BOLD: Blood-gas and Oximetry Linked Dataset.

Pulse oximeters measure peripheral arterial oxygen saturation (SpO2) noninvasively, while the gold standard (SaO2) involves arterial blood gas measurement. There are known racial and ethnic disparities in their performance. BOLD is a dataset that aims to underscore the importance of addressing biases in pulse oximetry accuracy, which disproportionately affect darker-skinned patients. The dataset was created by harmonizing three Electronic Health Record databases (MIMIC-III, MIMIC-IV, eICU-CRD) comprising Intensive Care Unit stays of US patients. Paired SpO2 and SaO2 measurements were time-aligned and combined with various other sociodemographic and parameters to provide a detailed representation of each patient. BOLD includes 49,099 paired measurements, within a 5-minute window and with oxygen saturation levels between 70-100%. Minority racial and ethnic groups account for ~25% of the data - a proportion seldom achieved in previous studies. The codebase is publicly available. Given the prevalent use of pulse oximeters in the hospital and at home, we hope that BOLD will be leveraged to develop debiasing algorithms that can result in more equitable healthcare solutions.

CHEK2 germline variants identified in familial nonmedullary thyroid cancer lead to impaired protein structure and function.

Approximately 5 to 15% of nonmedullary thyroid cancers (NMTC) present in a familial form (familial nonmedullary thyroid cancers [FNMTC]). The genetic basis of FNMTC remains largely unknown, representing a limitation for diagnostic and clinical management. Recently, germline mutations in DNA repair-related genes have been described in cases with thyroid cancer (TC), suggesting a role in FNMTC etiology. Here, two FNMTC families were studied, each with two members affected with TC. Ninety-four hereditary cancer predisposition genes were analyzed through next-generation sequencing, revealing two germline CHEK2 missense variants (c.962A > C, p.E321A and c.470T > C, p.I157T), which segregated with TC in each FNMTC family. p.E321A, located in the CHK2 protein kinase domain, is a rare variant, previously unreported in the literature. Conversely, p.I157T, located in CHK2 forkhead-associated domain, has been extensively described, having conflicting interpretations of pathogenicity. CHK2 proteins (WT and variants) were characterized using biophysical methods, molecular dynamics simulations, and immunohistochemistry. Overall, biophysical characterization of these CHK2 variants showed that they have compromised structural and conformational stability and impaired kinase activity, compared to the WT protein. CHK2 appears to aggregate into amyloid-like fibrils in vitro, which opens future perspectives toward positioning CHK2 in cancer pathophysiology. CHK2 variants exhibited higher propensity for this conformational change, also displaying higher expression in thyroid tumors. The present findings support the utility of complementary biophysical and in silico approaches toward understanding the impact of genetic variants in protein structure and function, improving the current knowledge on CHEK2 variants' role in FNMTC genetic basis, with prospective clinical translation.

BOLD: Blood-gas and Oximetry Linked Dataset - Open Source Research.

Pulse oximeters measure peripheral arterial oxygen saturation (SpO 2 ) noninvasively, while the gold standard (SaO 2 ) involves arterial blood gas measurement. There are known racial and ethnic disparities in their performance. BOLD is a new comprehensive dataset that aims to underscore the importance of addressing biases in pulse oximetry accuracy, which disproportionately affect darker-skinned patients. The dataset was created by harmonizing three Electronic Health Record databases (MIMIC-III, MIMIC-IV, eICU-CRD) comprising Intensive Care Unit stays of US patients. Paired SpO 2 and SaO 2 measurements were time-aligned and combined with various other sociodemographic and parameters to provide a detailed representation of each patient. BOLD includes 49,099 paired measurements, within a 5-minute window and with oxygen saturation levels between 70-100%. Minority racial and ethnic groups account for ∼25% of the data - a proportion seldom achieved in previous studies. The codebase is publicly available. Given the prevalent use of pulse oximeters in the hospital and at home, we hope that BOLD will be leveraged to develop debiasing algorithms that can result in more equitable healthcare solutions.

DNA aneuploidy identifies a subset of Luminal subtype breast carcinoma patients with worse clinical outcome.

