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Autore: Grafiati

Pubblicato: 31 agosto 2024

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1

Omukai, Shiho, Shin-ich Arimura, Kinya Toriyama e Tomohiko Kazama. "Disruption of mitochondrial open reading frame 352 partially restores pollen development in cytoplasmic male sterile rice". Plant Physiology 187, n. 1 (20 maggio 2021): 236–46. http://dx.doi.org/10.1093/plphys/kiab236.

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Abstract Plant mitochondrial genomes sometimes carry cytoplasmic male sterility (CMS)-associated genes. These genes have been harnessed in various crops to produce high-yielding F1 hybrid seeds. The gene open reading frame 352 (orf352) was reported to be an RT102-type CMS gene in rice (Oryza sativa), although the mechanism underlying its role in CMS is unknown. Here, we employed mitochondrion-targeted transcription activator-like effector nucleases (mitoTALENs) to knockout orf352 from the mitochondrial genome in the CMS rice RT102A. We isolated 18 independent transformation events in RT102A that resulted in genome editing of orf352, including its complete removal from the mitochondrial genome in several plants. Sequence analysis around the mitoTALEN target sites revealed their induced double-strand breaks were repaired via homologous recombination. Near the 5ʹ-target site, repair involved sequences identical to orf284, while repair of the 3ʹ-target site yielded various new sequences that generated chimeric genes consisting of orf352 fragments. Plants with a chimeric mitochondrial gene encoding amino acids 179–352 of ORF352 exhibited the same shrunken pollen grain phenotype as RT102A, whereas plants either lacking orf352 or harboring a chimeric gene encoding amino acids 211–352 of ORF352 exhibited partial rescue of pollen viability and germination, although these plants failed to set seed. These results demonstrated that disruption of orf352 partially restored pollen development, indicating that amino acids 179–210 from ORF352 may contribute to pollen abortion.

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Hashimoto, Masami, Sandra R. Bacman, Susana Peralta, Marni J. Falk, Anne Chomyn, David C. Chan, Sion L. Williams e Carlos T. Moraes. "MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases". Molecular Therapy 23, n. 10 (ottobre 2015): 1592–99. http://dx.doi.org/10.1038/mt.2015.126.

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Bacman, Sandra R., Johanna H. K. Kauppila, Claudia V. Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L. Williams, Nils-Göran Larsson, James B. Stewart e Carlos T. Moraes. "MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation". Nature Medicine 24, n. 11 (24 settembre 2018): 1696–700. http://dx.doi.org/10.1038/s41591-018-0166-8.

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Bacman, Sandra R., Johanna H. K. Kauppila, Claudia V. Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L. Williams, Nils-Göran Larsson, James B. Stewart e Carlos T. Moraes. "Author Correction: MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation". Nature Medicine 24, n. 12 (5 ottobre 2018): 1940. http://dx.doi.org/10.1038/s41591-018-0234-0.

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Yashina, D. P., e Z. A. Afanasieva. "Experience of mitotane successful in the treatment of metastatic adrenocortical cancer". Endocrine Surgery 15, n. 4 (14 dicembre 2022): 12–13. http://dx.doi.org/10.14341/serg12764.

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Background. Adrenocortical cancer (ACC) is a rare malignant endocrine tumor endowed with an aggressive biological potential and a poor prognosis. Surgical adrenalectomy remains the only radical treatment for local ACC. The overall 5-year survival rate of stages with local ACC varies from 56% to 96% and depends on the level of surgical training of a specialized center and the use of adjuvant therapy. Mitotan is the only approved chemotherapeutic agent for the adjuvant treatment of both the primary tumor and relapse and metastases.Aim. To evaluate the experience of mitotane successful use in a young patient with recurrent ACC using the experience of a large medical institution.Clinical observation. Patient R., 31 years old, is under dispensary observation for recurrent adrenocortical cancer of the left adrenal gland T1N0M0 stage 1, class 3. Progression from 2015, 2017, February 2019, April 2019, September 2020 (in the bed, MTS to the left kidney, MTS to the retroperitoneal tissue, MTS to the soft tissues of the lumbar region on the left, MTS to the lungs). Eradication of the tumor tissue was performed surgically, followed by morphological confirmation of the removed foci. For the first time, the diagnosis was established at the age of 23 during an examination for Itsenko-Cushing’s syndrome. Morphologically, the diagnosis of ACC was established after a histological examination of the tumor biopsy obtained by left-sided adrenalectomy (adrenocortical cancer, ki67 up to 20%).During a scheduled dispensary examination in September 2020, according to CT scan of the chest with contrast, two foci were identified in the right lung: in C1 — 10 * 15 mm, in C2 — 30 * 21 mm. By decision of the council (consisting of an oncologist-endocrinologist, a thoracic surgeon and a chemotherapist), a decision was made to prescribe mitotane with dose titration under the control of the level of mitotane in the blood until it reaches 14–20 ng/l, without morphological examination of the foci. Hypocorticism was corrected by the simultaneous use of hydrocortisone with mitotane at a dose of 20 mg per day under the control of ACTH levels. In X-ray evaluation by CT of the chest with a frequency of 3 months, the therapeutic effect in the form of a decrease in the size of the foci (RESIST1.1) occurred in the first 3 months. Mitotan was canceled in November 2021 after complete regression of tumor foci according to CT scan of the chest (pneumosclerosis areas 10*4 mm). Currently, the patient is receiving hormone replacement therapy with hydrocortisone 25 mg per day and is under dispensary observation.Conclusion. Clinical observation has demonstrated the successful use of mitotane in the treatment of metastatic adrenocortical cancer.

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Sava, Alexandra Daniela, Tiberiu Bogdan Szekely, Cornelia Togănel, Adela Vacar e Simona Gurzu. "Adrenocortical carcinoma: A tumor with poor answer to classic chemotherapy". Acta Marisiensis - Seria Medica 69, n. 4 (1 dicembre 2023): 292–94. http://dx.doi.org/10.2478/amma-2023-0039.

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Abstract Introduction: Adrenocortical carcinoma (ACC) represents a rare endocrine malignancy being the second most aggressive endocrine cancer after anaplastic thyroid cancer. [1]. While most of them arise sporadically, up to 15% of adult ACC patients are related to germline mutations associated with familial cancer syndromes.[1,2]. Current treatment strategies include surgery as well as systemic therapy with mitotane and chemotherapy. Case report: A 60-year-old female patient with a family history of colon cancer, multinodular goiter, hypothyroidism treated with substitutive therapy, uterine fibroids, and hypertension, was diagnosed with adrenocortical carcinoma. No distant metastasis were present at the moment of diagnosis so an adrenalectomy was performed. Due to postoperative complications, a total nephrectomy was also needed. Adjuvant Mitotane treatment was given. A CT exam performed 5 months after the resection showed multiple pulmonary metastasis, a liver nodule and peritoneal carcinomatosis. The standard first-line chemotherapy of choice was Carboplatin and Etoposide. After completing 3 cycles of chemotherapy the imaging reassessment show the progression of liver and peritoneal lesions and the quasi-complete regression of lung lesions. Currently, the Mitotate treatment was stopped due to severe adverse reactions. Conclusions: Adrenocortical carcinoma is a rare endocrine malignancy with a poor prognosis. The recruitment of ACC patients for new clinical trials to investigate new treatment strategies is needed because currently, no significant therapeutic breakthrough is emerging.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 1385 (gennaio 2012): 33. http://dx.doi.org/10.2165/00128415-201213850-00121.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 1180 (dicembre 2007): 28. http://dx.doi.org/10.2165/00128415-200711800-00084.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 1155 (giugno 2007): 14. http://dx.doi.org/10.2165/00128415-200711550-00039.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 1399 (aprile 2012): 23. http://dx.doi.org/10.2165/00128415-201213990-00084.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 367 (settembre 1991): 10. http://dx.doi.org/10.2165/00128415-199103670-00051.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 407 (giugno 1992): 9. http://dx.doi.org/10.2165/00128415-199204070-00032.

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&NA;. "Mitotane". Reactions Weekly &NA;, n. 422 (ottobre 1992): 10. http://dx.doi.org/10.2165/00128415-199204220-00048.

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Kroiss, Matthias, Dietmar Plonné, Sabine Kendl, Diana Schirmer, Cristina L. Ronchi, Andreas Schirbel, Martina Zink et al. "Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma". European Journal of Endocrinology 174, n. 3 (marzo 2016): 343–53. http://dx.doi.org/10.1530/eje-15-0946.

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ObjectiveOral mitotane (o,p′-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC). AimSerum mitotane concentrations >14 mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p′-dichlorodiphenylacetic acid (o,p′-DDA) and o,p′-dichlorodiphenyldichloroethane (o,p′-DDE).DesignLipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI–H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins.ResultsChyle of the index patient contained 197 mg/ml mitotane, 53 mg/ml o,p′-DDA, and 51 mg/l o,p′-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction.DiscussionMitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p′-DDE was similarly distributed, but 87.9±4.2% of o,p′-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI–H295 cells and reduced ER stress marker gene expression.ConclusionMitotane absorption involves chylomicron binding. High concentrations of o,p′-DDA and o,p′-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.

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Takeshita, Akira, Junko Igarashi-Migitaka, Noriyuki Koibuchi e Yasuhiro Takeuchi. "Mitotane induces CYP3A4 expression via activation of the steroid and xenobiotic receptor". Journal of Endocrinology 216, n. 3 (22 novembre 2012): 297–305. http://dx.doi.org/10.1530/joe-12-0297.

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Adrenocortical carcinoma (ACC) is a rare disease with an extremely poor prognosis. Mitotane alone or in combination with other cytotoxic drugs is a common therapeutic option for ACC. In addition to its adrenolytic function, mitotane has been known for decades to increase the metabolic clearance of glucocorticoids. It was recently shown that the tyrosine kinase inhibitor sunitinib is also rapidly metabolized in patients treated with mitotane, indicating that mitotane engages in clinically relevant drug interactions. Although the precise mechanism of these interactions is not well understood, cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is a key enzyme to inactivate both glucocorticoids and sunitinib. The nuclear receptor steroid and xenobiotic receptor (SXR (NR1I2)) is one of the key transcriptional regulators ofCYP3A4gene expression in the liver and intestine. A variety of xenobiotics bind to SXR and stimulate transcription of xenobiotic-response elements (XREs) located in theCYP3A4gene promoter. In this study, we evaluated the effects of mitotane on SXR-mediated transcriptionin vitroby luciferase reporter analysis, SXR–steroid receptor coactivator 1 (SRC1) interactions, quantitative real-time PCR analysis ofCYP3A4expression, SXR knockdown, and CYP3A4 enzyme activity assays using human hepatocyte-derived cells. We found that mitotane activated SXR-mediated transcription of the XREs. Mitotane recruited SRC1 to the ligand-binding domain of SXR. Mitotane increasedCYP3A4mRNA levels, which was attenuated by SXR knockdown. Finally, we showed that mitotane increased CYP3A4 enzyme activity. We conclude that mitotane can induceCYP3A4gene expression and suggest that mitotane is used cautiously due to its drug–drug interactions.

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Jouinot, Anne, Bernard Royer, Etienne Chatelut, Sotheara Moeung, Guillaume Assié, Audrey Thomas-Schoemann, Jérôme Bertherat, François Goldwasser e Benoit Blanchet. "Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study". Endocrine Connections 7, n. 12 (dicembre 2018): 1409–14. http://dx.doi.org/10.1530/ec-18-0428.

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Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120–150 mg/m2 day 1–2–3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug–drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.

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Zatelli, Maria Chiara, Erica Gentilin, Fulvia Daffara, Federico Tagliati, Giuseppe Reimondo, Gianni Carandina, Maria Rosaria Ambrosio, Massimo Terzolo e Ettore C. degli Uberti. "Therapeutic Concentrations of Mitotane (o,p′-DDD) Inhibit Thyrotroph Cell Viability and TSH Expression and Secretion in a Mouse Cell Line Model". Endocrinology 151, n. 6 (14 aprile 2010): 2453–61. http://dx.doi.org/10.1210/en.2009-1404.

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Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T4, and free T3 levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TαT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TαT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.

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Puglisi, Soraya, Anna Calabrese, Vittoria Basile, Filippo Ceccato, Carla Scaroni, Barbara Altieri, Silvia Della Casa et al. "Mitotane Concentrations Influence Outcome in Patients with Advanced Adrenocortical Carcinoma". Cancers 12, n. 3 (20 marzo 2020): 740. http://dx.doi.org/10.3390/cancers12030740.

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Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

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Mauclère-Denost, Sophie, Sophie Leboulleux, Isabelle Borget, Angelo Paci, Jacques Young, Abir Al Ghuzlan, Desiree Deandreis et al. "High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up". European Journal of Endocrinology 166, n. 2 (febbraio 2012): 261–68. http://dx.doi.org/10.1530/eje-11-0557.

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BackgroundThe benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown.MethodsTo evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC.ResultsTwenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of >14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3–4 neurological or hematological toxicities were observed in three patients (13.6%).ConclusionEmploying a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

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van Koetsveld, Peter M., Sara G. Creemers, Fadime Dogan, Gaston J. H. Franssen, Wouter W. de Herder, Richard A. Feelders e Leo J. Hofland. "The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures". Journal of Clinical Endocrinology & Metabolism 105, n. 2 (5 ottobre 2019): 407–17. http://dx.doi.org/10.1210/clinem/dgz001.

