Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.

Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression. Next, we developed an in vitro evolutionary study to record the adaptive strategies of individual lineages in unperturbed parallel experiments. Our data demonstrate that ETs induce nongenetic cell state transitions into dormancy in a stochastic subset of cells via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably in the absence of recurrent genetic alterations. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs. SIGNIFICANCE: This study advances the understanding of therapy-induced dormancy with potential clinical implications for breast cancer. Estrogen receptor-positive breast cancer cells adapt to endocrine treatment by entering a dormant state characterized by strong heterochromatinization with no recurrent genetic changes. Targeting the epigenetic rewiring impairs the adaptation of cancer cells to ETs. See related commentary by Llinas-Bertran et al., p. 704. This article is featured in Selected Articles from This Issue, p. 695.

Neoadjuvant endocrine therapy for luminal breast tumors: State of the art, challenges and future perspectives.

Neoadjuvant endocrine treatment (NET) associates to satisfactory rates of breast conservative surgery and conversions from inoperable to operable hormone receptor-positive (HR+)/HER2-negative breast cancer (BC), with less toxicities than neoadjuvant chemotherapy (NACT) and similar outcomes. Hence, it has been proposed as a logical alternative to NACT in patients with HR+/HER2- BC candidate to a neoadjuvant approach. Nevertheless, potential barriers to the widespread use of NET include the heterogeneous nature of patient response coupled with the long duration needed to achieve a clinical response. However, interest in NET has significantly increased in the last decade, owing to more in-depth investigation of several biomarkers for a more adequate patient selection and on-treatment benefit monitoring, such as PEPI score, Ki67 and genomic assays. This review is intended to describe the state-of-the-art regarding NET, its future perspectives and potential integration with molecular biomarkers for the optimal selection of patients, regimen and duration of (neo)adjuvant treatments.

Comparison Among Ultrasound-Guided Thoracic Paravertebral Block, Erector Spinae Plane Block and Serratus Anterior Plane Block for Analgesia in Thoracotomy for Lung Surgery.

BACKGROUND: To compare the analgesic efficacy and safety of preoperative, single-shot ultrasound-guided thoracic paravertebral block (TPVB), erector spinae plane block (ESB), and serratus anterior plane block (SAPB) in thoracotomy pain. DESIGN: A prospective, randomized study. SETTING: The cardiothoracic operating room and intensive care unit of a tertiary-care hospital in India. PARTICIPANTS: Ninety adult patients scheduled to undergo posterolateral thoracotomy for lung surgery under general anesthesia were recruited and randomized into 3 equal groups. INTERVENTIONS: Preoperatively, the patients received ultrasound-guided, single-shot nerve blocks within their respective groups, as follows: Erector spinae plane block in the ESB group, Thoracic paravertebral block in the TPVB group, and Serratus anterior plane block in the SAPB group. MEASUREMENTS AND RESULTS: The primary outcome measure, the visual analog scale (VAS) score, was recorded postoperatively in the intensive care unit at 0, 3, 6, 12, and 24 hours. The secondary outcome measures were the time to first rescue analgesic, total rescue opioid dose used, patient satisfaction at 24 hours, success of one-time attempt, and occurrence of adverse events. Data were statistically analyzed and a significant difference was found in the VAS score at all time points, the time to rescue analgesic and total opioid dosage, and patient satisfaction level (p < 0.05) among the groups with only 1 incidence of hypotension in the TPVB group. From post hoc analysis, ESB was found to have better analgesic efficacy compared with TPVB and SAPB. Serratus anterior plane block was found to be least efficacious and shortest acting among the three. CONCLUSION: The nerve blocks in decreasing order of analgesic efficacy in relieving post-thoracotomy pain would be ESB, TPVB, and SAPB.

Identification of a polyketide synthase required for alternariol (AOH) and alternariol-9-methyl ether (AME) formation in Alternaria alternata.

Alternaria alternata produces more than 60 secondary metabolites, among which alternariol (AOH) and alternariol-9-methyl ether (AME) are important mycotoxins. Whereas the toxicology of these two polyketide-based compounds has been studied, nothing is known about the genetics of their biosynthesis. One of the postulated core enzymes in the biosynthesis of AOH and AME is polyketide synthase (PKS). In a draft genome sequence of A. alternata we identified 10 putative PKS-encoding genes. The timing of the expression of two PKS genes, pksJ and pksH, correlated with the production of AOH and AME. The PksJ and PksH proteins are predicted to be 2222 and 2821 amino acids in length, respectively. They are both iterative type I reducing polyketide synthases. PksJ harbors a peroxisomal targeting sequence at the C-terminus, suggesting that the biosynthesis occurs at least partly in these organelles. In the vicinity of pksJ we found a transcriptional regulator, altR, involved in pksJ induction and a putative methyl transferase, possibly responsible for AME formation. Downregulation of pksJ and altR caused a large decrease of alternariol formation, suggesting that PksJ is the polyketide synthase required for the postulated Claisen condensations during the biosynthesis. No other enzymes appeared to be required. PksH downregulation affected pksJ expression and thus caused an indirect effect on AOH production.

Simultaneous enzyme immunoassay for the screening of aflatoxin B1 and ochratoxin A in chili samples.

Membrane-based immunoassay has been developed for simultaneous estimation of aflatoxin B(1) (AFB(1)) and ochratoxin A (OA) in chili samples. The combined estimation of both the mycotoxins is more economical in respect of time, work and materials than two separate assays. The method uses a low cost test device consisting of a membrane with immobilized anti-AFB(1) and anti-OA antibodies and a filter paper attached to a polyethylene card below the membrane. It allows direct analysis of sample extracts containing substantial amount (40%) of methanol. This permits the use of two-fold diluted sample extracts resulting in minimum dilution error. The limit of quantitation obtained was 2 and 10 microg kg(-1) for AFB(1) and OA, respectively. The tolerance of 40% methanol was found to be due to the application of small size (0.8 mm diameter) spots on membranes, as the tolerance decreases to 20% with gradual increase in spot size. The combined method is capable of producing acceptable results to analyze AFB(1) and OA in chili with accuracy and precision. The AFB(1) and OA values obtained for spiked and naturally contaminated chili samples by the simultaneous method were in good correlation with those measured by individual ELISA. The method offers a simple, rapid and cost-effective screening tool to meet the requirements of the rapidly evolving EU legislation.