Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Cytokine modulation in abdominal septic shock via the crucial role of IL-6 signaling in endothelial dysfunction.

Background: Early recovery from shock improves prognosis in septic shock patients. We determined whether cytokine modulation by Continuous Renal Replacement Therapy (CRRT) following acute care surgery resulted in stable hemodynamics in them. To investigate our hypothesis, we measured proinflammatory cytokines IL-6, IL-1ra and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1) following CRRT with polymyxin B immobilized fiber (PMX-DHP) which has been utilized as an adjuvant treatment option for patients with severe septic shock. Methods: 66 septic shock patients requiring 2 h direct hemoperfusion therapy PMX-DHP were included. 36 patients of them also received continuous hemodiafiltration (CHDF) after performing PMX-DHP. Circulatory dynamics and levels of inflammatory mediators, namely IL-6, IL-1ra, and PAI-1 were assessed before, immediately after, and 24 h initiation of PMX-DHP. Results: Mean Arterial Pressure (MAP) rose intentionally by PMX-DHP just after enforcement 24 h later (p < 0.01). Levels of IL-6, IL-1ra, and PAI-1 significantly decreased after PMX-DHP (p < 0.05) and this trend was observed up to 24 h post initiation of PMX-DHP (p < 0.05). IL-6 modulation by PMX-DHP was enhanced with using CHDF and there was a significant correlation between IL-6 and MAP (p < 0.0001). In addition, levels of Il-6 and PAI-1 showed a significant correlation. Conclusion: Our data showed employing CRRT as cytokine modulators could be an additional therapeutic strategy to improve septic shock outcomes via the crucial role of IL-6 signaling in endothelial dysfunction.

Lanthanide and Actinide Ion Complexes Containing Organic Ligands Investigated by Surface-Enhanced Infrared Absorption Spectroscopy.

A new technique, surface-enhanced infrared absorption (SEIRA) spectroscopy, was used for the structural investigation of lanthanide (Ln) and actinide (An) complexes containing organic ligands. We synthesized thiol derivatives of organic ligands with coordination sites similar to those of 2-[N-methyl-N-hexanethiol-amino]-2-oxoethoxy-[N',N'-diethyl]-acetamide [diglycolamide (DGA)], Cyanex-272, and N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), which have been used for separating Ln and An through solvent extraction. These ligands were attached on a gold surface deposited on an Si prism through S-Au covalent bonds; the gold surface enhanced the IR absorption intensity of the ligands. Aqueous solutions of Ln (Eu3+, Gd3+, and Tb3+) and An (Am3+) ions were loaded onto the gold surface to form ion complexes. The IR spectra of the ion complexes were obtained using Fourier transform infrared spectroscopy in the attenuated total reflection mode. In this study, we developed a new sample preparation method for SEIRA spectroscopy that enabled us to obtain the IR spectra of the complexes with a small amount of ion solution (5 µL). This is a significant advantage for the IR measurement of radiotoxic Am3+ complexes. In the IR spectra of DGA, the band attributed to C═O stretching vibrations at ∼1630 cm-1 shifted to a lower wavenumber by ∼20 cm-1 upon complexation with Ln and An ions. Moreover, the amount of the red shift was inversely proportional to the extraction equilibrium constant reported in previous studies on solvent extraction. The coordination ability of DGA toward Ln and An ions could be assessed using the band position of the C═O band. The Cyanex-272- and TPEN-like ligands synthesized in this report also showed noticeable SEIRA signals for Ln and An complexes. This study indicates that SEIRA spectroscopy can be used for the structural investigation of ion complexes and provides a microscopic understanding of selective extraction of Ln and An.

Treatment of CLN1 disease with a blood-brain barrier penetrating lysosomal enzyme.

Neuronal ceroid lipofuscinosis type 1(CLN1 disease) is a rare autosomal recessive lysosomal storage disease caused by genetic defects of palmitoyl protein thioesterase-1(PPT1), leading to accumulation of lipofuscin granules in brain and progressive neurodegeneration. Psychomotor regression, seizures, loss of vision, and movement disorder begin in infancy and result in early death. Currently, no disease-modifying therapy is available. We report a 68-month-old boy with CLN1 treated on a compassionate use basis weekly for 26 months with a PPT1 enzyme fused to an anti-insulin receptor antibody (AGT-194), thereby enabling penetration of the blood-brain barrier (BBB). During treatment, no side effects were observed, while seizure frequency decreased, life quality improved, and the boy's general condition remained stable. This case documents for the first time that treatment of CLN1 is principally feasible by an intravenous BBB penetrating enzyme replacement therapy using PPT1 fused with the human insulin receptor. Monitoring of side effects raised no unacceptable or unexpected safety concerns.Observed improvement of life quality related to ameliorated epilepsy control raises hope that further robust clinical trials including patients in earlier stages of disease will show positive results.

Pharmacokinetics and pharmacodynamics of once-weekly administration of JR-142, a long-acting albumin-fused human growth hormone: A rondemized, placebo-controlled phase 1 study.

OBJECTIVE: Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2). DESIGN: A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures. RESULTS: JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues. CONCLUSIONS: Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD. ETHICS: This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Self-Assembling Behavior and Chiroptical Properties of Carbazole-Cored Phenyl Isoxazolyl Benzenes.

Carbazole-cored phenyl isoxazolyl benzenes possessing chiral moieties were synthesized. The molecules self-assembled to form stacked supramolecular assemblies in an isodesmic fashion in chloroform, whereas the molecules preferably assembled in a cooperative fashion in methylcyclohexane (MCH), which was determined by spectroscopic methods, including UV-vis absorption, fluorescence, and 1H NMR spectroscopy. Clear nucleation and elongation processes were observed in the plot of the degree of aggregation (αagg) against temperature, which allowed us to determine the elongation temperature (Te), the enthalpic gain in the elongation process (ΔHe), the equilibrium constant between nucleation and elongation (Ka), and the degree of polymerization at the elongation temperature ([Nn(Te)]). Circular dichroism (CD) and circularly polarized luminescence (CPL) studies revealed the formation of helically stacked assemblies in solution. Moreover, the majority-rule effect was clearly observed in the solutions of mixtures of (S)- and (R)-1, indicating the chiral amplification behavior of the helically stacked assemblies consisting of (S)- and (R)-1. AFM provided morphological insight into the assemblies on mica, which clearly indicates the formation of polymeric assemblies in the solid state.

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil.

In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.

A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis.

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis. Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis. Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (-1920*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067-6.877), P = 0.033 and OR 1.768 (1.060-2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086-2.338), P = 0.017]. Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II.

Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.

AIE-active micelles formed by self-assembly of an amphiphilic platinum complex possessing isoxazole moieties.

An increased interest in the use of platinum complex based luminescent micelles for imaging biological tissues has emerged in recent years due to their low cytotoxicity, synthetic flexibility, photostability, and high emission efficiency. Here, we report a luminescent micelle that is prepared through the self-assembly of an amphiphilic, neutral Pt(ii) complex with isoxazole moieties in THF/water on account of its aggregation-induced emission (AIE) property.

Helical assembly of a dithienogermole exhibiting switchable circularly polarized luminescence.

Dithienogermole derivatives S- and R-1 possessing phenylisoxazoles and chiral side chains were synthesized. The helical assembly of 1 in methylcyclohexane exhibited circularly polarized luminescence (CPL). The CPL signals of the assembly in the elongation regime were inverted with respect to those in the nucleation regime.

Comparative Evaluation of Endotoxin Activity Level and Various Biomarkers for Infection and Outcome of ICU-Admitted Patients.

Here, we concurrently measured the endotoxin activity (EA) level and levels of multiple biomarkers in patient blood obtained within 24 h after being admitted into the intensive care unit (ICU) and analyzed whether there were links between these markers and their associations with patient conditions and outcomes. The EA levels highly correlated with disease severity and patient survival, and showed a significant positive association with levels of lactate, procalcitonin, presepsin, and interleukin-6. Notably, the EA level was the marker that most highly correlated with the results of blood culture, and the presepsin level was the marker most highly correlated with the survival outcome at 28 days. Thus, the optimal biomarker should be selected based on whether it will be used to discriminate the presence of an infection or to predict survival.

Impact of Antithrombin Supplementation and Concomitant Anticoagulation Therapy in Pediatric Patients With Disseminated Intravascular Coagulation.

We aimed to evaluate the efficacy and safety of antithrombin (AT) supplementation and concomitant anticoagulation therapy in 65 children who met the Japanese Ministry of Health and Welfare (JMHW) disseminated intravascular coagulation (DIC) criteria and had received AT concentrate and/or other concomitant anticoagulants. The primary efficacy end point was to determine standardized mortality ratio (SMR). The secondary efficacy end points were DIC resolution rate and pediatric sequential organ failure assessment (pSOFA) score on day 3. The 28-day mortality rate was 6.8%; SMR was 0.55. Disseminated intravascular coagulation resolution rate on day 3 was 54.5%. The JMHW DIC scores at day 0 ( P = .005) and pSOFA scores at day 3 ( P = .018) were significantly lower in patients with resolution of DIC than in those without resolution of DIC. The target cutoff value for JMHW DIC score on day 0 was 6. No bleeding-related adverse events were associated with AT administration. In children with DIC, AT supplementation and concomitant anticoagulation therapy can be safely used as initial treatment when JMHW DIC score is 6; it may improve DIC resolution, organ failure, and mortality rates.

Pseudorotaxanes in the gas phase: structure and energetics of protonated dibenzylamine-crown ether complexes.