AIM: In breast carcinoma (BC), the relationship between the ploidy pattern and molecular subtyping is still unknown. We aim to investigate the prognostic impact of DNA ploidy within molecular subtypes of a large cohort of BC patients. METHODS: The series involved 520 BC patients with no neoadjuvant therapy and a median follow-up of 115.5 months. Immunohistochemical assessment of hormonal receptors, ERBB2 (HER2) status and Ki67 proliferative activity was the basis of the surrogate molecular subtyping. Ploidy was evaluated by DNA flow cytometry in fresh/frozen tumour samples. Kaplan-Meier (K-M) survival estimation was used for prognostic statistical analysis. RESULTS: Luminal A subtype had the lowest prevalence of disease recurrences (23.6 %) and deaths from disease (18.3 %), while Luminal B (42.2 %/37.9 %), Triple-negative (46.4 %/40.6 %), and HER2-positive (55.9 %/50.0 %) subtypes had the highest. The Triple-positive subtype shows an intermediate/low frequency of adverse events (29.4 % of disease recurrences and 17.6 % of deaths from disease). Luminal A tumours were mostly diploid (55.3 %), while Triple-negative and HER2-positive tumours showed a high incidence of aneuploidy (82.6 % and 88.2 %, respectively). Luminal B and Triple-positive tumours had an intermediate percentage of aneuploidy (63.8 % and 70.6 %, respectively). K-M survival curves showed that DNA aneuploidy is significantly associated with shorter disease-free survival and overall survival in Luminal A and Luminal B molecular subtypes. CONCLUSION: DNA aneuploidy identifies a subset of Luminal BC patients with worse clinical outcome, potentially eligible for more aggressive adjuvant therapy.

Cardiac MRI and Clinical Outcomes in TMEM43 Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy is an inherited cardiomyopathy that can involve both ventricles. Several genes have been identified as pathogenic in arrhythmogenic cardiomyopathy, including TMEM43. However, there are limited data on cardiac MRI findings in patients with TMEM43 variants to date. In this case series, cardiac MRI findings and clinical outcomes are described in 14 patients with TMEM43 variants, including eight (57%) with the pathogenic p.Ser358Leu variant (six female patients; mean age, 33 years ± 15 [SD]) and six (43%) with a TMEM43 variant of unknown significance (three female patients; mean age, 38 years ± 11). MRI findings demonstrated left ventricular systolic dysfunction in eight (57%) patients and right ventricular dysfunction in four (29%) patients. Among the nine patients with late gadolinium enhancement imaging, left ventricular late gadolinium enhancement was present in seven (78%; all subepicardial) patients. In summary, TMEM43 variants are associated with high prevalence of subepicardial late gadolinium enhancement and left ventricular dysfunction. Keywords: Arrhythmogenic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, TMEM43, Cardiac MRI, Genetic Variants Supplemental material is available for this article.

S-phase fraction, lymph node status and disease staging as the main prognostic factors to differentiate between young and older patients with invasive breast carcinoma.

The influence of age on the outcome of patients with invasive breast carcinoma (IBC) has not yet been fully established. The present study investigated two subgroups of patients either side of the age spectrum, and evaluated cytometric, histopathological and molecular characteristics. The series involved 219 patients with IBC that had long-term follow-up, which were divided into two subgroups: Young (≤45 years; n=103) and old patients (≥75 years; n=116). Immunohistochemical evaluation of hormonal receptors, Ki67 index and HER2 status (plus HER2 silver in situ hybridization in equivocal cases) were used as the basis for surrogate molecular subtyping. Ploidy and S-phase fraction (SPF) were analysed by DNA flow cytometry. Differences between the subgroups' characteristics were assessed by the two proportion Z test. Kaplan-Meier estimation and log-rank test were applied for survival analyses. The median age in the subgroups were 40 years (range, 19-45 years) in the young group and 78 years (range, 75-91 years) in the older subgroup. Young patients exhibited higher lymph node involvement, more advanced disease staging, higher SPF tumour proliferative activity, and a trend of lower incidence of Luminal A and higher incidence of Luminal B tumours. The median SPF value was significantly higher in young patients [7.1% (range, 1.5-23.7%) vs. 4.5% (range, 0.7-26.4%)], whereas the ploidy pattern showed no significant difference. In the whole series, as within IBC of no special type, young patients had a higher rate of recurrence (46.6 vs. 22.4%; P<0.001) and deaths from disease (35.9 vs. 20.7%; P=0.030), with a statistically significant difference for disease-free survival. In conclusion, the present study indicated that young patients with IBC exhibited more aggressive disease, with an increased risk of recurrence and shorter disease-free survival. SPF, lymph node status and staging appeared to be the main prognostic factors to differentiate young from older patients with IBC.

