Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

AIMS: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. METHODS: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. RESULTS: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year. CONCLUSIONS: The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

A comparison on the percentage of polymerase chain reaction positivity for SARS-CoV-2 between Public Health Center referrals and direct walk-in patients: A single center retrospective analysis in Tokyo.

INTRODUCTION: The Public Health Center (PHC)-known as hokenjo in Japan-assume a crucial role in disease control. Coronavirus disease 2019 (COVID-19) is one of many designated infectious diseases monitored by the agency. During the present pandemic, patients who suspected COVID-19 were instructed to call the Coronavirus Consultation Center in the PHC prior to visiting the hospital. The aim of this study was to elucidate the differences in polymerase chain reaction (PCR) positivity between PHC referrals and direct walk-in patients. METHODS: The present was a single-center, retrospective cohort study conducted at the Tokyo Metropolitan Hospital from March to September, 2020. Patients who received a PCR test for SARS-CoV-2 were included and categorized into the PHC referral or direct walk-in groups. The outcomes included the total number of patients undergoing PCR tests and the percentage of PCR positivity in each group. RESULTS: We identified 1680 patients (781 PHC referred and 899 direct walk-in groups). The percentage of PCR positivity did not significantly differ between the PHC referral and direct walk-in groups during the first wave (30.5% vs. 29.2%; p = 0.78). PCR positivity was significantly higher in the PHC referral group than the direct walk-in group during the second wave (30.1% vs. 23.1%; p = 0.051) and entire study period (30.2% vs. 24.7%; p = 0.011). CONCLUSIONS: Despite health authority recommendations, the number of direct walk-in patients were higher than PHC referral patients. The percentage of PCR positivity was significantly higher in the PHC referral group than in the direct walk-in group.

The 2-Minute Spontaneous Swallowing Screening Predicts Independence on Enteral Feeding in Patients with Acute Stroke.

BACKGROUND: It is recommended that enteral feeding should be offered to patients with dysphagia estimated to be unable to take adequate diet orally within 7 days of admission after acute stroke, but there is no clear criterion for initiation of enteral feeding. Recent studies have reported that the frequency of spontaneous swallowing is useful in screening for dysphagia in acute stroke. The present study was aimed to investigate whether measurement of frequency of spontaneous swallowing for 2 minutes could predict independence on enteral feeding 1 week after admission in patients with acute stroke. METHODS: Patients with acute stroke were subjected. Within 72 hours of stroke onset, the number of swallows for 2 minutes was measured by auscultation. Subsequently, 1-hour frequency of spontaneous swallowing was measured using a laryngeal microphone. Functional Oral Intake Scale (FOIS) was evaluated 1 week after admission. RESULTS: Twenty-six out of 40 patients were independent on enteral feeding 1 week after admission based on FOIS. The presence of spontaneous swallowing for 2 minutes had .89 sensitivity, .54 specificity to predict independence on enteral feeding 1 week after admission, whereas the 1-hour frequency of spontaneous swallowing had 1.00 sensitivity, .46 specificity. Logistic regression analysis demonstrated that the presence of spontaneous swallowing for 2 minutes was independent predictor for independence on enteral feeding 1 week after admission, independently of age, sex, and NIHSS. CONCLUSIONS: The 2-minute spontaneous swallowing screening predicts independence on enteral feeding 1 week after admission in patients with acute stroke.

Relationship Between Frequency of Spontaneous Swallowing and Salivary Substance P Level in Patients with Acute Stroke.

The frequency of spontaneous swallowing is useful for screening of dysphagia in acute stroke. Low levels of substance P (SP) in saliva attenuate the swallowing reflex. The aim of this study was to determine the relationship between the frequency of spontaneous swallowing and salivary SP levels. In 40 subjects, saliva was collected within 72 h after stroke onset and salivary SP levels were measured using ELISA kit at a later date. The frequency of spontaneous swallowing was measured over 1 h using a microphone placed on the neck. Pneumonia was diagnosed by the presence of pyrexia and at least two respiratory problems of four categories (sputum, cough or breathing pattern, breath sound, and gas change). The presence of detectable levels of SP in the saliva was confirmed in 17 patients (high SP group), whereas the level was below the detection limit of the ELISA kit in 23 patients (low SP group). The frequency of spontaneous swallowing was significantly lower in low SP group (16.1 ± 11.6 per hour) than in the high SP group (30.4 ± 20.4, p = 0.016). As the result of multiple regression analysis, salivary SP levels were correlated with frequency of spontaneous swallowing independently of age, NIHSS, and GCS. The incidence of pneumonia was significantly higher in the low than high SP group (p < 0.001). In conclusion, the frequency of spontaneous swallowing was decreased in acute stroke patients with low salivary SP levels. Salivary SP levels can be potentially a useful biomarker of risk of stroke-associated pneumonia in the acute stage.

Regioselective Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-Dienones under Deoxyfluorination Conditions.

The dienone-phenol rearrangement is a useful tool for the synthesis of highly substituted phenols. In our previous study of the rearrangement of 4,4-disubstituted 2-hydroxycyclohexa-2,5-dienone under deoxyfluorination conditions, bond migration proceeded with very poor regioselectivity. In this paper, an acid-mediated rearrangement of O-perfluoroalkylsulfonyl difluorides with regioselective migration toward the ß'-carbon is reported. This method allowed the synthesis of a fluorinated analog of allocolchicinoids with improved total yield. Successful application to other substrates was also demonstrated.

[Transoral Penetrating Cranial Injury by a Chopstick:A Case Report].

Intracranial injury resultant from a chopstick penetrating the oral cavity is often fatal in children, and only 5 clinical cases have been reported. If the depth of penetration is indeterminable, due to the chopstick being removed or the remaining piece not being located, then injury management is challenging; here, we report such a case. A 26-month-old girl fell over with a plastic chopstick in her mouth. The chopstick was removed immediately and without breakage by her father. He noted that around 3 cm of the pointed end had pierced the palate. CT revealed air bubbles in the retropharyngeal space but no abnormality in the cranium. Subsequent complications included bacterial meningitis and right hemiparesis but neither MRI nor any alternative imaging modality could aid in locating the intracranial lesion that induced the weakness. Neurological findings suggested injury of the right lateral corticospinal tract at the lower end of the medulla oblongata. An axial T2-weighted MRI showed a 30-mm high signal path of penetration from the posterior nasopharyngeal wall to the dura at the craniocervical junction. When the route is extended 36 mm intracranially from the wound orifice, the path makes superficial contact with the right lateral portion of the medulla oblongata, which corresponds with the lateral corticospinal tract. We therefore hypothesize that this was the lesion location but that it was too small to be detected using MRI.

Difunctionalization of Alkenes Using 1-Chloro-1,2-benziodoxol-3-(1H)-one.

Difunctionalization of alkenes with 1-chloro-1,2-benziodoxol-3-(1H)-one (1) was investigated. Various additional nucleophiles were tested, and oxychlorination, dichlorination, azidochlorination, chlorothiocyanation, and iodoesterfication were demonstrated. The oxychlorination product was obtained efficiently when the reaction was operated in water. Dichlorination occurred in the presence of a Lewis basic promoter, such as 4-phenylpyridine N-oxide, as an additive. The reaction with in situ-generated azido anion afforded azidochlorinated compounds with a chlorine atom at the terminal position, while the reaction with trimethylsilyl isothiocyanate produced chlorothiocyanation adducts with a chlorine atom at the benzylic position. On the other hand, when 1 was treated with tetra-n-butylammonium iodide prior to the addition of alkenes, only iodoesterification occurred selectively. These mild reactions enable convenient site-selective difunctionalizations of substrates having two alkene moieties. NMR experiments suggested that the electrophilic reactive species in each reaction varied depending on the nature of the added nucleophile.

Contralateral hyperacute intracerebral hemorrhage after carotid artery stenting with contralateral internal carotid artery occlusion.

An 87-year-old man sustained an intracerebral hemorrhage in the watershed area of the contralateral frontal lobe immediately after carotid artery stenting (CAS) for severe cervical internal carotid artery (ICA) stenosis. The contralateral cervical ICA was occluded. CAS resulted in increased cross-flow through the anterior communicating artery and increased flow in the contralateral middle cerebral artery. This case demonstrates that CAS in patients with contralateral ICA occlusion and insufficient collateral flow can cause dramatically increased collateral flow through the circle of Willis and result in contralateral hyperperfusion. In patients with severely compromised cerebral perfusion, measures should be taken to prevent hyperperfusion-related complications.

Dual catalysis with copper and rhenium for trifluoromethylation of propargylic alcohols: efficient synthesis of α-trifluoromethylated enones.

Trifluoromethylation of propargylic alcohols to provide (Z)-α-trifluoromethylated enones and ß-unsubstituted α-trifluoromethylated enones proceeded with high yield and selectivity in the presence of CuI/Re2O7. The Z isomer was formed under kinetic control, though it is less stable than the E isomer in terms of steric repulsion.

Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation.

BACKGROUND AND PURPOSE: The frequency and pattern of symptomatic recurrence of spontaneous intracranial arterial dissection (IAD) are unknown. METHODS: A follow-up study of 143 patients (85 men, 58 women; mean age, 50.7 [7-83] years) with spontaneous IADs at The University of Tokyo and affiliated hospitals from 1980 to 2000 was conducted. Tissue samples of IAD vessels obtained from 13 patients at various intervals from onset were also examined histologically. RESULTS: With a mean follow-up of 8.2 years, symptomatic recurrence occurred in 47 patients (33%). Of 37 cases initially presenting with hemorrhage, 35 developed hemorrhagic recurrence with a mean interval of 4.8 days, and 2 developed nonhemorrhagic recurrences after 21 and 85 months, respectively. Of 10 patients initially presenting with nonhemorrhagic symptoms, 1 developed hemorrhagic recurrence 4 days later, and 9 developed nonhemorrhagic recurrences with a mean interval of 8.6 months. Histopathologically, the affected vessels in the acute stage of hemorrhage (days 0-6) demonstrated insufficient granulation formation within the pseudolumen, followed by marked intimal thickening around the pseudolumen and recanalizing vessel formation in the late stage (>day 30). In the late stage of brain ischemia, subintimal and subadventitial hemorrhage accompanied with intimal thickening was observed. CONCLUSIONS: These data indicate that IAD is a disease carrying a relatively high risk of symptomatic recurrence, apparently occurring in 3 phases and patterns: early hemorrhagic recurrence, late nonhemorrhagic recurrence, and chronic fusiform aneurysm transformation. Knowledge of this triphasic recurrence and corresponding histopathological characteristics help determine the treatment and follow-up strategy for IAD patients.

Management of glioblastoma in an NF1 patient with moyamoya syndrome: a case report.

INTRODUCTION: Glioma and moyamoya syndrome are both potential complications of neurofibromatosis type 1 (NF1). Here, we report the first case of NF1 concomitantly presenting with glioblastoma 10 years after surgical treatment of moyamoya syndrome. CASE REPORT: A 14-year-old boy with NF1 was incidentally diagnosed by magnetic resonance imaging (MRI) with a thalamic tumor during a follow-up for moyamoya syndrome, which had been treated with surgery 10 years earlier. After observation for 36 months, he developed left hemiparesis, and MRI revealed an increase in tumor size and obstructive hydrocephalus due to the tumor. Needle biopsy was performed through small craniotomy, and the histological diagnosis was glioblastoma. After concurrent chemoradiotherapy with 23 cycles of temozolomide, partial response of the tumor was observed. However, 24 months after the start of the initial therapy, the tumor showed regrowth, and the patient died 30 months after the initial therapy. No cerebrovascular events associated with moyamoya syndrome and chemoradiotherapy were observed during the clinical course of glioblastoma. DISCUSSION: Glioblastoma is a fatal disease in children, and our patient successfully received chemoradiotherapy with temozolomide despite the diagnoses of NF1 and moyamoya syndrome. Although radiotherapy or chemotherapy potentially causes cerebrovascular complications, chemoradiotherapy might be feasible for glioblastoma treatment in patients with moyamoya syndrome and NF1. The following issues are discussed in the management of the present case: the indication of biopsy in NF1 cases, the method of surgery, and the treatment protocol for tumors concomitant with moyamoya disease or syndrome.

Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.

A case of unclassified high-grade glioma with polar spongioblastoma pattern.

Primitive polar spongioblastoma was first described by Russell and Cairns in 1947. However, the polar spongioblastoma pattern is often seen in many neuroepithelial tumors, and this category was deleted in the previous World Health Organization (WHO) classification. In 2010, Nagaishi et al. reported on a case involving a neuroepithelial tumor with the typical histological pattern of polar spongioblastoma and suggested that this tumor might not be suited to any of the neuroepithelial tumors in the current WHO classification. We report on an autopsy case involving an unclassified high-grade glioma with polar spongioblastoma pattern that was very similar to the case described by Nagaishi et al. A 44-year-old man who presented with a headache exhibited a tumor of the right frontal lobe on MRI. Histological diagnosis of the tumor obtained by gross total resection was high-grade glioma, which was composed of the parallel palisading of spindle tumor cells expressing GFAP, without microvascular proliferation (MVP) and necrosis. Conventional chemoradiotherapy was performed, but the case was complicated by cerebrospinal fluid (CSF) dissemination that resulted in multiple extraneural metastases through systemic diversionary CSF shunting. Finally, the patient died approximately 13 months after the initial treatment. Both the cerebral and Douglas pouch tumors that were obtained at autopsy were diagnosed as typical glioblastomas, and they were composed of the proliferation of atypical astrocytes with MVP and pseudopalisading necrosis without the formation of rhythmic palisading. Although the histological findings were different from that of the first operation, immunohistochemical and genetic profiles demonstrated almost the same results. This tumor was not classified as a typical glioblastoma by the initial findings, but it had the nature of a glioblastoma. These findings suggest that the tumor might be classified as a new subset of glioblastoma called glioblastoma with polar spongioblastoma pattern.

