Noninvasive Urine Oxygen Monitoring and the Risk of Acute Kidney Injury in Cardiac Surgery.

BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiac surgery. An intraoperative monitor of kidney perfusion is needed to identify patients at risk for AKI. The authors created a noninvasive urinary oximeter that provides continuous measurements of urinary oxygen partial pressure and instantaneous urine flow. They hypothesized that intraoperative urinary oxygen partial pressure measurements are feasible with this prototype device and that low urinary oxygen partial pressure during cardiac surgery is associated with the subsequent development of AKI. METHODS: This was a prospective observational pilot study. Continuous urinary oxygen partial pressure and instantaneous urine flow were measured in 91 patients undergoing cardiac surgery using a novel device placed between the urinary catheter and collecting bag. Data were collected throughout the surgery and for 24 h postoperatively. Clinicians were blinded to the intraoperative urinary oxygen partial pressure and instantaneous flow data. Patients were then followed postoperatively, and the incidence of AKI was compared to urinary oxygen partial pressure measurements. RESULTS: Intraoperative urinary oxygen partial pressure measurements were feasible in 86/91 (95%) of patients. When urinary oxygen partial pressure data were filtered for valid urine flows greater than 0.5 ml · kg-1 · h-1, then 70/86 (81%) and 77/86 (90%) of patients in the cardiopulmonary bypass (CPB) and post-CPB periods, respectively, were included in the analysis. Mean urinary oxygen partial pressure in the post-CPB period was significantly lower in patients who subsequently developed AKI than in those who did not (mean difference, 6 mmHg; 95% CI, 0 to 11; P = 0.038). In a multivariable analysis, mean urinary oxygen partial pressure during the post-CPB period remained an independent risk factor for AKI (relative risk, 0.82; 95% CI, 0.71 to 0.95; P = 0.009 for every 10-mmHg increase in mean urinary oxygen partial pressure). CONCLUSIONS: Low urinary oxygen partial pressures after CPB may be associated with the subsequent development of AKI after cardiac surgery.

Labeling phospholipid membranes with lipid mimetic luminescent metal complexes.

Lipid-mimetic metallosurfactant based luminophores are promising candidates for labeling phospholipid membranes without altering their biophysical characteristics. The metallosurfactants studied exhibit high structural and physicochemical similarity to phospholipid molecules, designed to incorporate into the membrane structure without the need for covalent attachment to a lipid molecule. In this work, two lipid-mimetic phosphorescent metal complexes are described: [Ru(bpy)2(dn-bpy)](2+) and [Ir(ppy)2(dn-bpy)](+) where bpy is 2,2'-bipyridine, dn-bpy is 4,4'-dinonyl-2,2'-bipyridine and ppy is 2-phenylpyridine. Apart from being lipid-mimetic in size, shape and physical properties, both complexes exhibit intense photoluminescence and enhanced photostability compared with conventional organic fluorophores, allowing for prolonged observation. Moreover, the large Stokes shift and long luminescence lifetime associated with these complexes make them more suitable for spectroscopic studies. The complexes are easily incorporated into dimyristoil-phosphatidyl-choline (DMPC) liposomes by mixing in the organic solvent phase. DLS reveals the labeled membranes form liposomes of similar size to that of neat DMPC membrane. Synchrotron Small-Angle X-ray Scattering (SAXS) measurements confirmed that up to 5% of either complex could be incorporated into DMPC membranes without producing any structural changes in the membrane. Fluorescence microscopy reveals that 0.5% label content is sufficient for imaging. Atomic Force Microscopic imaging confirms that liposomes of the labeled bilayers on a mica surface can fuse into a flat lamellar membrane that is morphologically identical to neat lipid membranes. These results demonstrate the potential of such lipid-mimetic luminescent metal complexes as a new class of labels for imaging lipid membranes.

The fate of NHC-stabilized dicarbon.

