A continuum mechanics model of the plant cell wall reveals interplay between enzyme action and cell wall structure

Plant cell growth is regulated through manipulation of the cell wall network, which consists of oriented cellulose microfibrils embedded within a ground matrix incorporating pectin and hemicellulose components. There remain many unknowns as to how this manipulation occurs. Experiments have shown that cellulose reorients in cell walls as the cell expands, while recent data suggest that growth is controlled by distinct collections of hemicellulose called biomechanical hotspots, which join the cellulose molecule together. The enzymes expansin and Cel12A have both been shown to induce growth of the cell wall; however, while Cel12A’s wall-loosening action leads to a reduction in the cell wall strength, expansin’s has been shown to increase the strength of the cell wall. In contrast, members of the XTH enzyme family hydrolyse hemicellulose but do not appear to cause wall creep. This experimentally observed behaviour still awaits a full explanation. We derive and analyse a mathematical model for the effective mechanical properties of the evolving cell wall network, incorporating cellulose microfibrils, which reorient with cell growth and are linked via biomechanical hotspots made up of regions of crosslinking hemicellulose. Assuming a visco-elastic response for the cell wall and using a continuum approach, we calculate the total stress resultant of the cell wall for a given overall growth rate. By changing appropriate parameters affecting breakage rate and viscous properties, we provide evidence for the biomechanical hotspot hypothesis and develop mechanistic understanding of the growth-inducing enzymes. </p

A continuum mechanics model of the plant cell wall reveals interplay between enzyme action and cell wall structure

Acknowledgements: We would like to thank Cara Neal and Alexander Brune for their helpful inputs and the reviewers. RJD and ETS thank EPSRC for funding via grants EP/M00015X/1 and EP/N509590/1, respectively.Plant cell growth is regulated through manipulation of the cell wall network, which consists of oriented cellulose microfibrils embedded within a ground matrix incorporating pectin and hemicellulose components. There remain many unknowns as to how this manipulation occurs. Experiments have shown that cellulose reorients in cell walls as the cell expands, while recent data suggest that growth is controlled by distinct collections of hemicellulose called biomechanical hotspots, which join the cellulose molecule together. The enzymes expansin and Cel12A have both been shown to induce growth of the cell wall; however, while Cel12A’s wall-loosening action leads to a reduction in the cell wall strength, expansin’s has been shown to increase the strength of the cell wall. In contrast, members of the XTH enzyme family hydrolyse hemicellulose but do not appear to cause wall creep. This experimentally observed behaviour still awaits a full explanation. We derive and analyse a mathematical model for the effective mechanical properties of the evolving cell wall network, incorporating cellulose microfibrils, which reorient with cell growth and are linked via biomechanical hotspots made up of regions of crosslinking hemicellulose. Assuming a visco-elastic response for the cell wall and using a continuum approach, we calculate the total stress resultant of the cell wall for a given overall growth rate. By changing appropriate parameters affecting breakage rate and viscous properties, we provide evidence for the biomechanical hotspot hypothesis and develop mechanistic understanding of the growth-inducing enzymes. Graphic Abstract

A continuum mechanics model of the plant cell wall reveals interplay between enzyme action and cell wall structure

Acknowledgements: We would like to thank Cara Neal and Alexander Brune for their helpful inputs and the reviewers. RJD and ETS thank EPSRC for funding via grants EP/M00015X/1 and EP/N509590/1, respectively.Plant cell growth is regulated through manipulation of the cell wall network, which consists of oriented cellulose microfibrils embedded within a ground matrix incorporating pectin and hemicellulose components. There remain many unknowns as to how this manipulation occurs. Experiments have shown that cellulose reorients in cell walls as the cell expands, while recent data suggest that growth is controlled by distinct collections of hemicellulose called biomechanical hotspots, which join the cellulose molecule together. The enzymes expansin and Cel12A have both been shown to induce growth of the cell wall; however, while Cel12A’s wall-loosening action leads to a reduction in the cell wall strength, expansin’s has been shown to increase the strength of the cell wall. In contrast, members of the XTH enzyme family hydrolyse hemicellulose but do not appear to cause wall creep. This experimentally observed behaviour still awaits a full explanation. We derive and analyse a mathematical model for the effective mechanical properties of the evolving cell wall network, incorporating cellulose microfibrils, which reorient with cell growth and are linked via biomechanical hotspots made up of regions of crosslinking hemicellulose. Assuming a visco-elastic response for the cell wall and using a continuum approach, we calculate the total stress resultant of the cell wall for a given overall growth rate. By changing appropriate parameters affecting breakage rate and viscous properties, we provide evidence for the biomechanical hotspot hypothesis and develop mechanistic understanding of the growth-inducing enzymes. Graphic Abstract

A randomized phase III trial of preoperative chemoradiation followed by surgery (CR-S) versus surgery alone (S) for localized resectable cancer of the esophagus

Purpose: To determine whether CR-S improves survival for resectable cancer of the esophagus. Method: Patients from 25 institutions in 3 countries randomized over a 70 month period - after stratification for histology, gender and institution. The neoadjuvant regimen (CT/RT) consisted of Cisplatin 80mg/m2 day 1 and 5FU 800mg/m2 days 2-5 combined with radiation therapy 35Gy in 15 fractions. Surgery was performed 4 -6 weeks after radiation was completed. Results: Median age was 62 yrs, (range 28 - 81). There were 206 males and 50 females. One hundred and fifty seven patients (61%) had adenocarcinoma (AC). Two hundred and five patients completed the intended protocol including the surgery. The toxicity of the CT/RT was mild and did not affect the morbidity of surgery or length of hospital stay. The overall treatment related mortality was 4.6%. Pathological complete response rate in the patients receiving CT/RT was 15.1 % ( SCC 26.3%, AC 9%). Median overall survival (OS) for CR-S therapy was 21.7 months and for S it was 18.5 months (p= 0.38). Relapse free (RF) and OS were identical in both arms for AC but for SCC there was a significant RF advantage to CR-S (p=0.04) which did not translate into an OS advantage (p=0.06). Conclusion: The findings are compatible with those from previous trials, indicating that the benefits of CT/RT are limited when surgical results are optimal

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial

Introduction: Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer

Summary Background Chemoradiation therapy using regimens containing cisplatin and 5-fluorouracil are most commonly used for inoperable cancer of the esophagus. Cisplatin is relatively toxic and is not suitable for many patients. Little data exists using platinum analogues together with protracted infusion 5-fluorouracil and radiation therapy in the curative setting. Methods Fourteen patients with localised oesophageal cancer suitable for curative chemoradiation therapy registered on the study. Chemotherapy consisted of 5-fluorouracil 225 mg/m2 daily throughout radiation therapy, with oxaliplatin 60 mg/m2 weekly. The radiation dose was 56 to 60 Gy in 28 to 30 fractions. Results The median age of the patients was 70.5 years. Therapy was associated with excessive grade 3 and 4 non-hematologic toxicity. There was one treatment related death. The median progression-free survival was 31.5 months and median overall survival 32.6 months. Six patients achieved a prolonged complete endoscopic and radiological response. Conclusions Although weekly oxaliplatin in combination with infusional 5 fluorouracil produces durable remissions in esophageal cancer, the regimen used in this trial was not acceptable for routine use. Future protocols should incorporate lower chemotherapy doses

Feasibility of chemoradiation therapy with protracted infusion of 5-fluorouracil for esophageal cancer patients not suitable for cisplatin

Chemoradiation therapy is the standard treatment for esophageal cancer in patients not fit for surgery. The regimen most commonly used includes cisplatin and 5-fluorouracil. Little data exists regarding alternative chemotherapy regimens in patients not suitable for cisplatin. We report on a regimen using protracted infusion 5-fluorouracil alone for both curative and palliative indications.Twenty-two patients with localized esophageal cancer suitable for curative chemoradiation therapy and 24 patients suitable for palliative therapy were enrolled. Chemotherapy consisted of 5-fluorouracil 225 mg/m(2) daily throughout the radiation therapy. The radiation dose was 56 to 60 Gy in 28 to 30 fractions (curative patients) and 30 to 35 Gy in 15 fractions (palliative patients).The median age of the patients was 75 years. The regimen was tolerable. Significant grade 3 toxicities experienced were esophagitis (11%) and venous catheter toxicity (9%). The median survival was 17 months for curative patients and 9 months for palliative patients. The complete response rate was 86% endoscopically and 45% radiologically for curative patients. Relief of dysphagia was experienced in 67% of palliative patients. Quality of life was satisfactory in both groups.This study showed that continuous-infusion 5-fluorouracil given concurrently with radiation therapy is a useful alternative to platinum-based chemoradiation therapy in patients with esophageal carcinoma

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy

Abstract Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials