How has the relationship between oil and the US stock market changed after the Covid-19 crisis?

In this paper, we investigate how the relationship between oil and the US stock market has changed after the onset of Covid-19 crisis. To do so, we compute upside and downside correlations between the two markets. Our findings are as follows. First, we document the correlation asymmetry: the downside correlation is higher than the upside correlation. Second, we find that both upside and downside correlations increased after the crisis. This indicates that after the start of the Covid-19 crisis, a positive (negative) oil shock is even better (worse) news for the stock market than an equivalent shock before the crisis.

Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases.

PURPOSE: The clinical efficacy of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib has been demonstrated in ALK fusion-positive non-small cell lung cancer (NSCLC); however, brain metastases are frequent sites of initial failure in patients due to poor penetration of the central nervous system by crizotinib. Here, we examined the efficacy of a selective ALK inhibitor alectinib/CH5424802 in preclinical models of intracranial tumors. METHODS: We established intracranial tumor implantation mouse models of EML4-ALK-positive NSCLC NCI-H2228 and examined the antitumor activity of alectinib in this model. Plasma distribution and brain distribution of alectinib were examined by quantitative whole-body autoradiography administrating a single oral dose of (14)C-labeled alectinib to rats. The drug permeability of alectinib was evaluated in Caco-2 cell. RESULTS: Alectinib resulted in regression of NCI-H2228 tumor in mouse brain and provided a survival benefit. In a pharmacokinetic study using rats, alectinib showed a high brain-to-plasma ratio, and in an in vitro drug permeability study using Caco-2 cells, alectinib was not transported by P-glycoprotein efflux transporter that is a key factor in blood-brain barrier penetration. CONCLUSIONS: We established intracranial tumor implantation models of EML4-ALK-positive NSCLC. Alectinib showed potent efficacy against intracranial EML4-ALK-positive tumor. These results demonstrated that alectinib might provide therapeutic opportunities for crizotinib-treated patients with brain metastases.

Injectable hydrogel for sustained protein release by salt-induced association of hyaluronic acid nanogel.

A hyaluronic acid-based anionic nanogel formed by self-assembly of cholesteryl-group-bearing HA is designed for protein delivery. The HA nanogel spontaneously binds various types of proteins without denaturation, such as recombinant human growth hormone, erythropoietin, exendin-4, and lysozyme. The HA nanogel shows unique colloidal properties, in particular that an injectable hydrogel is formed by salt-induced association of the HA nanogel. A pharmacokinetic study in rats shows that an in situ gel formulation, prepared by simply mixing rhGH and HA nanogel in phosphate buffer, maintains plasma rhGH levels within a narrow range over one week. Therefore, HA nanogels offer a simple method for easy formulation of therapeutic proteins and are effective for sustained protein release systems.

Pharmacokinetic significance of renal OAT3 (SLC22A8) for anionic drug elimination in patients with mesangial proliferative glomerulonephritis.

PURPOSE: Our previous studies showed that the mRNA level of human organic anion transporter (hOAT) 3 in the kidney was correlated with the rate of elimination of an anionic antibiotic cefazolin. However, the correlation coefficient was not so high. In the present study, therefore, we enrolled more patients to examine whether additional factors were responsible for the correlation. METHODS: hOAT mRNA levels in renal biopsy specimens were quantified using the real-time polymerase chain reaction method. The elimination rates for the free fraction of cefazolin were determined in patients with various renal diseases. RESULTS: In the present study, the coefficient of correlation between the hOAT3 mRNA level and the elimination rates for the free fraction of cefazolin was not so high in the patients overall as in our previous study (r = 0.536). However, following the classification of renal diseases, a better correlation was obtained in patients with mesangial proliferative glomerulonephritis (r = 0.723). In contrast, multiple regression analyses including gender, age, and liver function did not result in any improvements in the correlation coefficients. CONCLUSIONS: These results suggest that the hOAT3 mRNA level is a significant marker of pharmacokinetics with which to predict the rate of elimination of cefazolin in patients with mesangial proliferative glomerulonephritis.

Design, synthesis, photochemical properties and cytotoxic activities of water-soluble caged L-leucyl-L-leucine methyl esters that control apoptosis of immune cells.

L-Leucyl-L-leucine methyl esters (LeuLeuOMe) is a lysosomotropic agent that induces apoptosis of certain immune cells. Glucose-carrying 2-nitrobenzyl (2-NB) and 2-nitrophenethyl (2-NPE) caged LeuLeuOMe, 1a and b, were synthesized and their photochemical and immunological properties were studied. Caged glycine methyl esters (GlyOMe), 2a,b, were also prepared to examine the cytotoxic activity of the photolytic byproducts from 1a,b. All the caged compounds were soluble in PBS containing 1% DMSO more than 400 microM, and efficiently released the substrates upon irradiation at 350 nm. While both 1a and 1b were not toxic to HL60 cells, 1b released LeuLeuOMe more quickly and induced apoptosis of HL60 cells far more efficiently than 1a. Although GlyOMe was not cytotoxic, 2a and b were slightly toxic before and after irradiation almost to the similar extent. Therefore, the photolytic products from the caging groups appear to be not toxic to the cells, and the apoptosis inducing activity of 1a and b may be for the most part due to LeuLeuOMe.

Esterase-like activity of serum albumin: characterization of its structural chemistry using p-nitrophenyl esters as substrates.

PURPOSE: To elucidate the catalytic mechanism of the esterase-like activity of serum albumin (SA), the reactivity of SA from six species was investigated using p-nitrophenyl esters as model substrates. METHODS: The effect of pH and the energetic and thermodynamic profiles of SA were determined for all species for p-nitrophenyl acetate (PNPA). Then, kinetic and thermodynamic studies using a series of p- and o-nitrophenyl esters with different side chains and human SA (HSA) were carried out. The influence of deuterium oxide was also evaluated. Finally, the information gained was used to construct a computer model of the structural chemistry of the reaction. RESULTS: The pH profiles suggest that the nucleophilic character of the catalytic residue (Tyr-411 in the case of HSA) is essential for activity. This kcat-dependent activity was found to increase with a decrease in the activation free energy change (deltaG). Hence, the magnitude of deltaG, which is dependent on activation entropy change (deltaS), as calculated from the thermodynamic analysis, can be regarded as an indicator of hydrolytic activity. It indicates that p-nitrophenyl propionate (PNPP) is the best substrate by evaluating the reactions of nitrophenyl esters with HSA. The findings here indicate that deuterium oxide has no significant effect on the rate of hydrolysis of PNPA by HSA. CONCLUSIONS: The results are consistent with a scenario in which HSA becomes acylated due to a nucleophilic attack by Tyr-411 on the substrate and then is deacylated by general acid or base catalysis with the participation of water.

Gene expression levels and immunolocalization of organic ion transporters in the human kidney.

Renal excretion of organic anions and cations is mediated by the organic ion transporter family (SLC22A). In this study, the mRNA levels of the organic ion transporters were quantified by real-time PCR in normal parts of renal tissues from seven nephrectomized patients with renal cell carcinoma, and the distributions and localization of human (h)OAT1, hOAT3, and hOCT2 proteins were investigated by immunohistochemical analyses in the human kidney. The expression level of hOAT3 mRNA was the highest among the organic ion transporter family, followed by that of hOAT1 mRNA. The hOCT2 mRNA level was the highest in the human OCT family, and the level of hOCTN2 mRNA was higher than that of hOCTN1. hOCT1 mRNA showed the lowest level of expression in organic ion transporter family. hOAT1, hOAT3, and hOCT2 proteins were detected in crude membranes from the kidney of all patients by Western blot analyses, whereas hOCT1 protein could not be detected. Immunohistochemical analyses showed that both hOAT1 and hOAT3 were localized to the basolateral membrane of the proximal tubules in the cortex, and hOCT2 was localized to the basolateral membrane of the proximal tubules in both the cortex and medullary ray. Immunohistochemical analyses of serial sections indicated that hOAT1, hOAT3, and hOCT2 were coexpressed in a portion of the proximal tubules. These results suggest that hOAT1, hOAT3, and hOCT2 play predominant roles in the transport of organic ions across the basolateral membrane of human proximal tubules.

Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases.

PURPOSE: Because the urinary excretion of drugs is often decreased in renal diseases, dosage regimens are adjusted to avoid adverse drug reactions. The aim of present study was to clarify the alteration in the levels of renal drug transporters and their correlation with the urinary drug excretion in renal diseases patients. METHODS: We quantified the mRNA levels of human organic anion transporters (hOATs) by real-time polymerase chain reaction and examined the excretion of the anionic drug, cefazolin, in renal disease patients. Moreover, transport of cefazolin by hOAT1 and hOAT3 were examined using HEK293 transfectants. RESULTS: Among four hOATs, the level of hOAT1 mRNA was significantly lower in the kidney of patients with renal diseases than in the normal controls. The elimination constant of cefazolin showed a significant correlation with the values of phenolsulfonphthalein test and mRNA levels of hOAT3. The uptake study using HEK293 transfectants revealed that cefazolin and phenolsulfonphthalein were transported by hOAT3. CONCLUSIONS: These results suggest that hOAT3 plays an important role for anionic drug secretion in patients with renal diseases and that the expression levels of drug transporters may be related to the alteration of renal drug secretion.