The attempted synthesis of NHC-stabilized dicarbon (NHC=C=C=NHC) through deprotonation of a doubly protonated precursor ([NHC-CH=CH-NHC](2+) ) is reported. Rather than deprotonation, a clean reduction to NHC=CH-CH=NHC is observed with a variety of bases. The apparent resistance towards deprotonation to the target compound led to a reinvestigation of the electronic structure of NHC→CC←NHC, which showed that the highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO) gap is likely too small to allow for isolation of this species. This is in contrast to the recent isolation of the cyclic alkylaminocarbene analogue (cAAC=C=C=cAAC), which has a large HOMO-LUMO gap. A detailed theoretical study illuminates the differences in electronic structures between these molecules, highlighting another case of the potential advantages of using cAAC rather than NHC as a ligand. The bonding analysis suggests that the dicarbon compounds are well represented in terms of donor-acceptor interactions L→C2 ←L (L=NHC, cAAC).

Facile formation of homoleptic Au(III) trications via simultaneous oxidation and ligand delivery from [PhI(pyridine)2](2+).

We report the first examples of Au(III) tricationic complexes bound only by neutral monodentate ligands, which are a new class of gold reagents. Oxidative addition to the bis-pyridine Au(I) cation, [Au(4-DMAP)2](+), using a series of dicationic I(III) oxidants of the general form [PhI(L)2](2+) (L = pyridine, 4-DMAP, 4-cyanopyridine) allows ready access to homoleptic and pseudo-homoleptic Au(III) complexes [Au(4-DMAP)2(L)2](3+). The facile oxidative addition of Au(I) species additionally demonstrates the efficacy of PhI(L)2](2+) reagents as halide-free oxidants for Au(I). Comparisons are made via attempts to oxidize NHC-Au(I)Cl, where introduction of the chloride anion results in complex mixtures via ligand and chloride exchange, demonstrating the advantage of using the pyridine-based homoleptic compounds. The new Au(III) trications show intriguing reactivity with water, yielding dinuclear oxo-bridged and rare terminal Au(III)-OH complexes.

Analysis of skew of visible laser reflections in a living sheep heart.

Limited methods exist to confirm the position of cardiovascular devices in the heart. In our earlier work, an optical fiber was enclosed in a central catheter and guided to known positions in the superior vena cava and right atrium in the heart of a living sheep. The tissues were illuminated with two wavelengths of visible light and the reflections were analyzed using frequency domain techniques. In this follow-up work, the data were reanalyzed using statistical estimates of skew and kurtosis as a function of anatomic position. Skew values from a 520 nm laser were able to determine catheter tip position near the cavoatrial junction as validated against known positions previously determined with electrocardiogram and contrast-enhanced video fluoroscopy. This method successfully confirmed the location of the catheter tip at the cavoatrial junction in 84% of 840 trials. Further research with refined apparatus and algorithms on additional animal subjects is strongly suggested.

Joint time-frequency analysis of visible laser reflections in a sheep heart.

Limited methods exist to confirm the position of cardiovascular devices in the superior vena cava or right atrium of the heart. The aim of this study was to design, test and validate the feasibility of whether an optical fiber-based instrument could accurately distinguish when a cardiovascular catheter was located in the superior vena cava vs in the right atrium. An optical fiber was placed in a cardiovascular catheter which was inserted into a living sheep and guided to the vicinity of the heart where diode laser-based reflection intensity data were simultaneously gathered from two visible wavelengths of light reflected from the venous and atrial tissue surfaces near the cavoatrial junction. The time series data were postoperatively analyzed using methods of joint time-frequency analysis and validated against catheter positions determined with fluoroscopy and ECG. The system was successful in distinguishing the location of the superior vena cava from the right atrium.

Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts.

Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).

Tuning the electrochemiluminescent properties of iridium complexes of N-heterocyclic carbene ligands.

A series of five heteroleptic Ir(iii) complexes of the general form Ir(dfppy)2(C^C) have been prepared (where dfppy represents 2-(2,4-difluorophenyl)pyridine and C^C represents a bidentate cyclometalated phenyl substituted imidazolylidene ligand). The cyclometalated phenyl ring of the imidazolylidene ligand was either unsubstituted or substituted with electron donating (OMe and Me) or electron withdrawing (Cl and F) groups in the 2 and 4 positions. The synthesised Ir(iii) complexes have been characterised by elemental analysis, NMR spectroscopy, cyclic voltammetry and electronic absorption and emission spectroscopy. The molecular structures for four Ir(iii) complexes were determined by single crystal X-ray diffraction. Each of the Ir(iii) complexes exhibited intense photoluminescence in acetonitrile solution at room temperature with quantum yields (ΦPL) ranging from 58% to 86%. Cyclic voltammetry experiments revealed one oxidation process (formally ascribed to the metal centre), and two ligand-based reductions for each complex. Complexes 1-5 gave moderate to intense annihilation and co-reactant electrochemiluminescence (ECL). Consideration of the electrochemical, spectroscopic and theoretical investigations provide insights into the electrochemiluminescence behaviour.

Dual-wavelength reflectance spectroscopy of the superior vena cava: A method for placing central venous catheters at the cavoatrial junction.

There are a limited number of methods to guide and confirm the placement of a peripherally inserted central catheter (PICC) at the cavoatrial junction. The aim of this study was to design, test and validate a dual-wavelength, diode laser-based, single optical fiber instrument that would accurately confirm PICC tip location at the cavoatrial junction of an animal heart, in vivo. This was accomplished by inserting the optical fiber into a PICC and ratiometrically comparing simultaneous visible and near-infrared reflection intensities of venous and atrial tissues found near the cavoatrial junction. The system was successful in placing the PICC line tip within 5 mm of the cavoatrial junction.

Unusually Strong Electrochemiluminescence from Iridium-Based Redox Polymers Immobilized As Thin Layers or Polymer Nanoparticles.

A new class of redox metallopolymer based on cyclometalated iridium(III) centers is described, with unusually intense luminescence properties in aqueous media. We report the facile synthesis, photophysical and electrochemical characterization, supported by DFT calculations and their electrochemiluminescence (ECL) properties which, under some circumstances, are significantly greater than the analogous ruthenium-based materials. The photoluminescence (PL) and ECL of these materials are further dramatically enhanced when dispersed or immobilized as polymeric nanoparticles (PNPs). This aggregation-induced emission (AIE and AIECL) operates by providing important protection for the cyclometalated iridium(III) centers against the types of quenching processes which commonly afflict iridium-based luminophores in aqueous media. The results suggest interesting new avenues of research for the application of such materials in and PL and ECL-based detection and imaging as well as light-emitting devices.

Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models.

BACKGROUND: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker. METHODS: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. RESULTS: GCC protein expression was analyzed by immunoblotting in both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models. CONCLUSION: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.

A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment.

The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

Bespoke human hypertrophic chondrocytic cell lines provide the osteoinductive signals required for vascularized bone formation.

Hypertrophic cartilage provides the morphological and biochemical template for orchestrating bone growth. To produce a bone-inductive material such as hypertrophic cartilage for clinical use, we have conditionally immortalized hypertrophic chondrocytic cells from human femur and expanded them in vitro through more than 145 divisions. The clonal cell lines generated by this process consistently express signals that induce both rat and human marrow cells to differentiate in vitro into osteoblastic cells. Further, implantation of the cell-free extracellular matrix from the immortalized chondrocytic cells causes vascularized bone to form in vivo in bony defects, but not in ectopic sites such as skeletal muscle. This study shows that molecular techniques can be used to generate bespoke human cell lines for bone tissue engineering. It also demonstrates that matrix material generated from human immortalized hypertrophic chondrocytic cells may provide an abundant, efficacious, and safer alternative to bone autograft--the currently preferred material for fracture repair.

PDGF C is a selective alpha platelet-derived growth factor receptor agonist that is highly expressed in platelet alpha granules and vascular smooth muscle.

OBJECTIVE: The platelet-derived growth factor (PDGF) family consists of four members, PDGF A, PDGF B, and 2 new members, PDGF C and PDGF D, which signal through the alpha and beta PDGF receptor (PDGFR) tyrosine kinases. This study was performed to determine the receptor specificity and cellular expression profile of PDGF C. METHODS AND RESULTS: PDGF C growth factor domain (GFD) was shown to preferentially bind and activate alpha PDGFR and activate beta PDGFR when it is co-expressed with alpha PDGFR through heterodimer formation. An investigation of PDGF C mRNA and protein expression revealed that during mouse fetal development, PDGF C was expressed in the mesonephric mesenchyme, prefusion skeletal muscle, cardiac myoblasts, and in visceral and vascular smooth muscle, whereas in adult human tissues expression was largely restricted to smooth muscle. Microarray analysis of various cell types showed PDGF C expression in vascular smooth muscle cells, renal mesangial cells, and platelets. PDGF C mRNA expression in platelets was confirmed by real-time polymerase chain reaction, and PDGF C protein was localized in alpha granules by immuno-gold electron microscopy. Western blot analysis of platelets identified 55-kDa and 80-kDa PDGF C isoforms that were secreted on platelet activation. CONCLUSIONS: Taken together, our results demonstrated for the first time to our knowledge that like PDGF A and B, PDGF C is likely to play a role in platelet biology.

Expression of nuclear factor-kappa B and I kappa B alpha proteins in prostatic adenocarcinomas: correlation of nuclear factor-kappa B immunoreactivity with disease recurrence.

PURPOSE: The nuclear transcription factor nuclear factor-kappa B (NF kappa B) and its inhibitor, I kappa B, regulate the transcription of various genes involved in cell proliferation, adhesion, and survival. The NF kappa B transcription factor complex plays a role in cancer development and progression through its influence on apoptosis. More recently, NF kappa B has been shown to be activated in human and androgen-independent prostate cancer cells. To our knowledge, this is the first study demonstrating the prognostic significance of NF kappa B immunoreactivity in prostate adenocarcinomas (PACs). EXPERIMENTAL DESIGN: Using prostatectomy specimens, we performed immunohistochemical staining for NF kappa B and I kappa B alpha (Santa Cruz Biotechnology) on formalin-fixed, paraffin-embedded sections obtained from 136 patients with PAC. Cytoplasmic and nuclear immunoreactivity was scored for intensity and distribution, and results were correlated with preoperative serum prostate-specific antigen, tumor grade, stage, DNA ploidy (Feulgen spectroscopy), and biochemical disease recurrence. RESULTS: Forty-nine percent of PACs overexpressed cytoplasmic NF kappa B, and 63% showed decreased I kappa B expression. Cytoplasmic NF kappa B overexpression correlated with advanced tumor stage (P = 0.048), aneuploidy (P = 0.022), and biochemical disease recurrence (P = 0.001). When we compared the means for the NF kappa B-positive and -negative subgroups, NF kappa B overexpression correlated with preoperative serum prostate-specific antigen (P = 0.04) and DNA index (P = 0.05). Fifteen percent of PACs expressed nuclear NF kappa B, which correlated with high tumor grade (P = 0.001) and advanced stage (P = 0.05). Decreased I kappa B alpha expression correlated with high tumor grade (P = 0.015). On multivariate analysis, tumor stage (P = 0.043) and NF kappa B overexpression (P = 0.006) were independent predictors of biochemical recurrence. CONCLUSION: These results support a role for NF kappa B pathway proteins in the tumorigenesis of PACs. The findings are also consistent with reported experimental studies suggesting a new strategy of combined chemotherapy and specific NF kappa B blockade in decreasing the rate of disease relapse.

Iridium(III) N-heterocyclic carbene complexes: an experimental and theoretical study of structural, spectroscopic, electrochemical and electrogenerated chemiluminescence properties.

Four cationic heteroleptic iridium(III) complexes have been prepared from methyl- or benzyl-substituted chelating imidazolylidene or benzimidazolylidene ligands using a Ag(I) transmetallation protocol. The synthesised iridium(III) complexes were characterised by elemental analysis, (1)H and (13)C NMR spectroscopy and the molecular structures for three complexes were determined by single crystal X-ray diffraction. A combined theoretical and experimental investigation into the spectroscopic and electrochemical properties of the series was performed in order to gain understanding into the factors influencing photoluminescence and electrochemiluminescence efficiency for these complexes, with the results compared with those of similar NHC complexes of iridium and ruthenium. The N^C coordination mode in these complexes is thought to stabilise thermally accessible non-emissive states relative to the case with analogous complexes with C^C coordinated NHC ligands, resulting in low quantum yields. As a result of this and the instability of the oxidised and reduced forms of the complexes, the electrogenerated chemiluminescence intensities for the compounds are also low, despite favourable energetics. These studies provide valuable insights into the factors that must be considered when designing new NHC-based luminescent complexes.

KRAS Genotype Correlates with Proteasome Inhibitor Ixazomib Activity in Preclinical In Vivo Models of Colon and Non-Small Cell Lung Cancer: Potential Role of Tumor Metabolism.

In non-clinical studies, the proteasome inhibitor ixazomib inhibits cell growth in a broad panel of solid tumor cell lines in vitro. In contrast, antitumor activity in xenograft tumors is model-dependent, with some solid tumors showing no response to ixazomib. In this study we examined factors responsible for ixazomib sensitivity or resistance using mouse xenograft models. A survey of 14 non-small cell lung cancer (NSCLC) and 6 colon xenografts showed a striking relationship between ixazomib activity and KRAS genotype; tumors with wild-type (WT) KRAS were more sensitive to ixazomib than tumors harboring KRAS activating mutations. To confirm the association between KRAS genotype and ixazomib sensitivity, we used SW48 isogenic colon cancer cell lines. Either KRAS-G13D or KRAS-G12V mutations were introduced into KRAS-WT SW48 cells to generate cells that stably express activated KRAS. SW48 KRAS WT tumors, but neither SW48-KRAS-G13D tumors nor SW48-KRAS-G12V tumors, were sensitive to ixazomib in vivo. Since activated KRAS is known to be associated with metabolic reprogramming, we compared metabolite profiling of SW48-WT and SW48-KRAS-G13D tumors treated with or without ixazomib. Prior to treatment there were significant metabolic differences between SW48 WT and SW48-KRAS-G13D tumors, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. Ixazomib treatment resulted in significant metabolic regulation, and some of these changes were specific to KRAS WT tumors. Depletion of free amino acid pools and activation of GCN2-eIF2α-pathways were observed both in tumor types. However, changes in lipid beta oxidation were observed in only the KRAS WT tumors. The non-clinical data presented here show a correlation between KRAS genotype and ixazomib sensitivity in NSCLC and colon xenografts and provide new evidence of regulation of key metabolic pathways by proteasome inhibition.

Plk1 inhibition causes post-mitotic DNA damage and senescence in a range of human tumor cell lines.

Plk1 is a checkpoint protein whose role spans all of mitosis and includes DNA repair, and is highly conserved in eukaryotes from yeast to man. Consistent with this wide array of functions for Plk1, the cellular consequences of Plk1 disruption are diverse, spanning delays in mitotic entry, mitotic spindle abnormalities, and transient mitotic arrest leading to mitotic slippage and failures in cytokinesis. In this work, we present the in vitro and in vivo consequences of Plk1 inhibition in cancer cells using potent, selective small-molecule Plk1 inhibitors and Plk1 genetic knock-down approaches. We demonstrate for the first time that cellular senescence is the predominant outcome of Plk1 inhibition in some cancer cell lines, whereas in other cancer cell lines the dominant outcome appears to be apoptosis, as has been reported in the literature. We also demonstrate strong induction of DNA double-strand breaks in all six lines examined (as assayed by γH2AX), which occurs either during mitotic arrest or mitotic-exit, and may be linked to the downstream induction of senescence. Taken together, our findings expand the view of Plk1 inhibition, demonstrating the occurrence of a non-apoptotic outcome in some settings. Our findings are also consistent with the possibility that mitotic arrest observed as a result of Plk1 inhibition is at least partially due to the presence of unrepaired double-strand breaks in mitosis. These novel findings may lead to alternative strategies for the development of novel therapeutic agents targeting Plk1, in the selection of biomarkers, patient populations, combination partners and dosing regimens.

MLN0905, a small-molecule plk1 inhibitor, induces antitumor responses in human models of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic.