Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated Derivatives from Epoxides toward the Synthesis of Aza Heterocycles.

A new method for directly synthesizing acylated and alkylated quinazoline derivatives by the epoxide ring-opening reaction in the presence of I2/DMSO with 2-aminobenzamide is described herein. The developed mild protocol is efficient and displays a wide variety of functional group tolerance and substrate-controlled high selectivity, and the application of a continuous flow technique allows for faster reaction time and higher yields. Moreover, the robustness of the method is applicable in gram-scale synthesis.

Extract of Ficus septica modulates apoptosis and migration in human oral squamous cell carcinoma cells.

According to the alarming statistical analysis of global cancer, there are over 19 million new diagnoses and more than 10 million deaths each year. One such cancer is the oral squamous cell carcinoma (OSCC), which requires new therapeutic strategies. Ficus septica extract has been used in traditional medicine to treat infectious diseases. In this study, we examined the anti-proliferative effects of an extract of F. septica bark (FSB) in OSCC cells. Our results showed that FSB caused a concentration-dependent reduction in the viability of SCC2095 OSCC cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and was less sensitive to fibroblasts. In addition, FSB induced apoptosis by activating caspases, accompanied by the modulation of Akt/mTOR/NF-κB and mitogen-activated protein kinase signaling. Moreover, FSB increased reactive oxygen species generation in a concentration-dependent manner in SCC2095 cells. Furthermore, FSB inhibited cell migration and modulated the levels of the cell adhesion molecules including E-cadherin, N-cadherin, and Snail in SCC2095 cells. Pinoresinol, a lignan isolated from FSB, showed antitumor effects in SCC2095 cells, implying that this compound might play an important role in FSB-induced OSCC cell death. Taken together, FSB is a potential anti-tumor agent against OSCC cells.

Genome-wide association study identifies kallikrein 5 in type 2 inflammation-low asthma.

BACKGROUND: Clinical studies of type 2 (T2) cytokine-related neutralizing antibodies in asthma have identified a substantial subset of patients with low levels of T2 inflammation who do not benefit from T2 cytokine neutralizing antibody treatment. Non-T2 mechanisms are poorly understood in asthma but represent a redefined unmet medical need. OBJECTIVE: We sought to gain a better understanding of genetic contributions to T2-low asthma. METHODS: We utilized an unbiased genome-wide association study of patients with moderate to severe asthma stratified by T2 serum biomarker periostin. We also performed additional expression and biological analysis for the top genetic hits. RESULTS: We identified a novel protective single nucleotide polymorphism at chr19q13.41, which is selectively associated with T2-low asthma and establishes Kallikrein-related peptidase 5 (KLK5) as the causal gene mediating this association. Heterozygous carriers of the single nucleotide polymorphisms have reduced KLK5 expression. KLK5 is secreted by human bronchial epithelial cells and elevated in asthma bronchial alveolar lavage. T2 cytokines IL-4 and IL-13 downregulate KLK5 in human bronchial epithelial cells. KLK5, dependent on its catalytic function, induces epithelial chemokine/cytokine expression. Finally, overexpression of KLK5 in airway or lack of an endogenous KLK5 inhibitor, SPINK5, leads to spontaneous airway neutrophilic inflammation. CONCLUSION: Our data identify KLK5 to be the causal gene at a novel locus at chr19q13.41 associated with T2-low asthma.

Metal-Free N-H/C-H Carbonylation by Phenyl Isocyanate: Divergent Synthesis of Six-Membered N-Heterocycles.

We disclose a method using phenyl isocyanate to synthesize carbonyl-containing N-heterocycles. The metal-free novel approach for both N-H and C-H carbonylation processes was successfully refined, delivering a range of synthetically valuable derivatives of quinazoline-2,4(1H,3H)-dione, 2H-benzo[e] [1,2,4] thiadiazin-3(4H)-one 1,1-dioxide, and pyrrolo[1,2-a] quinoxalin-4(5H)-one. The protocol features broad substrates with diverse reactions suitable for excellent yields, mild conditions, and good functional group compatibility. Moreover, the applicability of the reaction was characterized by gram-scale synthesis and synthetic transformations for drug molecules.

Comparison of oncological outcomes for hand-assisted and pure laparoscopic radical nephroureterectomy: results from the Taiwan Upper Tract Urothelial Cancer Collaboration Group.

PURPOSE: Laparoscopic radical nephroureterectomy (LNU) has gradually become the new standard treatment for localized upper tract urothelial cancer (UTUC). With more blunt dissection and tactile sensation, hand-assisted LNU might shorten the operative time compared with the pure laparoscopic approach. However, whether the use of the hand-assisted or the pure laparoscopic approach has an effect on oncological outcomes remains unclear. METHODS: We retrospectively identified 629 patients with non-metastatic UTUC who underwent hand-assisted (n = 515) or pure LNU (n = 114) at 9 hospitals in Taiwan between 2004 and 2019. Overall survival, cancer-specific survival, recurrence-free survival, and bladder recurrence-free survival were compared between these two groups using inverse-probability of treatment weighting (IPTW) derived from the propensity scores for baseline covariate adjustment. RESULTS: The median follow-up period was 32.9 and 28.7 months in the hand-assisted and the pure groups, respectively. IPTW-adjusted Cox proportional hazards models showed that the laparoscopic approach (pure vs. hand-assisted) was not significantly associated with all-cause mortality (HR 0.79, 95% CI 0.49-1.24, p = 0.304), cancer-specific mortality (HR 0.88, 95% CI 0.51-1.51, p = 0.634), or extra-vesical recurrence (HR 0.65, 95% CI 0.41-1.04, p = 0.071). However, the pure laparoscopic approach was significantly associated with lower intra-vescial recurrence (HR 0.64, 95% CI 0.43-0.96, p = 0.029) for patients who underwent LNU. Kaplan-Meier curves also revealed that the pure laparoscopic approach was associated with better bladder recurrence-free survival compared with the hand-assisted laparoscopic approach in both the original cohort and the IPTW-adjusted cohort (log-rank p = 0.042 and 0.027, respectively). CONCLUSIONS: The performance of hand-assisted or pure LNU does not significantly affect the all-cause mortality, cancer-specific mortality, or extra-vesical recurrence for patients with non-metastatic UTUC. However, the hand-assisted laparoscopic approach could increase the risk of intra-vesical recurrence for patients who undergo LNU.

Evaluating the comparative efficiency of medical centers in Taiwan: a dynamic data envelopment analysis application.

BACKGROUND: People in Taiwan enjoy comprehensive National Health Insurance coverage. However, under the global budget constraint, hospitals encounter enormous challenges. This study was designed to examine Taiwan medical centers' efficiency and factors that influence it. METHODS: We obtained data from open sources of government routine publications and hospitals disclosed by law to the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan. The dynamic data envelopment analysis (DDEA) model was adopted to estimate all medical centers' efficiencies during 2015-2018. Beta regression models were used to model the efficiency level obtained from the DDEA model. We applied an input-oriented approach under both the constant returns-to-scale (CRS) and variable returns-to-scale (VRS) assumptions to estimate efficiency. RESULTS: The findings indicated that 68.4% (13 of 19) of medical centers were inefficient according to scale efficiency. The mean efficiency scores of all medical centers during 2015-2018 under the CRS, VRS, and Scale were 0.85, 0.930, and 0.95,respectively. Regression results showed that an increase in the population less than 14 years of age, assets, nurse-patient ratio and bed occupancy rate could increase medical centers' efficiency. The rate of emergency return within 3-day and patient self-pay revenues were associated significantly with reduced hospital efficiency (p < 0.05). The result also showed that the foundation owns medical center has the highest efficiency than other ownership hospitals. CONCLUSIONS: The study results provide information for hospital managers to consider ways they could adjust available resources to achieve high efficiency.

Presence of pathogenic copy number variants (CNVs) is correlated with socioeconomic status.

Socioeconomic status (SES) is a major determinant of health. We studied the Index of Multiple Deprivation Rank of 473 families with individuals with pathogenic autosomal copy number variants (CNVs) and known inheritance status. The IMDR distribution of families with pathogenic CNVs was significantly different from the general population. Families with inherited CNVs were significantly more likely to be living in areas of higher deprivation when compared with families that had individuals with de novo CNVs. These results provide unique insights into biological determinants of SES. As CNVs are relatively frequent in the general population, these results have important medical and policy consequences.

Antitumor Effects of a Sesquiterpene Derivative from Marine Sponge in Human Breast Cancer Cells.

