Anti-CD19 chimeric antigen receptor T-cell therapy in older patients with relapsed or refractory large B-cell lymphoma: A multicenter study.

Chimeric antigen receptor T-cell (CAR-T) therapy, despite being a potentially curative therapy in relapsed or refractory (RR) large B-cell lymphoma (LBCL), remains underutilized in older patients due to limited clinical data. We therefore studied the safety and efficacy of CAR-T therapy in older patients with RR LBCL in the real-world setting. Patients aged ≥65 years with RR LBCL, treated with anti-CD19 CAR-T therapy at 7 US institutions were included in this multicenter, retrospective, observational study. In total, 226 patients were included. Median age at infusion was 71 years (range 65-89). Best objective and complete response rates were 86% and 62%, respectively. Median follow-up after infusion was 18.3 months. The median progression-free survival (PFS) was 6.9 months, with 6- and 12-month PFS estimates of 54% and 44%, respectively. The nonrelapse mortality (NRM) rate was 10.9% at day 180, primarily due to infections, and not impacted by the age groups. Grade ≥3 cytokine release syndrome and neurotoxicity occurred in 7% and 26%, respectively. In univariate analysis, no significant difference in PFS was seen regardless of the age groups or CAR-T type, whereas ECOG PS ≥2, elevated LDH, bulky disease, advanced stage, extranodal involvement, the need for bridging therapy, and prior bendamustine exposure were associated with shorter PFS. These findings support the use of CAR-T in older patients, including those aged ≥80 years. The age at CAR-T therapy did not influence safety, survival, and NRM outcomes. Older patients should not be excluded from receiving CAR-T therapy solely based on their chronological age.

Age Is a Prognostic Factor for the Overall Survival of Patients with Multiple Myeloma Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation.

In this retrospective analysis, we evaluated the impact of age on the outcome of patients with multiple myeloma who received an autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. A total of 1128 patients were divided into the older (>70 years; 182 [16%]) and the younger (≤70 years; 946 [84%]) groups. Compared with the younger cohort, older patients had a higher International Staging System (ISS) stage (ISS-II, 57 [31%] versus 215 [23%]; ISS-III, 52 [28%] versus 211 [22%]; P = .01), higher use of reduced-dose melphalan as a conditioning regimen (140 mg/m², 59 [32%] versus 29 [3%]; P < .001), and a higher comorbidity index (median, 3 versus 2; P = .01). Nonrelapse mortality at 1 year after auto-HCT was significantly higher in older patients (7 [4%] versus 9 [1%]; hazard ratio [HR], 4.1; P = .005). Complete remission rates after auto-HCT for the older and the younger groups were 41% and 46%, respectively. With a median follow-up of 52 months, the 5-year progression-free survival (PFS) was 24% (95% confidence interval [CI], 17% to 32%) and 37% (95% CI, 33% to 40%) in the older and younger groups, respectively (HR, 1.3; P = .02). Five-year OS for the older and younger groups was 56% (95% CI, 47% to 64%) and 73% (95% CI, 70% to 76%; P < .001), respectively. Older age emerged as one of the predictors of shorter OS but not PFS in the multivariate classification and regression tree analysis. In conclusion, age ≥70 years was associated with shorter PFS and OS in patients with multiple myeloma who underwent an auto-HCT.

Player Performance After Returning From a Concussion in the National Football League: A Pilot Study.

This study aimed to determine if gameplay performance in the National Football League (NFL) is adversely affected after returning to play from a sport-related concussion (SRC). Players who sustained a SRC between the 2007-2008 and 2013-2014 seasons were identified. Concussed players were matched to nonconcussed control players in a 2:1 (control-case) fashion by position, season, experience, age, body mass index, and time missed. Gameplay statistics were recorded for the three games before and after returning from SRC. When compared with the control group, the majority of NFL players did not demonstrate any performance-based deficits on returning to play after SRC. However, concussed quarterbacks (QBs) displayed a reduced QB rating compared with controls. These results indicate that performance immediately following return from SRC may be adversely affected in certain populations and circumstances, though the overwhelming majority of players showed no decline in performance. (Journal of Surgical Orthopaedic Advances 27(3):187-197, 2018).

Effects of a ketogenic diet on adipose tissue, liver, and serum biomarkers in sedentary rats and rats that exercised via resisted voluntary wheel running.

