CONTENTS: 717 I. 717 II. 718 III. 718 IV. 720 V. 722 VI. 722 VII. 728 730 References 730 SUMMARY: It is estimated that around half of all species of flowering plants show self‐incompatibility (SI). ...However, the great majority of species alleged to have SI simply comply with ‘the inability of a fully fertile hermaphrodite plant to produce zygotes when self‐pollinated’ – a definition that is neutral as to cause. Surprisingly few species have been investigated experimentally to determine whether their SI has the type of genetic control found in one of the three established mechanisms, that is, homomorphic gametophytic, homomorphic sporophytic or heteromorphic SI. Furthermore, our knowledge of the molecular basis of homomorphic SI derives from a few species in just five families – a small sample that has nevertheless revealed the existence of three different molecular mechanisms. Importantly, a sizeable cohort of species are self‐sterile despite the fact that self‐pollen tubes reach the ovary and in most cases penetrate ovules, a phenomenon called late‐acting self‐incompatibility (LSI). This review draws attention to the confusion between species that show ‘self‐incompatibility’ and those that possess one of the ‘conventional SI mechanisms’ and to argue the case for recognition of LSI as having a widespread occurrence and as a mechanism that inhibits selfing and promotes outbreeding in many plant species.
Abstract
Background
ASPirin in Reducing Events in the Elderly, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause ...mortality, primarily due to cancer. In contrast, prior randomized controlled trials, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality.
Methods
19 114 Australian and US community-dwelling participants aged 70 years and older (US minorities 65 years and older) without cardiovascular disease, dementia, or physical disability were randomly assigned and followed for a median of 4.7 years. Fatal and nonfatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records.
Results
981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (hazard ratio HR = 1.04, 95% confidence interval CI = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64).
Conclusions
In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and, thus, suggest caution with its use in this age group.
In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA ...(ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study.
We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing.
We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM.
ACTRN12612000345886.
ABSTRACT
Biliverdin reductase A (BVR) and Akt isozymes have overlapping pleiotropic functions in the insulin/PI3K/MAPK pathway. Human BVR (hBVR) also reduces the hemeoxygenase activity product ...biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK). Akt isoenzymes (Akt1‐3) are downstream of IRK and are activated by phosphatidylinositol‐dependent kinase 1 (PDK1) phosphorylating T308 before S473 autophosphorylation. Akt (RxRxxSF) and PDK1 (RFxFPxFS) binding motifs are present in hBVR. Phosphorylation of glycogen synthase kinase 3 (GSK3) isoforms α/β by Akts inhibits their activity; nonphosphorylated GSK3β inhibits activation of various genes. We examined the role of hBVR in PDK1/Akt1/GSK3 signaling and Akt1 in hBVR phosphorylation. hBVR activates phosphorylation of Aktl at S473 independent of hBVR's kinase competency. hBVR and Aktl coimmunoprecipitated, and in‐cell Förster resonance energy transfer (FRET) and glutathione S‐transferase pulldown analyses identified Aktl pleckstrin homology domain as the interactive domain. hBVR activates phosphorylation of Akt1 at S473 independent of hBVR'skinase competency. Site‐directed mutagenesis, mass spectrometry, and kinetic analyses identified S230 in hBVR 225RNRYLSF sequence as the Aktl target. Underlined amino acids are the essential residues of the signaling motifs. In cells, hBVR‐activated Aktl increased both GSK3α/β and forkhead box of the O class transcription class 3 (FoxO3) phosphorylation and inhibited total GSK3 activity; depletion of hBVR released inhibition and stimulated glucose uptake. Immunoprecipitation analysis showed that PDK1 and hBVR interact through hBVR's PDK1 binding 161RFGFPAFS motif and formation of the PDK1/hBVR/Akt1 complex. sihBVR blocked complex formation. Findings identify hBVR as a previously unknown coactivator of Aktl and as a key mediator of Akt1/GSK3 pathway, as well as define a key role for hBVR in Aktl activation by PDKl.—Miralem, T., Lerner‐Marmarosh, N., Gibbs, P. E. M., Jenkins, J. L., Heimiller, C., Maines, M. D. Interactionof human biliverdin reductase with Akt/protein kinase B and phosphatidylinositol‐dependent kinase l regulates glycogen synthase kinase 3 activity: a novel mechanism of Akt activation. FASEB J. 30, 2926‐2944 (20l6). www.fasebj.org
The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas ...its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.
We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.
Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval CI, 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 noninferiority margin, -8.5 percentage points). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.