Effect of preservation solution and distension pressure on saphenous vein's endothelium.

OBJECTIVES: Approaches to improve saphenous vein (SV) patency in coronary artery bypass graft (CABG) surgery remain relevant. This study aimed to evaluate the effects of different preservation solutions and different pressures of intraluminal distention on the endothelium of SV segments in CABG. METHODS: Forty-two SV segments obtained from 12 patients undergoing CABG were divided into 7 groups. Group 1 (control) was prepared without preservation or intraluminal distension, while the other 6 groups were preserved in autologous heparinized autologous arterial blood or normal saline (NS), with distention pressures 30, 100 and 300 mmHg. To assess the effects of using these solutions and pressures on the endothelium, the grafts were analysed by scanning electron microscopy, with the measurement of endothelial damage degree. RESULTS: Segments in group 1 showed minimal endothelial damage. SV grafts preserved with NS had significantly greater endothelial damage both compared to the control group and compared to groups preserved with autologous arterial blood (P < 0.001). Segments distended with pressures up to 100 mmHg showed less damage when compared to those distended at 300 mmHg, with the ones subjected to higher pressures presenting a maximum degree of damage, with considerable loss and separation of endothelial cells, extensive foci of exposure of the basement membrane and numerous fractures of the intimate layer, without differences regarding the solution used. CONCLUSIONS: Preparation of SV using NS and with intraluminal distension pressures above 100 mmHg is factors related to increased damage to the venous endothelium.

The CDK1-TOPBP1-PLK1 axis regulates the Bloom's syndrome helicase BLM to suppress crossover recombination in somatic cells.

Bloom's syndrome is caused by inactivation of the BLM helicase, which functions with TOP3A and RMI1-2 (BTR complex) to dissolve recombination intermediates and avoid somatic crossing-over. We show here that crossover avoidance by BTR further requires the activity of cyclin-dependent kinase-1 (CDK1), Polo-like kinase-1 (PLK1), and the DDR mediator protein TOPBP1, which act in the same pathway. Mechanistically, CDK1 phosphorylates BLM and TOPBP1 and promotes the interaction of both proteins with PLK1. This is amplified by the ability of TOPBP1 to facilitate phosphorylation of BLM at sites that stimulate both BLM-PLK1 and BLM-TOPBP1 binding, creating a positive feedback loop that drives rapid BLM phosphorylation at the G2-M transition. In vitro, BLM phosphorylation by CDK/PLK1/TOPBP1 stimulates the dissolution of topologically linked DNA intermediates by BLM-TOP3A. Thus, we propose that the CDK1-TOPBP1-PLK1 axis enhances BTR-mediated dissolution of recombination intermediates late in the cell cycle to suppress crossover recombination and curtail genomic instability.

Involvement of nuclear factor κB and descending pain pathways in the anti-hyperalgesic effect of ß-citronellol, a food ingredient, complexed in ß-cyclodextrin in a model of complex regional pain syndrome - Type 1.

Complex regional pain syndrome type 1 (CRPS-1) is a painful syndrome without effective treatment. In order to explore possible new treatments, we used an animal model of CRPS-1 to examine the effects of ß-Citronellol (ßCT), a monoterpene found in a variety of plants that has been shown to have analgesic effects. We aimed to assess its effects alone, and complexed with ß-cyclodextrin (ßCD), which has been previously used to enhance the effects of a number of medicines. The ßCT-ßCD was characterized physiochemically using high performance liquid chromatography (HPLC) and differential scanning calorimetry (DSC) and shown to have 80% efficiency. In the animal model, Swiss mice were treated with ßCT, ßCT-ßCD, vehicle, pregabalin or sham and evaluated for hyperalgesia and motor coordination. Inflammatory mediators were measured by Western blot or ELISA and the descending pain pathway by immunofluorescence. ßCT was shown to have an anti-hyperalgesic effect (without affecting motor coordination) that reduced inflammatory mediators and activated the descending pain pathway, and these effects were increased with complexation in ßCD. Our results showed ßCT-ßCD to be a promising treatment for CRPS-1.

Regulation of the MLH1-MLH3 endonuclease in meiosis.

During prophase of the first meiotic division, cells deliberately break their DNA1. These DNA breaks are repaired by homologous recombination, which facilitates proper chromosome segregation and enables the reciprocal exchange of DNA segments between homologous chromosomes2. A pathway that depends on the MLH1-MLH3 (MutLγ) nuclease has been implicated in the biased processing of meiotic recombination intermediates into crossovers by an unknown mechanism3-7. Here we have biochemically reconstituted key elements of this pro-crossover pathway. We show that human MSH4-MSH5 (MutSγ), which supports crossing over8, binds branched recombination intermediates and associates with MutLγ, stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutSγ directly stimulates DNA cleavage by the MutLγ endonuclease. MutLγ activity is further stimulated by EXO1, but only when MutSγ is present. Replication factor C (RFC) and the proliferating cell nuclear antigen (PCNA) are additional components of the nuclease ensemble, thereby triggering crossing-over. Saccharomyces cerevisiae strains in which MutLγ cannot interact with PCNA present defects in forming crossovers. Finally, the MutLγ-MutSγ-EXO1-RFC-PCNA nuclease ensemble preferentially cleaves DNA with Holliday junctions, but shows no canonical resolvase activity. Instead, it probably processes meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points9. As DNA nicking by MutLγ depends on its co-factors, the asymmetric distribution of MutSγ and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. This mode of MutLγ nuclease activation might explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes4.

Evaluation of novel coronavirus disease (COVID-19) using quantitative lung CT and clinical data: prediction of short-term outcome.

BACKGROUND: Computed tomography (CT) enables quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, helping in outcome prediction. METHODS: From 1 to 22 March 2020, patients with pneumonia symptoms, positive lung CT scan, and confirmed SARS-CoV-2 on reverse transcription-polymerase chain reaction (RT-PCR) were consecutively enrolled. Clinical data was collected. Outcome was defined as favourable or adverse (i.e., need for mechanical ventilation or death) and registered over a period of 10 days following CT. Volume of disease (VoD) on CT was calculated semi-automatically. Multiple linear regression was used to predict VoD by clinical/laboratory data. To predict outcome, important features were selected using a priori analysis and subsequently used to train 4 different models. RESULTS: A total of 106 consecutive patients were enrolled (median age 63.5 years, range 26-95 years; 41/106 women, 38.7%). Median duration of symptoms and C-reactive protein (CRP) was 5 days (range 1-30) and 4.94 mg/L (range 0.1-28.3), respectively. Median VoD was 249.5 cm3 (range 9.9-1505) and was predicted by lymphocyte percentage (p = 0.008) and CRP (p < 0.001). Important variables for outcome prediction included CRP (area under the curve [AUC] 0.77), VoD (AUC 0.75), age (AUC 0.72), lymphocyte percentage (AUC 0.70), coronary calcification (AUC 0.68), and presence of comorbidities (AUC 0.66). Support vector machine had the best performance in outcome prediction, yielding an AUC of 0.92. CONCLUSIONS: Measuring the VoD using a simple CT post-processing tool estimates SARS-CoV-2 burden. CT and clinical data together enable accurate prediction of short-term clinical outcome.

Diagnostic value of retrospectively fused 64CuCl2 PET/MRI in biochemical relapse of prostate cancer: comparison with fused 18F-Choline PET/MRI, 64CuCl2 PET/CT, 18F-Choline PET/CT, and mpMRI.

PURPOSE: To assess the diagnostic value of retrospectively fused PET/MRI by comparing the detection rates (DRs) of fused 64CuCl2 PET/MRI vs. fused 18F-Choline PET/MRI in patients with suspected prostatic cancer (PCa) recurrence. The secondary objective was to compare the DRs of fused PET/MRI vs. those of the separate imaging modalities. METHODS: We retrospectively evaluated 50 PCa patients with biochemical relapse after radical prostatectomy (RP) or radiotherapy (RT). All patients underwent 64CuCl2 PET/CT, 18F-Choline PET/CT, and multiparametric magnetic resonance imaging (mpMRI) within 15 days. Fused 64CuCl2-PET/MRI and fused 18F-Choline PET/MRI images were obtained by retrospective co-registration of MRI and PET images. Experienced readers interpreted the images, and the DRs of each imaging modality were assessed. RESULTS: In the patient-based analysis, overall DRs of fused 64CuCl2 PET/MRI, fused 18F-Choline PET/MRI, 64CuCl2 PET/CT, 18F-Choline PET/CT, and mpMRI were 88%, 68%, 82%, 56%, and 74%, respectively. In the lesion-based analysis, overall DRs of fused 64CuCl2 PET/MRI, fused 18F-Choline PET/MRI, 64CuCl2 PET/CT, 18 F-Choline PET/CT, and mpMRI were 95%, 66%, 87%, 58%, and 71%, respectively. CONCLUSIONS: Retrospectively fused PET/MRI is able to overcome the limitations of the separate interpretation of the individual imaging modalities. Fused 64CuCl2 PET/MRI provided the highest diagnostic performance in the detection of PCa local relapse.

Solitary Fibrous Tumor of the Prostate.

Even though most tumors located in the prostate derive from prostatic glands, there is a long list of malignant and nonmalignant causes for prostatic growths that clinicians should be aware of. Tumors of the prostate can be grouped in epithelial, neuroendocrine, stromal, mesenchymal, hematolymphoid, and miscellaneous. Solitary fibrous tumor of the prostate (SFT), is an extremely rare mesenchymal tumor (only about 20 cases reported in the literature). Histologic features resemble those of the more common variant pleural SFT. Of all, 10%-20% of SFTs, also known as malignant SFTs, behave aggressively. Herein, we describe a case of prostatic SFT in a 66-year-old patient that presented with obstructive urinary symptoms and normal prostate-specific antigen levels.

Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops.

Formation of co-transcriptional R-loops underlies replication fork stalling upon head-on transcription-replication encounters. Here, we demonstrate that RAD51-dependent replication fork reversal induced by R-loops is followed by the restart of semiconservative DNA replication mediated by RECQ1 and RECQ5 helicases, MUS81/EME1 endonuclease, RAD52 strand-annealing factor, the DNA ligase IV (LIG4)/XRCC4 complex, and the non-catalytic subunit of DNA polymerase δ, POLD3. RECQ5 disrupts RAD51 filaments assembled on stalled forks after RECQ1-mediated reverse branch migration, preventing a new round of fork reversal and facilitating fork cleavage by MUS81/EME1. MUS81-dependent DNA breaks accumulate in cells lacking RAD52 or LIG4 upon induction of R-loop formation, suggesting that RAD52 acts in concert with LIG4/XRCC4 to catalyze fork religation, thereby mediating replication restart. The resumption of DNA synthesis after R-loop-associated fork stalling also requires active transcription, the restoration of which depends on MUS81, RAD52, LIG4, and the transcription elongation factor ELL. These findings provide mechanistic insights into transcription-replication conflict resolution.

Correction: Premature activation of Cdk1 leads to mitotic events in S phase and embryonic lethality.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Restitution volumes at the end of dialysis sessions: A potential influencing factor on patients' haemoglobin levels?

AIM: To evaluate whether haemoglobin (Hb) levels are influenced by the restitution volume (RestVol) at the end of the dialysis session, independently of erythropoiesis-stimulating agents (ESA) and iron doses. DESIGN: Over 12 months, 4,386 haemodialysis patients from 34 centres were enrolled in this observational descriptive study according to the checklist STrengthening the Reporting of Observational Studies in Epidemiology (STROBE). METHOD: RestVol, Hb levels, ESA and iron doses of every patient were assessed on a monthly basis. To determine the ideal RestVol, the clinics were classified into three groups according to the restitution volumes at the end of the dialysis sessions. RESULTS: Mean age was 69 ± 14 years, and 58.9% were men. The evaluation of 665,712 treatments revealed that RestVol of 380 ml seems to be the most efficient, since the clinics in this group managed to reduce ESA consumption with a negligible reduction in Hb levels.

Breast cancer Ki-67 expression prediction by digital breast tomosynthesis radiomics features.

BACKGROUND: To investigate whether quantitative radiomic features extracted from digital breast tomosynthesis (DBT) are associated with Ki-67 expression of breast cancer. MATERIALS AND METHODS: This is a prospective ethically approved study of 70 women diagnosed with invasive breast cancer in 2018, including 40 low Ki-67 expression (Ki-67 proliferation index <14%) cases and 30 high Ki-67 expression (Ki-67 proliferation index ≥ 14%) cases. A set of 106 quantitative radiomic features, including morphological, grey/scale statistics, and texture features, were extracted from DBT images. After applying least absolute shrinkage and selection operator (LASSO) method to select the most predictive features set for the classifiers, low versus high Ki-67 expression was evaluated by the area under the curve (AUC) at receiver operating characteristic analysis. Correlation coefficient was calculated for the most significant features. RESULTS: A combination of five features yielded AUC of up to 0.698. The five most predictive features (sphericity, autocorrelation, interquartile range, robust mean absolute deviation, and short-run high grey-level emphasis) showed a statistical significance (p ≤ 0.001) in the classification. Thirty-four features were significantly (p ≤ 0.001) correlated with Ki-67, and five of these had a correlation coefficient of > 0.5. CONCLUSION: The present study showed that quantitative radiomic imaging features of breast tumour extracted from DBT images are associated with breast cancer Ki-67 expression. Larger studies are needed in order to further evaluate these findings.

Small Bowel Adenocarcinoma of Ileal Ureter 40 Years After Ureteral Reconstructive Surgery.

Malignant neoplasm arising from ileal ureter used for ureteral reconstructive surgery is an exceedingly rare event. Ureteroileoplasty was being performed since the beginning of the last century, but it was described more extensively in literature during the 1950s.1,2 Recurrent urinary infections, chronic renal failure, urolithiasis, anastomotic stricture, metabolic acidosis, and chronic dilation of the graft had been described as late complications of ureteroileoplasty.3,4 Herein, we describe history, imaging and pathologic findings of a small bowel adenocarcinoma arising from ileal ureter in a woman of 78-year-old, subjected to ureteroileoplasty about 40 years earlier.

Premature activation of Cdk1 leads to mitotic events in S phase and embryonic lethality.

Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used. Here, we investigate in vivo the importance of WEE1- and MYT1-dependent inhibitory phosphorylation of mammalian CDK1. We generated Cdk1AF knockin mice, in which two inhibitory phosphorylation sites are replaced by the non-phosphorylatable amino acids T14A/Y15F. We uncovered that monoallelic expression of CDK1AF is early embryonic lethal in mice and induces S phase arrest accompanied by γH2AX and DNA damage checkpoint activation in mouse embryonic fibroblasts (MEFs). The chromosomal fragmentation in Cdk1AF MEFs does not rely on CDK2 and is partly caused by premature activation of MUS81-SLX4 structure-specific endonuclease complexes, as well as untimely onset of chromosome condensation followed by nuclear lamina disassembly. We provide evidence that tumor development in liver expressing CDK1AF is inhibited. Interestingly, the regulatory mechanisms that impede cell proliferation in CDK1AF expressing cells differ partially from the actions of the WEE1 inhibitor, MK-1775, with p53 expression determining the sensitivity of cells to the drug response. Thus, our work highlights the importance of improved therapeutic strategies for patients with various cancer types and may explain why some patients respond better to WEE1 inhibitors.