Nowsheen, Somaira

Abstract Pancreatic adenocarcinoma remains one of the most lethal malignancies, primarily due to its robust resistance to genotoxic therapies, such as chemotherapy and radiotherapy. Understanding the mechanisms underlying this resistance is essential to improve clinical outcomes. In this study, we identified trimethylguanosine synthase 1 (TGS1), previously known for its role in RNA modification, as a critical mediator of homologous recombination (HR) repair that specifically contributes to resistance in pancreatic adenocarcinoma. TGS1 was significantly overexpressed in pancreatic adenocarcinoma tissues, correlating strongly with advanced disease stages, therapy resistance, and poor patient prognosis. Following DNA damage, ATM kinase phosphorylated TGS1 at serine residues S389 and S531, which mediated its direct interaction with BRCA1 and subsequent recruitment of BRCA1 to DNA damage sites. The phosphorylation-dependent interaction enhanced HR repair efficiency, enabling cancer cells to survive genotoxic stress. Depletion or pharmacologic inhibition of TGS1 induced HR deficiency and markedly enhanced sensitivity to DNA-damaging agents, particularly PARP inhibitors, in pancreatic adenocarcinoma cell lines in vitro and in both cell line– and patient-derived xenograft models in vivo. Collectively, these findings uncover an ATM–TGS1–BRCA1 signaling axis that promotes DNA repair and resistance to genotoxic therapies in pancreatic cancer, positioning TGS1 as a promising predictive biomarker and therapeutic target to enhance treatment efficacy. Significance: The ATM–TGS1–BRCA1 signaling axis is a critical regulator of DNA repair that can be targeted to overcome genotoxic therapy resistance, providing a promising therapeutic strategy that could transform pancreatic cancer treatment.

Metastatic castration-resistant prostate cancer (mCRPC) progresses aggressively and resists existing therapies. Although poly(ADP-ribose) polymerase inhibitors (PARPis) benefit a subset of patients with mCRPC and BRCA1/2 deficiencies, therapeutic options remain limited for those without such mutations. Here, we uncover a critical role for the ATM-TRMT10A-BRCA1 signaling axis in regulating homologous recombination (HR) repair and PARPi sensitivity. We demonstrate that ATM phosphorylates TRMT10A at serine-28 after DNA damage, promoting BRCA1 recruitment and efficient HR repair. TRMT10A deletion disrupts HR repair, sensitizing cells to PARPis. Moreover, TRMT10A is up-regulated in mCRPC through stabilization by USP10. Targeting USP10 with spautin-1 induces TRMT10A degradation and enhances tumor sensitivity to PARPis in cell-derived xenografts and patient-derived xenograft models. These findings identify TRMT10A as a therapeutic vulnerability in mCRPC and demonstrate that combined inhibition of PARP and USP10 offers a promising synthetic lethal strategy for a broader group of patients lacking classical BRCA mutations.

Abstract The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).

AbstractBackgroundThe purpose of this study was to retrospectively assess clinical characteristics and mortality rate of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients who developed disseminated intravascular coagulation (DIC).MethodsA systematic retrospective chart review of all patients with concurrent clinical diagnosis of DIC and SJS/TEN between July 1, 2012, and January 1, 2020, at the Mayo Clinic was performed.ResultsThe incidence of DIC in patients with SJS/TEN was 1.3% at our institution (5 of 396 DIC patients). Triggers of SJS/TEN included lamotrigine, clofarabine, antibiotics, and sepsis. Two patients diagnosed with SJS and two patients with TEN succumbed to the disease.ConclusionDIC is a rare underlying risk in patients with SJS/TEN and is associated with increased mortality. Early clinician awareness and aggressive intervention is advised.

AbstractBackgroundTo retrospectively review the outcomes of two rare cutaneous diseases, Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and to question the practice of averaging the mortality rate on the assumption that they are one disease.MethodsA retrospective chart review of all patients diagnosed with SJS and TEN by a dermatologist between January 1, 2000, and January 1, 2020, at our institution was performed. Seventy‐one patients were identified (21 pediatric and 50 adults). Pathology slides from 32 adult patients (64%) were evaluated by a blinded board‐certified dermatopathologist.ResultsOf the adult patients, 31 had SJS, two had SJS‐TEN overlap, and 17 had TEN. All 21 patients in the pediatric group were diagnosed with SJS mainly caused by Mycoplasma. Mortality rates were 6.5% for SJS among adults and 35.3% for TEN. Chemotherapy‐induced TEN is a trigger with 50% mortality.ConclusionsSJS was more common in adults and pediatric cases than TEN (3:1) and had a much better prognosis and outcome. Combining and averaging the mortality rates of TEN and SJS are not advised as SJS is mainly a mucocutaneous disorder with good prognosis versus TEN, a systemic toxicity of multiple organs with deep skin detachment.

AbstractBackground/objectivesStudies assessing the utility of spironolactone for treating acne in adolescent females are lacking. Thus, we sought to examine spironolactone's role in treating this patient population.MethodsA retrospective review was performed to determine the efficacy of spironolactone treatment in adolescent females seen at Mayo Clinic in Rochester, Minnesota, from 2007 to 2017.ResultsIn a cohort of 80 pediatric patients with a median age of 19 years (range, 14‐20 years), 64 patients (80%) experienced improvement of acne on treatment with spironolactone (median dose, 100 mg daily) with a favorable side effect profile. Approximately a quarter of patients (22.5%) had a complete response; more than half (58.8%) had a complete response or a partial response greater than 50%. Initial and maximal responses were observed at a median of 3 months and 5 months, respectively. Patients received treatment with spironolactone for a median duration of 7 months (range, 3‐45 months) with limited side effects.ConclusionsSpironolactone demonstrated efficacy in treating acne in adolescent females and is a safe long‐term alternative to systemic antibiotics in these patients.

Extracellular matrix stiffness controls DNA damage response.

STK38, a reader of histone H4 ufmylation, regulates ATM activation.

Background: The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. Methods and Results: In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74–0.85]; P <0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39–1.69] and odds ratio, 1.42 [95% CI, 1.3–1.53]; P <0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance. Conclusions: The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.

AbstractBackgroundFew large studies have assessed spironolactone treatment of adult female acne.ObjectivesTo explore the role of spironolactone in the treatment of adult female acne.MethodsWe performed a retrospective case series assessing the efficacy of spironolactone treatment of a cohort of women evaluated at Mayo Clinic in Rochester, Minnesota, from 2007 through 2017.ResultsIn total, 395 patients (median age, 32 years) received a median spironolactone dose of 100 mg daily. Approximately two‐thirds of patients (66.1%) had a complete response; 85.1% had a complete response or a partial response greater than 50%. Median times to initial response and maximum response were 3 and 5 months. Efficacy was observed across all severity subtypes of acne, including those with papulopustular and nodulocystic acne. Patients received long‐term treatment with spironolactone (median duration, 13 months) and had few adverse effects.ConclusionsSpironolactone is a safe and effective treatment of acne for women.