A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
Activation of the MEK/ERK/Elk-signaling cascade is a mechanism for relaying mitogenic and stress stimuli for gene activation. MEK1 is the proximate kinase for activation of ERK1/2, and nuclear ...targeting of ERK1/2 is obligatory for Elk1 transcriptional activity. Human biliverdin reductase (hBVR) is a recently described Ser/Thr/Tyr kinase in the MAPK insulin/insulin-like growth factor 1 (IGF1)-signaling cascade. Using 293A cells and in vitro experiments, we detail the formation of a ternary complex of MEK/ERK/hBVR, activation of MEK1 and ERK1/2 kinase activities by hBVR, and phosphorylation of hBVR by ERK1/2. hBVR is nearly as effective as IGF1 in activating ERK; intact hBVR ATP-binding domain is necessary for Elk1 activation, whereas protein-protein interaction is the basis for hBVR activation of MEK1 and ERK. The two MAPK docking consensus sequences present in hBVR, F¹⁶²GFP and K²⁷⁵KRILHCLGL (C- and D-box, respectively), are ERK interactive sites; interaction at each site is critical for ERK/Elk1 activation. Transfection with mutant hBVR-P¹⁶⁵ or peptides corresponding to the C- or D-box blocked activation of ERK by IGF1. Transfection with D-box mutant hBVR prevented the activation of ERK by wild-type protein and dramatically decreased Elk1 transcriptional activity. hBVR is a nuclear transporter of ERK; experiments with hBVR nuclear export signal (NES) and nuclear localization signal (NLS) mutants demonstrated its critical role in the nuclear localization of IGF-stimulated ERK for Elk1 activation. These findings, together with observations that si-hBVR blocked activation of ERK and Elk1 by IGF1 and prevented formation of ternary complex between MEK/ERK/hBVR, define the critical role of hBVR in ERK signaling and nuclear functions of the kinase.
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. While there have been significant developments in the treatments for patients with metastatic CRC in recent ...years, improving outcomes in the adjuvant setting has been more challenging. Recent technological advances in circulating tumour DNA (ctDNA) assay with the ability to detect minimal residual disease (MRD) after curative intent surgery will fundamentally change how we assess recurrence risk and conduct adjuvant trials. Studies in non-metastatic CRC have now demonstrated the prognostic impact of ctDNA analysis after curative intent surgery over and above current standard of care clinicopathological criteria. This ability of ctDNA analysis to stratify patients into low- and very-high-risk groups provides a window of opportunity to personalise adjuvant treatment where escalation/de-escalation of adjuvant systemic therapy could potentially increase cure rates and also reduce treatment-related physical and financial toxicity. Emerging data suggest that conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy may reflect treatment efficacy. This real-time assessment of treatment benefit could be used as a surrogate endpoint for adjuvant novel drug development. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer.
Background There is an increasing focus over time on the discovery and validation of biomarkers in cancer medicine, which can inform the identification of patients that are most likely to benefit ...from treatment, which therapy is most likely to be effective, and treatments that may not be safe. Body Creating the necessary evidence base for biomarker-informed management is a different challenge to developing a new therapy, and many biomarkers have been adopted into routine clinical practice without phase III randomised studies where the primary endpoint was to evaluate the direct impact of a biomarker-informed approach. This has generated a robust discussion in the research and clinical community regarding the most appropriate trial methodologies for biomarker validation, and the level of evidence required to support the incorporation of individual biomarker-driven approaches as a standard of care. This ongoing debate is key to optimising clinical trial design and ultimately delivering the best possible care to patients in an environment increasingly focused on personalised and patient-focused management. Conclusion Ongoing deliberation as to the optimal design of biomarker-driven clinical trials is critical to informing future clinical trial design and will ultimately greatly benefit patients and the clinicians that care for them. Keywords: Biomarker, ctDNA, Minimal residual disease
Abstract Context The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS) is a prognostic factor. It should be used in analyzing health outcomes such as ...risk-adjusted hospital performance models in cancer populations. Performance status is rarely recorded in surgery, often the place where cancer is first diagnosed. Could a universally collected preoperative measure be substituted for ECOG/WHO PS? Objectives The aim of this study was to assess whether the American Society of Anesthesiologists (ASA) score could be used as a proxy for ECOG/WHO PS in risk adjustment models predicting extended length of stay (LOS) after cancer surgery. Methods Data were obtained from the BioGrid Colorectal Cancer Database for 2540 treatment episodes (2528 patients) at five hospitals in Victoria and Tasmania, Australia, from 2003 to 2012. Using extended LOS as the index outcome measure, a risk adjustment model was developed using patient demographic and clinical variables. The ECOG/WHO PS and ASA score were added to this model, and the relative percentage change in hospital coefficients were examined. Model fit was compared using Akaike's information criterion (AIC) and concordance statistic (c). Results Adding ECOG/WHO PS or ASA score to the model resulted in relative changes in the hospital coefficients of up to 27%. The ECOG/WHO PS and ASA score performed similarly, with addition of either improving the AIC from 988.2 to 976.3. Inclusion of both measures further improved AIC to 972.4. Conclusion The ASA score can be used as a proxy for ECOG/WHO PS in risk adjustment models predicting cancer surgery. Further studies should assess its broader application for other outcomes and in other settings.
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