We investigated the effects of different diets on adipose tissue, liver, serum morphology, and biomarkers in rats that voluntarily exercised. Male Sprague-Dawley rats (∼9-10 wk of age) exercised with resistance-loaded voluntary running wheels (EX; wheels loaded with 20-60% body mass) or remained sedentary (SED) over 6 wk. EX and SED rats were provided isocaloric amounts of either a ketogenic diet (KD; 20.2%-10.3%-69.5% protein-carbohydrate-fat), a Western diet (WD; 15.2%-42.7-42.0%), or standard chow (SC; 24.0%-58.0%-18.0%); n = 8-10 in each diet for SED and EX rats. Following the intervention, body mass and feed efficiency were lowest in KD rats, independent of exercise (P < 0.05). Absolute and relative (body mass-adjusted) omental adipose tissue (OMAT) masses were greatest in WD rats (P < 0.05), and OMAT adipocyte diameters were lowest in KD-fed rats (P < 0.05). None of the assayed OMAT or subcutaneous (SQ) protein markers were affected by the diets [total acetyl coA carboxylase (ACC), CD36, and CEBPα or phosphorylated NF-κB/p65, AMPKα, and hormone-sensitive lipase (HSL)], although EX unexpectedly altered some OMAT markers (i.e., higher ACC and phosphorylated NF-κB/p65, and lower phosphorylated AMPKα and phosphorylated HSL). Liver triglycerides were greatest in WD rats (P < 0.05), and liver phosphorylated NF-κB/p65 was lowest in KD rats (P < 0.05). Serum insulin, glucose, triglycerides, and total cholesterol were greater in WD and/or SC rats compared with KD rats (P < 0.05), and serum ß-hydroxybutyrate was greater in KD vs. SC rats (P < 0.05). In conclusion, KD rats presented a healthier metabolic profile, albeit the employed exercise protocol minimally impacts any potentiating effects that KD has on fat loss.

Gingival Crevicular Blood Glucose as a Novel Method for Screening Diabetes Mellitus in Periodontally Compromised Patients.

INTRODUCTION: Patients with periodontitis are significantly more likely to have undetected diabetes mellitus (DM). Self­monitoring devices like glucometers provide a simple method for rapid monitoring of the glucose level in blood by utilizing a blood sample from the finger, but this method requires puncturing to obtain blood. Bleeding from the gingival sulcus, obtained during oral hygiene examination, can be utilized for screening DM patients. Therefore, this study was performed with the aim of determining the efficacy of gingival crevicular blood as a non-invasive screening method for DM patients, as well as correlating and comparing gingival crevicular blood glucose (GCBG) levels with finger capillary blood glucose (FCBG) and fasting blood glucose (FBG) among non-diabetic and diabetic group patients. METHODS: In this cross-sectional comparative study, a total of 120 participants having moderate to severe gingivitis/periodontitis with an age range of 40 to 65 years were divided into two groups on the basis of FBG range taken from an antecubital vein: non-diabetic (≤126, n=60) and diabetic (≥126, n=60) groups. Blood oozing during the routine periodontal examination from the periodontal pocket was recorded using a test strip of a glucose self-monitoring device (AccuSure®Simple) as GCBG. Concomitantly FCBG was collected from the fingertip. These three parameters were statistically analyzed using the Student's t-test and the one-way ANOVA test and correlated with Pearson's correlation coefficient for both groups. RESULTS: The mean and standard deviation for the three parameters GCBG, FBG, and FCBG were 93.78±12.03, 89.98±13.22, and 93.08±15.56, respectively, for the non-diabetic group and 154.52±45.05, 159±47.00, and 162.23±50.60 subsequently for the diabetic group. Comparing glucose level parameters among the non-diabetic and diabetic groups suggests a significant difference with the p-value <0.001*(inter-group). ANOVA test was done for both groups suggesting no significant difference among these three methods of measuring blood glucose level, where the p-value found was 0.272 for the non-diabetic and 0.665 for the diabetic group (intra-group comparison). Pearson's correlation values suggested a good positive correlation for the non-diabetic group, with parameters GCBG and FBG (r=0.864), GCBG and FCBG (r=0.936), and FBG and FCBG (r=0.837). The diabetic group's Pearson's correlation suggested a highly significant positive correlation between three different methods in which GCBG and FBG (r=0.978), GCBG and FBG (r=0.977), and FBG and FCBG (r= 0.982). CONCLUSION: Blood oozing from the periodontal pocket during routine oral hygiene examination can be utilized by dental healthcare professionals to screen pre-diabetic patients which can be used as a simple and less invasive method for DM patients.

