal PC who underwent CRS-HIPEC between January 2010 and December 2016 were included. Until March 2014 patients had preferentially been treated with MMC and thereafter with oxaliplatin in an iso-osmotic glucose/electrolyte dialysis (Dianeal®) carrier solution. Main outcomes were postoperative complications, disease free survival (DFS) and overall survival (OS). Survival analyses and multivariable analyses were performed.ResultsOne hundred four patients received MMC and 73 patients oxaliplatin. Postoperative complications did not differ between groups (44.2% (MMC) versus 43.8% (oxaliplatin); P=0.958). Median DFS was 12.5 months (IQR 6.4-32.4) in the MMC-group and 13.1 months (IQR 6.1-NA) in the oxaliplatin-group (P=0.669). Median OS was 37.2 months (IQR 17.2-NA) in the MMC-group and 29.4 months (IQR 17.0-NA) in the oxaliplatin-group (P=0.764). The type of chemotherapeutic agent did not influence OS in multivariable analysis (oxaliplatin versus MMC HR 1.09 (95%CI 0.58-2.06)). The HIPEC-phase was shorter for oxaliplatin (median 32 (IQR 31-34) versus 91 minutes (IQR 90-92) for MMC (P<0.001)).ConclusionIntraperitoneal oxaliplatin reduced the chemoperfusion time when compared to intraperitoneal MMC without adversely influencing complication rates or short-term survival. It may therefore be the preferential drug in CRS-HIPEC procedures for colorectal PC.



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