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Abstract Context Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome. Objective Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics. Methods In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. Results The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC50) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3–17.9), in partial responders 41.6 µM (95% CI, 33.5–51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC50 of 1.4 µM (95% CI, 0.9–2.1), which was considerably lower than the EC50 on cell growth. RRM1, SOAT1, and CYP2W1 expression levels were not predictive for mitotane sensitivity in vitro. Conclusion Direct antitumor effects of mitotane on human primary ACC cultures are highly variable between patients, reflecting heterogeneous responses in patients. Cortisol was inhibited at lower concentrations, compared with its effect on cell amount. Cortisol secretion by ACC might be associated with enhanced mitotane sensitivity due to increased direct antitumor effects of mitotane.

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Zhulikov, Ya A., E. I. Kovalenko, V. Yu Bohyan, M. V. Khoroshilov, M. M. Gabrava e E. V. Artamonova. "Efficacy of EDP ± mitotane chemotherapy in the treatment of metastatic adrenocortical carcinoma. Predictive and prognostic factors of efficacy". Malignant tumours 11, n. 1 (26 luglio 2021): 37–46. http://dx.doi.org/10.18027/2224-5057-2021-11-1-37-46.

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Introduction. Adrenocortical carcinoma (ACC) is an orphan disease with an unfavorable prognosis. The most effective therapeutic option in the treatment of ACC is EDP plus mitotane combination chemotherapy. However, no studies comparing the efficacy of the EDP regimen with or without mitotane have been published.Materials and methods. A retrospective analysis of health records of patients with histologically confirmed metastatic ACC, who received at least one chemotherapy cycle with EDP ± mitotane. The study included 73 patients, 49 of which received a combination of EDP and mitotane and 24 were treated with EDP chemotherapy.Results. The objective response rate was 18,4 % in the EDP + mitotane group versus 4,1 % in the EDP group. Disease control was reported in 25 (51 %) and 13 (54,2 %) patients, respectively. No significant differences were found in progression-free survival (PFS) rates between the EDP and EDP + mitotane groups; the median PFS rate was 6,5 and 6,0 months, respectively. The median overall survival (OS) in the total population was 20,9 months; no significant differences were found between the groups. However, an increase in median PFS was observed in patients who achieved a therapeutic concentration of mitotane. Moreover, the achievement of therapeutic mitotane concentrations was the only factor significantly associated with improved PFS (HR 0.44, p = 0.006). Significant unfavorable prognostic factors associated with lower OS were Ki-67 level in the primary tumor > 20 % (HR 10.5, p = 0.006) and more than 1 site of metastases (HR 3.82, p = 0.02).Conclusions. This study showed that the addition of mitotane to EDP chemotherapy does not improve the median PFS and OS in the total patient population, however, the achievement of therapeutic mitotane concentrations is significantly associated with improved progression-free survival.

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Haberbosch, Linus, Lukas Maurer, Arvid Sandforth, Charlotte Wernicke, Joachim Spranger, Knut Mai e Reiner Jumpertz von Schwartzenberg. "Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients". Endocrine-Related Cancer 29, n. 3 (1 marzo 2022): 121–28. http://dx.doi.org/10.1530/erc-21-0202.

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Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options.

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Puglisi, Soraya, Anna Calabrese, Vittoria Basile, Filippo Ceccato, Carla Scaroni, Chiara Simeoli, Massimo Torlontano et al. "Mitotane Concentrations Influence the Risk of Recurrence in Adrenocortical Carcinoma Patients on Adjuvant Treatment". Journal of Clinical Medicine 8, n. 11 (2 novembre 2019): 1850. http://dx.doi.org/10.3390/jcm8111850.

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Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28–62) with a median maintenance dose of 2.0 g/day (IQR 1.5–2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5–19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7–M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88–0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

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Basile, Vittoria, Soraya Puglisi, Barbara Altieri, Letizia Canu, Rossella Libè, Filippo Ceccato, Felix Beuschlein et al. "What Is the Optimal Duration of Adjuvant Mitotane Therapy in Adrenocortical Carcinoma? An Unanswered Question". Journal of Personalized Medicine 11, n. 4 (4 aprile 2021): 269. http://dx.doi.org/10.3390/jpm11040269.

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Abstract (sommario):

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

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Wängberg, B., A. Khorram-Manesh, S. Jansson, B. Nilsson, O. Nilsson, C. E. Jakobsson, S. Lindstedt, A. Odén e H. Ahlman. "The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane". Endocrine-Related Cancer 17, n. 1 (marzo 2010): 265–72. http://dx.doi.org/10.1677/erc-09-0190.

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Adrenocortical carcinoma (ACC) is a rare tumour disease with sinister prognosis also after attempts to radical surgery; better prognosis is seen for low-stage tumours. Adjuvant treatment with the adrenolytic drug mitotane has been attempted, but not proven to prevent from recurrence. The drug may offer survival advantage in case of recurrence. The aim of this single-centre study (1979–2007) of 43 consecutive patients was to evaluate the long-term survival after active surgical treatment combined with monitored mitotane (to reduce side effects of the drug). The series is unique, since all patients were offered a period of mitotane as adjuvant or palliative treatment; six patients refused mitotane. Despite a high proportion of high-stage tumours (67%), the complete resection rate was high (77%). The disease-specific 5-year survival was high (64.1%); very high for patients with low-stage tumours without evident relation to mitotane levels. Patients with high-stage tumours had a clear survival advantage with mitotane levels above a threshold of 14 mg/l in serum. The hazard ratio for patients with high mitotane levels versus all patients indicates a significant effect of the drug. The results indicate that adjuvant mitotane may be the standard of care for patients with high-stage ACC after complete resection.

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Zhulikov, Ya A., E. I. Kovalenko, V. Yu Bokhian e E. V. Artamonova. "Сurrent options and perspectives of systemic therapy for advanced or metastatic adrenocortical cancer". Malignant tumours 11, n. 3 (4 gennaio 2022): 36–44. http://dx.doi.org/10.18027/2224-5057-2021-11-3-36-44.

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Adrenocortical cancer is an orphan tumor with poor prognosis. The combination of EDP chemotherapy regimen and mitotane is the standard for the first‑line therapy. But there are no effective options for the second and consequent lines of therapy. The standard of second‑line therapy is the combination of gemcitabine, capecitabine and mitotane, which provides an objective response in 4–7 % of patients. Achievement of the therapeutic concentration of mitotane is the most important predictive factor of efficiency of GemCap + mitotane regimen, and, therefore, it is recommended to continue mitotane therapy after progression to mitotane. Recently, many researches regarding the efficiency of targeted and immunotherapy of adrenocortical cancer have been published. However, there are no standards for the third and subsequent lines of treatment. This review outlines the current views and perspectives of systemic therapy for advanced and metastatic adrenocortical cancer.

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Aurora, John A., Feyza Erenler, Stephany Matta e Ronald M. Lechan. "PCSK9 Inhibitors for the Management of Mitotane-Induced Hypercholesterolemia in Adrenocortical Carcinoma". Journal of the Endocrine Society 5, Supplement_1 (1 maggio 2021): A310—A311. http://dx.doi.org/10.1210/jendso/bvab048.634.

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Abstract Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin. Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range <130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily. Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane. References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.

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Altieri, Barbara, Silviu Sbiera, Sabine Herterich, Silvia De Francia, Silvia Della Casa, Anna Calabrese, Alfredo Pontecorvi et al. "Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study". Cancers 12, n. 2 (4 febbraio 2020): 359. http://dx.doi.org/10.3390/cancers12020359.

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Abstract (sommario):

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

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Sbiera, Silviu, Ellen Leich, Gerhard Liebisch, Iuliu Sbiera, Andreas Schirbel, Laura Wiemer, Silke Matysik et al. "Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells". Endocrinology 156, n. 11 (25 agosto 2015): 3895–908. http://dx.doi.org/10.1210/en.2015-1367.

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Abstract (sommario):

Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.

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Head, Lia, Katja Kiseljak-Vassiliades, Toshimasa J. Clark, Hilary Somerset, Jonathan King, Christopher Raeburn, Maria Albuja-Cruz et al. "Response to Immunotherapy in Combination With Mitotane in Patients With Metastatic Adrenocortical Cancer". Journal of the Endocrine Society 3, n. 12 (11 ottobre 2019): 2295–304. http://dx.doi.org/10.1210/js.2019-00305.

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Abstract Adrenocortical carcinoma (ACC) is a rare orphan disease with a dismal prognosis. Surgery remains the first-line treatment, but most patients eventually develop metastatic disease. Mitotane is often used with chemotherapy with modest success. Little information is available concerning the efficacy of immunotherapy in combination with mitotane. We conducted a retrospective review of our initial six patients with metastatic ACC, for whom mitotane alone or with chemotherapy failed, and who were subsequently treated with a combination of pembrolizumab and mitotane, between July 2016 and March 2019. Imaging was analyzed per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Two patients had a partial response and four patients had stable disease (8 to 19 months). One patient had grade 3 hepatitis and pembrolizumab was discontinued after 8 months. She died with disease progression 16 months after initiating pembrolizumab. One patient developed brain metastasis after 19 months of treatment and was transitioned to hospice. One patient had focal pneumonitis after 18 months of treatment, and pembrolizumab was discontinued. Three remaining patients continue pembrolizumab plus mitotane at the time of this writing. The current standard of care for ACC is a combination of etoposide, doxorubicin, cisplatin, and mitotane with an overall survival of 14.8 months. All six patients lived for at least 16 months after starting pembrolizumab added to mitotane therapy. The therapy appeared to be effective in both microsatellite instability-high and microsatellite stable tumors, suggesting some synergistic effect with mitotane. Combined immunotherapy and mitotane should be considered in future clinical trials in patients with ACC.

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Nicolia, Alessandro, Nunzia Scotti, Nunzio D’Agostino, Giovanna Festa, Lorenza Sannino, Gaetano Aufiero, Shin-ichi Arimura e Teodoro Cardi. "Mitochondrial DNA editing in potato through mitoTALEN and mitoTALECD: molecular characterization and stability of editing events". Plant Methods 20, n. 1 (5 gennaio 2024). http://dx.doi.org/10.1186/s13007-023-01124-9.

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Abstract Background The aim of this study was to evaluate and characterize the mutations induced by two TALE-based approaches, double-strand break (DSB) induction by the FokI nuclease (mitoTALEN) and targeted base editing by the DddA cytidine deaminase (mitoTALECD), to edit, for the first time, the mitochondrial genome of potato, a vegetatively propagated crop. The two methods were used to knock out the same mitochondrial target sequence (orf125). Results Targeted chondriome deletions of different sizes (236–1066 bp) were induced by mitoTALEN due to DSB repair through ectopic homologous recombination of short direct repeats (11–12 bp) present in the target region. Furthermore, in one case, the induced DSB and subsequent repair resulted in the amplification of an already present substoichiometric molecule showing a 4288 bp deletion spanning the target sequence. With the mitoTALECD approach, both nonsense and missense mutations could be induced by base substitution. The deletions and single nucleotide mutations were either homoplasmic or heteroplasmic. The former were stably inherited in vegetative offspring. Conclusions Both editing approaches allowed us to obtain plants with precisely modified mitochondrial genomes at high frequency. The use of the same plant genotype and mtDNA region allowed us to compare the two methods for efficiency, accuracy, type of modifications induced and stability after vegetative propagation.

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Kuwabara, Kosuke, Shin-ichi Arimura, Kenta Shirasawa e Tohru Ariizumi. "orf137 triggers cytoplasmic male sterility in tomato". Plant Physiology, 25 febbraio 2022. http://dx.doi.org/10.1093/plphys/kiac082.

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Bacman, Sandra R., Jose Domingo Barrera-Paez, Milena Pinto, Derek Van Booven, James B. Stewart, Anthony J. Griswold e Carlos T. Moraes. "mitoTALEN Reduces the Mutant mtDNA Load in Neurons". Molecular Therapy - Nucleic Acids, febbraio 2024, 102132. http://dx.doi.org/10.1016/j.omtn.2024.102132.

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Ayabe, Hiroki, Atsushi Toyoda, Akitoshi Iwamoto, Nobuhiro Tsutsumi e Shin-ichi Arimura. "Mitochondrial gene defects in Arabidopsis can broadly affect mitochondrial gene expression through copy number". Plant Physiology, 27 gennaio 2023. http://dx.doi.org/10.1093/plphys/kiad024.

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Abstract How mitochondria regulate the expression of their genes is poorly understood, partly because methods have not been developed for stably transforming mitochondrial genomes. In recent years, the disruption of mitochondrial genes has been achieved in several plant species using mitochondria-localized TALEN (mitoTALEN). In this study, we attempted to disrupt the NADH dehydrogenase subunit7 (NAD7) gene, a subunit of respiratory chain complex I, in Arabidopsis (Arabidopsis thaliana) using the mitoTALEN method. In some of the transformants, disruption of NAD7 was accompanied by severe growth inhibition and lethality, suggesting that NAD7 has an essential function in Arabidopsis. In addition, the mitochondrial genome copy number and overall expression of genes encoding mitochondrial proteins were generally increased by nad7 knockout. Similar increases were also observed in mutants with decreased NAD7 transcripts and with dysfunctions of other mitochondrial respiratory complexes. In these mutants, expression of nuclear genes involved in mitochondrial translation or protein transport was induced in sync with mitochondrial genes. Mitochondrial genome copy number was also partly regulated by the nuclear stress-responsive factors NAC domain containing protein 17 (ANAC017) and Radical cell death 1 (RCD1). These findings suggest the existence of overall gene-expression control through mitochondrial genome copy number in Arabidopsis and that disruption of single mitochondrial genes can have additional broad consequences in both the nuclear and mitochondrial genomes. (206/250 words)

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Bi, Chongwei, Lin Wang, Yong Fan, Baolei Yuan, Gerardo Ramos-Mandujano, Yingzi Zhang, Samhan Alsolami et al. "Single-cell individual full-length mtDNA sequencing by iMiGseq uncovers unexpected heteroplasmy shifts in mtDNA editing". Nucleic Acids Research, 31 marzo 2023. http://dx.doi.org/10.1093/nar/gkad208.

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Abstract The ontogeny and dynamics of mtDNA heteroplasmy remain unclear due to limitations of current mtDNA sequencing methods. We developed individual Mitochondrial Genome sequencing (iMiGseq) of full-length mtDNA for ultra-sensitive variant detection, complete haplotyping, and unbiased evaluation of heteroplasmy levels, all at the individual mtDNA molecule level. iMiGseq uncovered unappreciated levels of heteroplasmic variants in single cells well below the conventional NGS detection limit and provided accurate quantitation of heteroplasmy level. iMiGseq resolved the complete haplotype of individual mtDNA in single oocytes and revealed genetic linkage of de novo mutations. iMiGseq detected sequential acquisition of detrimental mutations, including large deletions, in defective mtDNA in NARP/Leigh syndrome patient-derived induced pluripotent stem cells. iMiGseq identified unintended heteroplasmy shifts in mitoTALEN editing, while showing no appreciable level of unintended mutations in DdCBE-mediated mtDNA base editing. Therefore, iMiGseq could not only help elucidate the mitochondrial etiology of diseases, but also evaluate the safety of various mtDNA editing strategies.

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Noémie, Dehaene, Boussardon Clément, Andrey Philippe, Charif Delphine, Brandt Dennis, Gilouppe Taillefer Clémence, Nietzel Thomas et al. "The mitochondrial orf117Sha gene desynchronizes pollen development and causes pollen abortion in the Arabidopsis Sha CMS". Journal of Experimental Botany, 11 maggio 2024. http://dx.doi.org/10.1093/jxb/erae214.

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Abstract Cytoplasmic male sterility (CMS) is of major agronomical relevance in hybrid breeding. In gametophytic CMS, abortion of pollen is determined by the grain genotype, while in sporophytic CMS, it is determined by the mother plant genotype. While several CMS mechanisms have been dissected at the molecular level, gametophytic CMS has not been straightforwardly accessible. We used the gametophytic Sha-CMS in Arabidopsis to characterize the cause and process of pollen abortion by implementing in vivo biosensing in single pollen and mitoTALEN mutagenesis. We obtained conclusive evidence that orf117Sha is the CMS-causing gene, despite distinct characteristics from other CMS-genes. We measured the in vivo cytosolic ATP content in single pollen, followed pollen development and analyzed pollen mitochondrial volume in two genotypes that differed only by the presence of the orf117Sha locus. Our results show that the Sha-CMS is not triggered by ATP deficiency. Instead, we observed desynchronization of a pollen developmental program. Pollen death occurred independently in pollen grains at diverse stages and was preceded by mitochondrial swelling. We conclude that pollen death is grain-autonomous in Sha-CMS and propose that mitochondrial permeability transition, which was previously described as a hallmark of developmental and environmental-triggered cell death programs, precedes pollen death in Sha-CMS.

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Gokce, Birsen Ozturk, Goknur Yorulmaz, Medine Nur Kebapci e Elif Seray Kavak Korkmaz. "P-04 Adrenocortical carcinoma case with long-term follow-up". JCEM Case Reports 2, Supplement_1 (gennaio 2024). http://dx.doi.org/10.1210/jcemcr/luad146.007.

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Abstract Description Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with an incidence of 0.7–2.0 cases/million/year. We present a case of ACC that we followed for a long period of approximately 5.5 years. Clinical Case A 50-year-old female patient was referred to our hospital because of a left adrenal mass. She had no complaints except left flank pain. There were no features on her resume. There were no findings related to hypercortisolemia on physical examination. Hormone levels were examined (Table 1). In the upper abdomen tomography, a 9×13×10.8 cm sized, sharply defined, lobulated contoured, heterogeneous-enhancing mass lesion with central cystic components was observed in the left adrenal region (Figure 1). The patient underwent left adrenalectomy and left partial nephrectomy. Pathology was reported as adrenocortical carcinoma. Weis score was 6/9, and the Ki-67 index was 15-20%. She was evaluated as a stage 2 disease according to ENSAT staging and followed up with thoracoabdominal CT. A 30*15 mm recurrent mass lesion was detected in the first-year postoperative follow-up. The patient underwent implant excision, left nephrectomy, and left paraaortic lymphadenectomy. Then the patient was given 6 cycles of Cisplatin-Etoposide-Adriamycin chemotherapy. On follow-up imaging after chemotherapy, a mass of approximately 13 mm in diameter was detected adjacent to the small intestine. Bridectomy and malignant soft tissue resection were performed on the patient. Mitotane treatment was started after the operation. After 6 weeks, the target mitotane level was reached. The patient was followed closely for glucocorticoid needs. Oral hydrocortisone treatment was started in the patient who complained of fatigue and nausea in the 8th month of mitotan. Since there was no hyponatremia/hyperkalemia and clinically no hypotension/orthostatic hypotension, mineralocorticoid therapy was not initiated. While under mitotane treatment, liver function tests, thyroid function tests, complete blood count and lipid parameters were evaluated intermittently. She was hospitalized 4 times in total with the clinic of infection and adrenal insufficiency. At that time, mitotane treatment was interrupted and parenteral steroid treatment was started. The patient received 4.5 years of mitotane therapy. No recurrence was detected in the follow-up scans during mitotane treatment and 6 months after the treatment was discontinued. PET-CT imaging was performed in the 1st year while the patient was in the follow-up without treatment. In the retroperitoneal region, 38×21 mm focal increased activity involvement was observed (SUV Max: 17.82). Left hemicolectomy operation was performed on the patient and chemotherapy was planned. Conclusion In conclusion, we presented a case that we followed for a long time without recurrence under mitotane treatment. It can be thought that mitotane treatment keeps ACC disease under control. Figure 1. 9×13×10.8 cm left adrenal mass. Table 1

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"Mitotane". Reactions Weekly 1854, n. 1 (maggio 2021): 232. http://dx.doi.org/10.1007/s40278-021-95563-7.

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"Mitotane". Reactions Weekly 1907, n. 1 (maggio 2022): 307. http://dx.doi.org/10.1007/s40278-022-15566-8.

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"Mitotane". Reactions Weekly 1907, n. 1 (maggio 2022): 306. http://dx.doi.org/10.1007/s40278-022-15565-8.

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"Mitotane". Reactions Weekly 1909, n. 1 (giugno 2022): 357. http://dx.doi.org/10.1007/s40278-022-16644-5.

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"Mitotane". Reactions Weekly 1899, n. 1 (marzo 2022): 252. http://dx.doi.org/10.1007/s40278-022-12226-1.

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"Mitotane". Reactions Weekly 1876, n. 1 (ottobre 2021): 207. http://dx.doi.org/10.1007/s40278-021-03456-0.

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"Mitotane". Reactions Weekly 1708, n. 1 (giugno 2018): 231. http://dx.doi.org/10.1007/s40278-018-48324-x.

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"Mitotane". Reactions Weekly 1722, n. 1 (ottobre 2018): 234. http://dx.doi.org/10.1007/s40278-018-52563-3.

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"Mitotane". Reactions Weekly 1635, n. 1 (gennaio 2017): 210. http://dx.doi.org/10.1007/s40278-017-25459-1.

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"Mitotane". Reactions 194, n. 1 (marzo 1988): 7. http://dx.doi.org/10.1007/bf03293899.

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"Mitotane". Reactions Weekly 1639, n. 1 (febbraio 2017): 193. http://dx.doi.org/10.1007/s40278-017-26490-7.

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"Mitotane". Reactions Weekly 1640, n. 1 (febbraio 2017): 255. http://dx.doi.org/10.1007/s40278-017-26808-8.

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"Mitotane". Reactions Weekly 1640, n. 1 (febbraio 2017): 256. http://dx.doi.org/10.1007/s40278-017-26809-8.

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