Variability in the Processing of Fresh Osteochondral Allografts.

The indications for fresh osteochondral allograft continue to increase. As a result, variations in graft processing and preservation methods have emerged. An understanding of these techniques is important when evaluating the optimal protocol for processing fresh osteochondral allografts prior to surgical implantation. The aim of this study is to review the literature and understand various tissue processing protocols of four leading tissue banks in the United States. Donor procurement, serological and microbiological testing, and storage procedures were compared among companies of interest. Similarities between the major tissue banks include donor screening, aseptic processing, and testing for microorganisms. Variability exists between these companies with relation to choice of storage media, antibiotic usage, storage temperature, and graft expiration dates. Potential exists for increased chondrocyte viability and lengthened time-to-expiration of the graft through a protocol of delicate tissue handling, proper choice of storage medium, adding hormones and growth factors like insulin growth factor-1 (IGF-1) to serum-free nutrient media, and storing these grafts closer to physiologic temperatures.

Outcomes of patients with secondary central nervous system lymphoma following CAR T-cell therapy: a multicenter cohort study.

Chimeric antigen receptor T-cell therapy (CAR-T) has been successful in treating relapsed/refractory B-cell lymphomas. However, its role in the treatment of diseases involving the central nervous system (CNS) is not well studied. We performed a multicenter retrospective cohort study to evaluate the outcomes of patients with secondary CNS lymphoma (SCNSL) who received CAR-T. Eligibility required active CNSL at the time of apheresis. The objectives included evaluation of overall survival (OS), progression-free survival (PFS), identification of predictors of complete response (CR) post-CAR-T, and assessment of risk factors for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Sixty-one patients were included in the analysis. The overall response rate was 68% with a CR rate of 57%. In the multivariable analysis, patients who experienced any grade CRS had higher odds of achieving CR (OR = 3.9, 95% CI = 1.01-15.39, p = 0.047). The median PFS was 3.3 months (95% CI = 2.6-6.0 months) with 6- and 12-month PFS rates of 35% and 16%, respectively. The median OS was 7.6 months (95% CI = 5.0-13.5 months) with 6- and 12-month OS rates of 59% and 41%, respectively. Any grade CRS and ICANS were 70% (n = 43) and 57% (n = 34), respectively with grade ≥ 3 CRS and ICANS rates of 16% and 44%. Factors associated with increased risk of CRS and ICANS included receiving axi-cel or having leptomeningeal ± parenchymal + CNS involvement, respectively. Despite achieving high response rates, most patients experience early relapse or death following CAR-T in SCNSL. The current study provides a benchmark for future trials exploring novel therapeutic options in SCNSL.

Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma.

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028]. SIGNIFICANCE: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.

Impact of Cell of Origin Classification on Survival Outcomes after Autologous Transplantation in Relapsed/Refractory Diffuse Large B Cell Lymphoma.

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P < .004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.

Extracellular Vesicles as Biomarkers in Cancer Immunotherapy.

Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound vesicles secreted by most cell types during both physiologic conditions as well in response to cellular stress. EVs play an important role in intercellular communication and are emerging as key players in tumor immunology. Tumor-derived EVs (TDEs) harbor a diverse array of tumor neoantigens and contain unique molecular signature that is reflective of tumor's underlying genetic complexity. As such they offer a glimpse into the immune tumor microenvironment (TME) and have the potential to be a novel, minimally invasive biomarker for cancer immunotherapy. Immune checkpoint inhibitors (ICI), such as anti- programmed death-1(PD-1) and its ligand (PD-L1) antibodies, have revolutionized the treatment of a wide variety of solid tumors including head and neck squamous cell carcinoma, urothelial carcinoma, melanoma, non-small cell lung cancer, and others. Typically, an invasive tissue biopsy is required both for histologic diagnosis and next-generation sequencing efforts; the latter have become more widespread in daily clinical practice. There is an unmet need for noninvasive or minimally invasive (e.g., plasma-based) biomarkers both for diagnosis and treatment monitoring. Targeted analysis of EVs in biospecimens, such as plasma and saliva could serve this purpose by potentially obviating the need for tissue sample. In this review, we describe the current challenges of biomarkers in cancer immunotherapy as well as the mechanistic role of TDEs in modulating antitumor immune response.

Factors affecting the outcomes of tibiotalocalcaneal fusion.

AIMS: Tibiotalocalcaneal (TTC) fusion is used to treat a variety of conditions affecting the ankle and subtalar joint, including osteoarthritis (OA), Charcot arthropathy, avascular necrosis (AVN) of the talus, failed total ankle arthroplasty, and severe deformity. The prevalence of postoperative complications remains high due to the complexity of hindfoot disease seen in these patients. The aim of this study was to analyze the relationship between preoperative conditions and postoperative complications in order to predict the outcome following primary TTC fusion. METHODS: We retrospectively reviewed the medical records of 101 patients who underwent TTC fusion at the same institution between 2011 and 2019. Risk ratios (RRs) associated with age, sex, diabetes, cardiovascular disease, smoking, preoperative ankle deformity, and the use of bone graft during surgery were related to the postoperative complications. We determined from these data which pre- and perioperative factors significantly affected the outcome. RESULTS: Out of the 101 patients included in the study, 29 (28.7%) had nonunion, five (4.9%) required below-knee amputation (BKA), 40 (39.6%) returned to the operating theatre, 16 (15.8%) had hardware failure, and 22 (21.8%) had a postoperative infection. Patients with a preoperative diagnosis of Charcot arthropathy and non-traumatic OA had significantly higher nonunion rates of 44.4% (12 patients) and 39.1% (18 patients) (p = 0.016) and infection rates of 29.6% (eight patients) and 37% (17 patients) compared to patients with traumatic arthritis, respectively (p = 0.002). There was a significantly increased rate of nonunion in diabetic patients (RR 2.22; p = 0.010). Patients with chronic kidney disease were 2.37-times more likely to have a nonunion (p = 0.006). Patients aged over 60 years had more than a three-fold increase in the rate of postoperative infection (RR 3.60; p = 0.006). The use of bone graft appeared to be significantly protective against postoperative infection (p = 0.019). CONCLUSION: We were able to confirm, in the largest series of TTC ankle fusions currently in the literature, that there remains a high rate of complications following this procedure. We found that patients with a Charcot or non-traumatic arthropathy had an increased risk of nonunion and postoperative infection compared to individuals with traumatic arthritis. Those with diabetes, chronic kidney disease, or aged over 60 years had an increased risk of nonunion. These findings help to confirm those of previous studies. Additionally, our study adds to the literature by showing that autologous bone graft may help in decreasing infection rates. These data can be useful to surgeons and patients when considering, discussing and planning TTC fusion. It helps surgeons further understand which patients are at a higher risk for postoperative complications when undergoing TTC fusion. Cite this article: Bone Joint J. 2020;102-B(3):345-351.

Trends in postrelapse survival in classic Hodgkin lymphoma patients after experiencing therapy failure following auto-HCT.

Patients with classic Hodgkin lymphoma (cHL) who relapse after autologous hematopoietic cell transplantation (auto-HCT) historically have had poor outcomes. We hypothesized that, post-auto-HCT relapse, overall survival (PR-OS) has improved in recent years as a result of more widespread use of novel therapies and allogeneic HCT (allo-HCT). We conducted a retrospective study in 4 US academic centers, evaluating 215 patients who underwent auto-HCT from 2005 to 2016 and relapsed thereafter. Patients were divided into 2 cohorts based on timing of auto-HCT, 2005 through 2010 (cohort 1; n = 118) and 2011 to 2016 (cohort 2; n = 97), to compare differences in clinical outcomes. The median age and disease status at auto-HCT were similar in cohorts 1 and 2. The proportions of patients who received brentuximab vedotin (Bv; 55% vs 69%; P = .07), checkpoint inhibitors (CPIs; 3% vs 36%; P ≤ .001), and allogeneic-HCT (22% vs 35%, P = .03) were significantly different between cohorts 1 and 2, respectively. At the 5-year follow-up after auto relapse, 32% and 50% of patients were alive in cohorts 1 and 2, respectively (P = .01). In multivariate analysis for PR-OS, cohort 1 vs 2 (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.14-4.60; P = .01), age at auto-HCT (HR, 1.48; 95% CI, 1.18-1.87; P ≤ .001), and time to relapse from auto-HCT (HR, 0.59; 95% CI, 0.47-74; P ≤ .0001), retained independent prognostic significance for PR-OS. Our study supports the hypothesis that survival of cHL patients after auto-HCT failure has significantly improved in recent years, most likely because of incorporation of novel therapies and more widespread use of allo-HCT.

Internal hernia complications of gastric bypass surgery in the acute setting: spectrum of imaging findings.

Bariatric surgery is increasingly becoming an option for the treatment of morbid obesity. Patients who have undergone gastric bypass surgery have varied post-surgical complications which present acutely in the emergency medical setting, particularly internal hernias. It may be difficult to identify an internal hernia in the absence of intestinal obstruction. This article will review the various types of imaging presentations to highlight the complexity of making a radiographic diagnosis. Recognition of internal hernia as the cause of intermittent or acute abdominal pain symptoms in these patients in the emergency setting can prompt immediate surgical intervention, thus avoiding life-threatening outcomes.

Functional conservation of RecQ helicase BLM between humans and Drosophila melanogaster.

RecQ helicases are a family of proteins involved in maintaining genome integrity with functions in DNA repair, recombination, and replication. The human RecQ helicase family consists of five helicases: BLM, WRN, RECQL, RECQL4, and RECQL5. Inherited mutations in RecQ helicases result in Bloom Syndrome (BLM mutation), Werner Syndrome (WRN mutation), Rothmund-Thomson Syndrome (RECQL4 mutation), and other genetic diseases, including cancer. The RecQ helicase family is evolutionarily conserved, as Drosophila melanogaster have three family members: DmBlm, DmRecQL4, and DmRecQL5 and DmWRNexo, which contains a conserved exonuclease domain. DmBlm has functional similarities to human BLM (hBLM) as mutants demonstrate increased sensitivity to ionizing radiation (IR) and a decrease in DNA double-strand break (DSB) repair. To determine the extent of functional conservation of RecQ helicases, hBLM was expressed in Drosophila using the GAL4 > UASp system to determine if GAL4 > UASp::hBLM can rescue DmBlm mutant sensitivity to IR. hBLM was able to rescue female DmBlm mutant sensitivity to IR, supporting functional conservation. This functional conservation is specific to BLM, as human GAL4 > UASp::RECQL was not able to rescue DmBlm mutant sensitivity to IR. These results demonstrate the conserved role of BLM in maintaining the genome while reinforcing the applicability of using Drosophila as a model system to study Bloom Syndrome.

Postrelapse survival in diffuse large B-cell lymphoma after therapy failure following autologous transplantation.

Outcomes for diffuse large B-cell lymphoma (DLBCL) patients relapsing after autologous hematopoietic cell transplantation (auto-HCT) have been historically poor. We studied outcomes of such patients using data from 4 transplantation centers. Eligibility criteria included adult patients (age ≥18 years) with DLBCL experiencing disease relapse after auto-HCT performed during 2006 to 2015. The time period was stratified into 2 eras (era 1, 2006-2010; era 2, 2011-2015). The primary end point was postrelapse overall survival (PR-OS). Secondary end points were factors prognostic of PR-OS. Of the 700 patients with DLBCL who underwent auto-HCT, 248 (35%) relapsed after auto-HCT. Median PR-OS of all relapsed DLBCL patients after auto-HCT (n = 228) was 9.8 months (95% confidence interval [CI], 7-15). Median PR-OS was significantly better for patients in complete (17.8 months; 95% CI, 7.9-41.6) vs partial remission at auto-HCT (7.1 months; 95% CI, 5.4-11; P = .01), those undergoing auto-HCT >1 year (12.8 months; 95% CI, 7.6-24.9) vs ≤1 year after DLBCL diagnosis (6.3 months; 95% CI, 4.5-9.2; P = .01), and those with late (56.4 months; 95% CI, 23.7-∞) vs early relapse (5.9 months; 95% CI, 4.5-8.8; P < .0001). On multivariate analysis, although late relapse (hazard ratio [HR], 0.21; 95% CI, 0.13-0.34; P < .0001) was associated with significantly lower mortality, the risk of mortality increased with age (HR, 1.25 per decade; 95% CI, 1.06-1.48; P = .009). This is the largest study to date to evaluate outcomes of DLBCL patients relapsing after auto-HCT. Our study provides benchmarking for future trials of chimeric antigen receptor T cells and other promising agents evaluating PR-OS after auto-HCT.

Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function.

53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability.