An Introduction to Machine Unlearning

Removing the influence of a specified subset of training data from a machine learning model may be required to address issues such as privacy, fairness, and data quality. Retraining the model from scratch on the remaining data after removal of the subset is an effective but often infeasible option, due to its computational expense. The past few years have therefore seen several novel approaches towards efficient removal, forming the field of "machine unlearning", however, many aspects of the literature published thus far are disparate and lack consensus. In this paper, we summarise and compare seven state-of-the-art machine unlearning algorithms, consolidate definitions of core concepts used in the field, reconcile different approaches for evaluating algorithms, and discuss issues related to applying machine unlearning in practice

Study of the 25Mg(d,p)26Mg reaction to constrain the 25Al(p,γ )26Si resonant reaction rates in nova burning conditions

The rate of the $$^{25}$$Al(p, $$\gamma$$)$$^{26}$$Si reaction is one of the few key remaining nuclear uncertainties required for predicting the production of the cosmic $$\gamma$$-ray emitter $$^{26}$$Al in explosive burning in novae. This reaction rate is dominated by three key resonances ($$J^{\pi }=0^{+}$$, $$1^{+}$$ and $$3^{+}$$) in $$^{26}$$Si. Only the $$3^{+}$$ resonance strength has been directly constrained by experiment. A high resolution measurement of the $$^{25}$$Mg(d, p) reaction was used to determine spectroscopic factors for analog states in the mirror nucleus, $$^{26}$$Mg. A first spectroscopic factor value is reported for the $$0^{+}$$ state at 6.256 MeV, and a strict upper limit is set on the value for the $$1^{+}$$ state at 5.691 MeV, that is incompatible with an earlier ($$^{4}$$He, $$^{3}$$He) study. These results are used to estimate proton partial widths, and resonance strengths of analog states in $$^{26}$$Si contributing to the $$^{25}$$Al(p, $$\gamma$$)$$^{26}$$Si reaction rate in nova burning conditions

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Measurement of the 25Mg(d, p)26Mg reaction to constrain nucleosynthesis in novae and the weak s-process

The 25Al(p, γ) 26Si reaction rate is one of the few outstanding uncertainties in modelling the contribution from novae to the galactic budget of the long-lived radioactive isotope 26Al. The rate is dominated by three key resonances in 26Si (J π = 1+, 0+ and 3+), of which only the 3+ resonance has been directly constrained. The first experiment described in this thesis used the 25Mg(d, p) reaction to measure the spectroscopic factors of the three analog states in the mirror nucleus 26Mg, including a spectroscopic factor for the 0+ state. The proton partial widths estimated from these spectroscopic factors established the 0+ state contributes .10% of the 25Al(p, γ) reaction rate, with the 3+ state dominating at higher temperatures. The upper limit extracted for the 1+ proton partial width, which disagreed with a previous (4He, 3He) study, found it only contributes to the reaction rate at low temperatures. Previous studies presented evidence for a negative parity state in 26Mg around 5.7 MeV, consistent with the angular distribution measured in the current work, which has not had an analog state in 26Si confirmed. Future work should focus on identifying such a state and further constraining the parameters of the dominant 3+ resonance. The amount of neutrons available for the weak s-process depends on the 22Ne(α, n) and 22Ne(α, γ) reaction rates, which proceed through natural-parity states of 26Mg above the alpha and neutron thresholds. The second experiment in this thesis used the 25Mg(d, p) reaction to populate states above the 26Mg alpha threshold. The shapes of the angular distributions constrained the `-transfers populating those states. This established the spin/parities of states at 10.82, 10.95, 11.08 and 11.11 MeV as 2+, 1−, 2+ and 2+ respectively. Combining these assignments with previous alpha-transfer studies allowed alpha partial widths to be extracted, which were used to calculate reaction rates for both reactions. Studies seeking to further reduce these rate uncertainties should focus on constraining the properties of the 10.95 and 11.11 MeV states, which dominate the reactions at temperatures whenever the 22Ne(α, n) rate overtakes that of the 22Ne(α, γ) reaction

Laminin Polymerization and Inherited Disease: Lessons From Genetics

The laminins (LM) are a family of basement membranes glycoproteins with essential structural roles in supporting epithelia, endothelia, nerves and muscle adhesion, and signaling roles in regulating cell migration, proliferation, stem cell maintenance and differentiation. Laminins are obligate heterotrimers comprised of α, β and γ chains that assemble intracellularly. However, extracellularly these heterotrimers then assemble into higher-order networks via interaction between their laminin N-terminal (LN) domains. In vitro protein studies have identified assembly kinetics and the structural motifs involved in binding of adjacent LN domains. The physiological importance of these interactions has been identified through the study of pathogenic point mutations in LN domains that lead to syndromic disorders presenting with phenotypes dependent on which laminin gene is mutated. Genotype-phenotype comparison between knockout and LN domain missense mutations of the same laminin allows inferences to be drawn about the roles of laminin network assembly in terms of tissue function. In this review, we will discuss these comparisons in terms of laminin disorders, and the therapeutic options that understanding these processes have allowed. We will also discuss recent findings of non-laminin mediators of laminin network assembly and their implications in terms of basement membrane structure and function

Laminin N-terminus α31 protein distribution in adult human tissues.

Laminin N-terminus α31 (LaNt α31) is a netrin-like protein derived from alternative splicing of the laminin α3 gene. Although LaNt α31 has been demonstrated to influence corneal and skin epithelial cell function, its expression has not been investigated beyond these tissues. In this study, we used immunohistochemistry to characterise the distribution of this protein in a wide-array of human tissue sections in comparison to laminin α3. The data revealed widespread LaNt α31 expression. In epithelial tissue, LaNt α31 was present in the basal layer of the epidermis, throughout the epithelium of the digestive tract, and in much of the epithelium of the reproductive system. LaNt α31 was also found throughout the vasculature of most tissues, with enrichment in reticular-like fibres in the extracellular matrix surrounding large vessels. A similar matrix pattern was observed around the terminal ducts in the breast and around the alveolar epithelium in the lung, where basement membrane staining was also evident. Specific enrichment of LaNt α31 was identified in sub-populations of cells of the kidney, liver, pancreas, and spleen, with variations in intensity between different cell types in the collecting ducts and glomeruli of the kidney. Intriguingly, LaNt α31 immunoreactivity was also evident in neurons of the central nervous system, in the cerebellum, cerebral cortex, and spinal cord. Together these findings suggest that LaNt α31 may be functionally relevant in a wider range of tissue contexts than previously anticipated, and the data provides a valuable basis for investigation into this interesting protein