We observe UV spectra of protonated dibenzylamine (dBAMH+) and its complexes with 15-crown-5 (dBAMH+-15C5), 18-crown-6 (dBAMH+-18C6), and 24-crown-8 (dBAMH+-24C8) under cold (∼10 K) gas-phase conditions by UV photodissociation (UVPD) and UV-UV hole-burning (HB) spectroscopy. The UVPD spectrum of the dBAMH+-15C5 complex shows an extensive low-frequency progression, which originates from a unique conformation of the dBAMH+ part with benzene rings facing closely to each other, while UVPD and calculation results suggest open conformations of the dBAMH+ part for dBAMH+-18C6 and dBAMH+-24C8. UV-UV HB spectra of the dBAMH+-24C8 complex indicate that there exist at least two conformers; multiple conformations can contribute to high stability of dBAMH+-24C8 pseudorotaxane due to "conformational" entropic effects. The UVPD experiment indicates that the dissociation probability of dBAMH+-24C8 into dBAMH+ and 24C8 is substantially smaller than that of dBAMH+-15C5 and dBAMH+-18C6, which can be related to the barrier height in the dissociation process. The energetics of the dBAMH+-24C8 complex is investigated experimentally with NMR spectroscopy and theoretically with the global reaction route mapping (GRRM) method. An energy barrier of ∼60 kJ mol-1 is present in the pseudorotaxane formation in solution, whereas there is no barrier in the gas phase. In the course of the photodissociation, excited dBAMH+-24C8 complexes can be trapped at many local minima corresponding to multiple conformations. This can result in effective dissipation of internal energy into degrees of freedom not correlated to the dissociation and decrease the dissociation probability for the dBAMH+-24C8 complex in the gas phase. The energy barrier for the pseudorotaxane formation in solution originates not simply from the slippage process but rather from solvent effects on the dBAMH+-24C8 complex.

Supramolecular Copolymerization by Sequence Reorganization of a Supramolecular Homopolymer.

The homopolymeric sequence formed by the head-to-head association of tetrakisporphyrin 1 is completely dissociated by the competitive association of the ditopic guest G2, resulting in the supramolecular copolymer poly-1⋅G2 with an alternatingly repeating host-guest sequence. The 1:1 stoichiometry of 1 and G2 is confirmed by a Job plot using UV/Vis titration and diffusion-ordered NMR spectroscopy (DOSY). The solution viscometry for poly-1 and poly-1⋅G2 suggests that the supramolecular chain of poly-1 behaves like a rod, whereas the supramolecular copolymer chain of poly-1⋅G2 behaves like a swelled fat chain, which is entangled in the semi-dilute regime. Atomic force microscopy shows that the supramolecular polymer poly-1⋅G2 is highly oriented through the interdigitation of the long alkyl chains.

Synthesis and Structure of Feet-to-Feet Connected Bisresorcinarenes.

Bisresorcinarenes 1a-d were obtained in excellent yields, and 1e was finally obtained in 50% yield. X-ray diffraction analysis showed that 1a and 1b adopted helical conformations, whereas the two resorcinarenes of 1c-e were in parallel orientations in which the clefts of the aliphatic chains entrapped one or two solvent molecules. The conformational study revealed that the helix interconversion between the (P)- and (M)-helical conformers depended on the length of the aliphatic chains. 1a had the largest energetic barrier to helix interconversion, while in 1b, its more flexible aliphatic chains lowered its energetic barriers. The P/M interconversion of 1a was coupled with the clockwise/anticlockwise interconversion of the interannular hydrogen bonding of the two resorcinarenes. The large negative entropic contributions indicate that the transition state is most likely more ordered than the ground states, suggesting that the transition state is most likely symmetric and is solvated by water molecules. Calculations at the M06-2X/6-31G(d,p) level revealed that the more stable (P)-conformation has clockwise interannular hydrogen bonding between the two resorcinarenes.

Induced-Dipole-Directed, Cooperative Self-Assembly of a Benzotrithiophene.

A benzotrithiophene derivative possessing phenylisoxazoles self-assembled to form stacks. The molecule isodesmically self-assembled in chloroform, whereas it self-assembled in a cooperative fashion in decalin and in methylcyclohexane. Thermodynamic studies based on isodesmic, van der Schoot, and Goldstein-Stryer mathematical models revealed that the self-assembly processes are enthalpically driven and entropically opposed. An enthalpy-entropy compensation plot indicates that the assembly processes in chloroform, decalin, and methylcyclohexane are closely related. The enthalpic gains in less-polar solvents are greater than those in more-polar solvents, resulting in the formation of large assemblies in decalin and in methylcyclohexane. The formation of large assemblies leads to cooperative assemblies. The elongation process is enthalpically more favored than the nucleation process, which drives the cooperativity of the self-assembly. DFT calculations suggested that a hexameric assembly is more stable than tetrameric or dimeric assemblies. Cooperative self-assemblies based on intermolecular interactions other than hydrogen bonding have rarely been reported. It is demonstrated herein that van der Waals interactions, including induced dipole-dipole interactions, can drive the cooperative assembly of planar π-conjugated molecules.