In this study, the anti-proliferative effect of ilimaquinone, a sesquiterpene derivative from the marine sponge, in breast cancer cells was investigated. Ilimaquinone inhibited the proliferation of MCF-7 and MDA-MB-231 breast cancer cells with IC50 values of 10.6 µM and 13.5 µM, respectively. Non-tumorigenic human breast epithelial cells were less sensitive to ilimaquinone than breast cancer cells. Flow cytometric and Western blot analysis showed that ilimaquinone induced S-phase arrest by modulating the expression of p-CDC-2 and p21. Ilimaquinone induces apoptosis, which is accompanied by multiple biological biomarkers, including the downregulation of Akt, ERK, and Bax, upregulation of p38, loss of mitochondrial membrane potential, increased reactive oxygen species generation, and induced autophagy. Collectively, these findings suggest that ilimaquinone causes cell cycle arrest as well as induces apoptosis and autophagy in breast cancer cells.

Tribulus terrestris fruit extract inhibits autophagic flux to diminish cell proliferation and metastatic characteristics of oral cancer cells.

Elevated autophagy is highly associated with cancer development and progression. Fruit extracts of several plants inhibit activity of autophagy-related protease ATG4B and autophagy activity in colorectal cancer cells. However, the effects of these plant extracts in oral cancer cells remain unclear. In this study, we found that the extracted Tribulus terrestris fruit (TT-(fr)) and Xanthium strumarium fruit had inhibitory effects on autophagy inhibition in both SAS and TW2.6 oral cancer cells. Moreover, the fruit extracts had differential effects on cell proliferation of oral cancer cells. In addition, the fruit extracts hampered cell migration and invasion of oral cancer cells, particularly in TT-(fr) extracts. Our results indicated that TT-(fr) extracts consistently inhibited autophagic flux, cell growth and metastatic characteristics of oral cancer cells, suggesting TT-(fr) might contain function ingredient to suppress oral cancer cells.

A macrolide from Streptomyces sp. modulates apoptosis and autophagy through Mcl-1 downregulation in human breast cancer cells.

Secondary metabolites in marine organisms exhibit various pharmacological activities against diseases, such as cancer. In this study, the anti-proliferative effect of JBIR-100, a macrolide isolated from Streptomyces sp., was investigated in breast cancer cells. Cell growth was inhibited in response to JBIR-100 treatment concentration- and time-dependently in both MCF-7 and MDA-MB-231 breast cancer cells. JBIR-100 caused apoptosis, as verified by caspase activation and the cleavage of PARP. Western blotting revealed that JBIR-100 modulated the expression of Akt/NF-κB signaling components and Bcl-2 family members. Overexpression of Mcl-1 partially rescued MCF-7 cells from JBIR-100-induced cytotoxicity. In addition, transmission electron microscopy analyses, confocal analysis, and western blot assay indicated that JBIR-100 inhibited autophagy in MCF-7 cells. Exposure to the autophagy inhibitor did not synergize JBIR-100-induced apoptosis. In summary, our results suggested that JBIR-100 may be potentially used for breast cancer therapy.

Biodegradable Stent with mTOR Inhibitor-Eluting Reduces Progression of Ureteral Stricture.

In this study, we investigated the effect of mTOR inhibitor (mTORi) drug-eluting biodegradable stent (DE stent), a putative restenosis-inhibiting device for coronary artery, on thermal-injury-related ureteral stricture in rabbits. In vitro evaluation confirmed the dose-dependent effect of mTORi, i.e., rapamycin, on fibrotic markers in ureteral component cell lines. Upper ureteral fibrosis was induced by ureteral thermal injury in open surgery, which was followed by insertion of biodegradable stents, with or without rapamycin drug-eluting. Immunohistochemistry and Western blotting were performed 4 weeks after the operation to determine gross anatomy changes, collagen deposition, expression of epithelial-mesenchymal transition markers, including Smad, α-SMA, and SNAI 1. Ureteral thermal injury resulted in severe ipsilateral hydronephrosis. The levels of type III collagen, Smad, α-SMA, and SNAI 1 were increased 28 days after ureteral thermal injury. Treatment with mTORi-eluting biodegradable stents significantly attenuated thermal injury-induced urinary tract obstruction and reduced the level of fibrosis proteins, i.e., type III collagen. TGF-ß and EMT signaling pathway markers, Smad and SNAI 1, were significantly modified in DE stent-treated thermal-injury-related ureteral stricture rabbits. These results suggested that intra-ureteral administration of rapamycin by DE stent provides modification of fibrosis signaling pathway, and inhibiting mTOR may result in fibrotic process change.