Population pharmacokinetic and exposure-response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma.

PURPOSE: Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure-response relationships for efficacy and safety in patients with RRMM. METHODS: A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure-response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. RESULTS: Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969-0.9997) and 0.9981 (0.9964-0.9998) for PFS and grade 3 + AEs, respectively. CONCLUSIONS: The PPK model adequately described the data and was appropriate for determining exposures for exposure-response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Model-Based Determination of Elotuzumab Pharmacokinetics in Japanese Patients With Multiple Myeloma Incorporating Time-Varying M Protein.

A population pharmacokinetic model was developed to evaluate the effects of Japanese ethnicity, prior line of therapy (0 or ≥1), time-varying M protein, and maintenance dosing regimens (10 mg/kg intravenously every 2 weeks or 20 mg/kg intravenously every 4 weeks beginning in cycle 19) on the pharmacokinetics of elotuzumab in patients with multiple myeloma treated with elotuzumab plus lenalidomide/dexamethasone. Elotuzumab pharmacokinetics were characterized by a 2-compartment model with parallel linear (nonspecific) and Michaelis-Menten elimination from the central compartment and target-mediated elimination from the peripheral compartment. Asian race on nonspecific clearance (CL) and central volume of distribution, prior line of therapy on CL, and maximum target-mediated elimination rate (Vmax ) were statistically significant but not considered clinically relevant (magnitude < 20%). Time-varying M protein on Vmax was statistically significant, and the magnitude was >20%; however, clinical implications in the setting of combination therapy were not expected. Model-predicted steady-state elotuzumab exposure in cycle 12 were similar in Japanese and non-Japanese patients and in Japanese patients with 0 and ≥1 prior lines of therapy. Elotuzumab 20 mg/kg intravenously every 4 weeks beginning in cycle 19 produced time-averaged concentrations similar to elotuzumab 10 mg/kg intravenously every 2 weeks, although maximum and minimum concentrations after elotuzumab 20 mg/kg intravenous every-4-week dosing were slightly higher and lower, respectively. In conclusion, the current analysis demonstrates that Japanese ethnicity, prior line of therapy, time-varying M protein, and change in elotuzumab dosing regimen in cycle 19 have no clinically meaningful impact on elotuzumab pharmacokinetics and exposure in Japanese patients with multiple myeloma.

Sumo-Associated Traumatic Vertebral Artery Dissection Precipitating Subarachnoid Hemorrhage in Association with Bifid Origins of the Posterior Inferior Cerebellar Artery.

BACKGROUND: Traumatic vertebral artery dissection (tVAD) is frequently accompanied by cerebellar infarction, but subarachnoid hemorrhage (SAH) is rare. CASE DESCRIPTION: We report a unique case of tVAD precipitating SAH, from which the patient fully recovered, most likely because of the protective effects of an anomalously duplicated posterior inferior cerebellar artery (PICA) origin. A 17-year-old Sumo wrestler experienced a brief loss of consciousness after an attack by an opponent to his neck. Head computed tomography imaging demonstrated diffuse posterior fossa SAH; cerebral angiography demonstrated left vertebral artery (VA) occlusion, which was thought to be most likely attributable to tVAD. Angiography revealed distal PICA reconstitution, supplied by collateral arterial flow from the meningeal branch of the proximal ipsilateral VA. An external ventricular drain was placed acutely for treatment of SAH-induced hydrocephalus; however, the patient had an otherwise uneventful course, and remained without clinical evidence of ischemic infarct. A repeat imaging confirming a probable duplicated PICA origin from the VA, distal to the tVAD-associated thrombosis. CONCLUSIONS: Of particular interest, the patient's abnormal anatomy may have been a mixed blessing, with a more fragile bifid PICA potentially underlying the unexpected development of SAH, whereas the sister branch simultaneously spared him a potentially catastrophic infarction via arterial collateralization.

Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle.

Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF165), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.