Association of ABO Blood Type with Bleeding Severity in Patients with Acute Gastroesophageal Variceal Bleeding.

Background and Objectives: ABO blood types have been implicated as potential risk factors for various hemorrhagic diseases. No study has investigated the association between gastroesophageal variceal bleeding and ABO blood types. We aimed to evaluate the impact of ABO blood types on mortality and bleeding risk in acute gastroesophageal variceal bleeding. Materials and Methods: This is a retrospective observational study. Patients presenting with acute gastroesophageal varices bleeding diagnosed by endoscopy were enrolled, and were divided by blood type into a type O group and non-type O group. The outcomes were death within 30 days and the proportion of further bleeding. We used generalized linear mixed-effects models to analyze the outcomes. Results: A total of 327 patients and 648 records of emergency room visits were included. The 30-day mortality was 14.8% (21 of 142 patients) in the type O group, and 16.2% (30 of 185 patients) in the non-type O group (p = 0.532). Further bleeding within 30 days occurred in 34 cases (12.6%) in the type O group, and in 26 cases (6.9%) in the non-type O group (p = 0.539). Conclusions: There was no significant difference in blood transfusion volume in 24 h, recurrent bleeding rates, or mortality between patients with blood type O and those with non-type O.

Bayesian variable selection using partially observed categorical prior information in fine-mapping association studies.

Several methods have been proposed to allow functional genomic information to inform prior distributions in Bayesian fine-mapping case-control association studies. None of these methods allow the inclusion of partially observed functional genomic information. We use functional significance (FS) scores that combine information across multiple bioinformatics sources to inform our effect size prior distributions. These scores are not available for all single-nucleotide polymorphisms (SNPs) but by partitioning SNPs into naturally occurring FS score groups, we show how missing FS scores can easily be accommodated via finite mixtures of elicited priors. Most current approaches adopt a formal Bayesian variable selection approach and either limit the number of causal SNPs allowed or use approximations to avoid the need to explore the vast parameter space. We focus instead on achieving differential shrinkage of the effect sizes through prior scale mixtures of normals and use marginal posterior probability intervals to select candidate causal SNPs. We show via a simulation study how this approach can improve localisation of the causal SNPs compared to existing mutli-SNP fine-mapping methods. We also apply our approach to fine-mapping a region around the CASP8 gene using the iCOGS consortium breast cancer SNP data.

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits.

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

Metal-Free Synthesis of Benzimidazoles via Oxidative Cyclization of d-Glucose with o-Phenylenediamines in Water.

d-Glucose has been identified as an efficient C1 synthon in the synthesis of benzimidazoles from o-phenylenediamines via an oxidative cyclization strategy. Isotopic studies with 13C6-d-glucose and D2O unambiguously confirmed the source of methine. The notable features of this method include the following: broad functional group tolerance, a biorenewable methine source, excellent reaction yields, a short reaction time, water as an environmentally benign solvent, and the synthesis of vitamin B12 component on the gram scale.

Effectiveness of a couple-based psychosocial intervention on patients with prostate cancer and their partners: A quasi-experimental study.

AIMS: To understand the effectiveness of a couple-based psychosocial information package (PIP) and multimedia psychosocial intervention (MPI) on patients with prostate cancer and their partners. DESIGN: A random assignment and quasi-experimental design were used. METHODS: From August 2015-March 2018, 103 newly diagnosed patients with prostate cancer and their partners were divided into a control group (CG) (N = 50), PIP group (N = 25) and MPI group (N = 28). The CG received usual care, the PIP group received information manuals and telephone counselling for 6-week and the MPI group received multimedia films and manuals and professional support for 6 weeks. The three groups were posttested 6, 10, 18 and 24 weeks after the pre-test. The outcome measurements included disease appraisals, emotion status, relationship satisfaction, health-related quality of life (HRQOL) and satisfaction with MPI. RESULTS/FINDINGS: Partners in the MPI and PIP groups experienced significant improvements in positive and negative affect or mental HRQOL as compared with the CG. The effectiveness of MPI and PIP on negative affect, mental HRQOL, however, were not statistically significant in patients with prostate cancer. Nevertheless, patients were satisfied with the MPI. CONCLUSION: Nurses can provide different types of interventions for partners, depending on personal preferences and available resources. IMPACT: There is a lack of studies that focus on the effectiveness of couple-based psychosocial intervention on both the patients with prostate cancer and their partners in Asia. Partners in the multimedia psychosocial intervention group and psychosocial information package group experienced improvements in positive affect, negative affect or health-related quality of life as compared with the control group. Patients in both intervention groups experienced similar negative affect and health-related quality of life as compared with the control group. The couple-based psychosocial interventions can be provided by nurses based on partners' preferences and available resources.

Antitumor Activity of the Cardiac Glycoside αlDiginoside by Modulating Mcl-1 in Human Oral Squamous Cell Carcinoma Cells.

We recently isolated a cardiac glycoside (CG), αldiginoside, from an indigenous plant in Taiwan, which exhibits potent tumor-suppressive efficacy in oral squamous cell carcinoma (OSCC) cell lines (SCC2095 and SCC4, IC50 < 0.2 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays). Here, we report that αldiginoside caused Sphase arrest and apoptosis, through the inhibition of a series of signaling pathways, including those mediated by cyclin E, phospho-CDC25C (p-CDC25C), and janus kinase/signal transducer and activator of transcription (JAK/STAT)3. αldiginoside induced apoptosis, as indicated by caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage. Equally important, αldiginoside reduced Mcl-1 expression through protein degradation, and overexpression of Mcl-1 partially protected SCC2095 cells from αldiginoside's cytotoxicity. Taken together, these data suggest the translational potential of αldiginoside to foster new therapeutic strategies for OSCC treatment.

Beneficial Effects of Inflammatory Cytokine-Targeting Aptamers in an Animal Model of Chronic Prostatitis.

Non-bacterial prostatitis is an inflammatory disease that is difficult to treat. Oligonucleotide aptamers are well known for their stability and flexibility in conjugating various inflammatory molecules. In this study, we investigated the effects of inflammatory cytokine-targeting aptamers (ICTA), putative neutralizers of TNF-alpha and IL-1 beta activation, on local carrageenan-induced prostate inflammation, allodynia, and hyperalgesia in rats. In vitro evaluation confirmed the binding capability of ICTA. Intraprostatic injection of carrageenan or control vehicle was performed in six-week-old rats, and ICTA (150 µg) or vehicle was administered in the prostate along with carrageenan injection. The von Frey filament test was performed to determine mechanical allodynia, and prostate inflammation was examined seven days after drug administration. Local carrageenan administration resulted in a reduction of the tactile threshold. The levels of mononuclear cell infiltration, pro-inflammatory cytokine interleukin-1 beta (b), caspase-1 (casp-1), and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing proteins 1 and 3 (NALP1 and NALP3) in the prostate of rats were increased seven days after carrageenan injection. Treatment with ICTA significantly attenuated the carrageenan-induced hyperalgesia and reduced the elevated levels of proteins including TNF-a and IL-1b in the rats. Apoptosis markers, B-cell lymphoma 2-associated X protein (Bax) and caspase-3, were elevated in ICTA-treated Chronic pelvic pain syndrome (CPPS) rats. These results suggest that ICTA provides protection against local carrageenan-induced enhanced pain sensitivity, and that the neutralization of proinflammatory cytokines may result in inflammatory cell apoptosis.

Non-genotoxic MDM2 inhibition selectively induces a pro-apoptotic p53 gene signature in chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous hematologic malignancy. In approximately 90% of cases the TP53 gene is in its wildtype state at diagnosis of this malignancy. As mouse double-minute-2 homolog (MDM2) is a primary repressor of p53, targeting this protein is an attractive therapeutic approach for non-genotoxic reactivation of p53. Since the discovery of the first MDM2 inhibitor, Nutlin-3a, newer potent and bioavailable compounds have been developed. In this study we tested the second-generation MDM2 inhibitor, RG7388, in patient-derived CLL cells and normal cells, examining its effect on the induction of p53-transcriptional targets. RG7388 potently decreased viability in p53-functional CLL cells, whereas p53-non-functional samples were more resistant to the drug. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic (PUMA, BAX) and extrinsic (TNFRSF10B, FAS) pathways of apoptosis, as well as MDM2 Only a slight induction of CDKN1A was observed and upregulation of pro-apoptotic genes dominated, indicating that CLL cells are primed for p53-dependent apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. Importantly, we observed a preferential pro-apoptotic signature in CLL cells but not in normal blood and bone marrow cells, including CD34+ hematopoietic cells. These data support the further evaluation of MDM2 inhibitors as a novel additional treatment option for patients with p53-functional CLL.