Loss of Y in leukocytes as a risk factor for critical COVID-19 in men.

Background: The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription.

Methods: Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells.

Comprehensive cancer-oriented biobanking resource of human samples for studies of post-zygotic genetic variation involved in cancer predisposition.

The progress in translational cancer research relies on access to well-characterized samples from a representative number of patients and controls. The rationale behind our biobanking are explorations of post-zygotic pathogenic gene variants, especially in non-tumoral tissue, which might predispose to cancers. The targeted diagnoses are carcinomas of the breast (via mastectomy or breast conserving surgery), colon and rectum, prostate, and urinary bladder (via cystectomy or transurethral resection), exocrine pancreatic carcinoma as well as metastases of colorectal cancer to the liver.

Pharmacokinetics and Tissue Distribution of Pilocarpine After Application to Eyelid Skin of Rats.

Extending the delivery of drugs into the eyes while reducing systemic bioavailability is of utmost importance in the management of chronic ocular diseases. Topical application onto the lower eyelid skin, as an alternative to eye drops, is seen to be a valuable strategy in the treatment of chronic eye diseases. To elucidate the critical value of delivering drugs in solution onto the eyeball through the eyelid skin, pharmacokinetic studies of pilocarpine were conducted, and the results were verified using a direct pharmacodynamic study in rats.

Estimation of skin concentrations of topically applied lidocaine at each depth profile.

Skin concentrations of topically administered compounds need to be considered in order to evaluate their efficacies and toxicities. This study investigated the relationship between the skin permeation and concentrations of compounds, and also predicted the skin concentrations of these compounds using their permeation parameters. Full-thickness skin or stripped skin from pig ears was set on a vertical-type diffusion cell, and lidocaine (LID) solution was applied to the stratum corneum (SC) in order to determine in vitro skin permeability.

Proteomics accelerating the identification of the target molecule of bioactive small molecules.

Failures in many drug development programs in the past decades were related to unspecified mechanism of action and poor pharmacokinetic (PK) properties. Recent developments are focused on well defined targets, improved PK profiles, however, not much is known about off-target effects, especially those responsible for diminishing drug activity. Steadily increasing application of proteomics in drug development should expose clinically relevant proteins for the analysis of drug effects, to show what group of patients will respond and who should not be treated with an agent.

[Spontaneous regression of cancer--review of cases from 1988 to 2006].

Spontaneous regression of malignant tumours is a rare and enigmatic phenomenon. We reviewed the cases of spontaneous regression of cancer in medical literature according to MEDLINE database in the period 1988-2006 and compared them with similar reviews from 1900-1987 period. The number of reported cases of spontaneous regression increased steadily in XX century, probably due to a rising interest in this problem and new possibilities of radiological and biopsy examinations.

Changes to the dihydropyrimidine dehydrogenase gene copy number influence the susceptibility of cancers to 5-FU-based drugs: Data mining of the NCI-DTP data sets and validation with human tumour xenografts.

Patient response to the anti-tumour drug 5-fluorouracil (5-FU) is variable, but predicting the response rate is important for the selection of effective chemotherapy. Our aim was to identify alterations in DNA copy number that influence susceptibility of cancer cells to 5-FU-based drugs. The NCI public database was used to identify chromosome loci associated with drug sensitivity and DNA copy number.

Synthesis and cytostatic activity of 4,7-dihydroxythioaurone derivatives. Effect of B ring substitution on the activity.

Biological activity of thioaurones was not tested so far and the group constitute completely unexplored source of new molecules of pharmacological interest. We report synthesis and evaluation of cytotoxic activity of thioaurone derivatives bearing p-hydroquinone system in ring A. Their activity was found to depend strongly on substitution pattern, so eventually both the activity and pharmacokinetic parameters of the molecules could be tailored by further structural modifications.

A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity.

The Cdc25 dual-specificity phosphatases are key regulators of cell cycle progression through activation of cyclin-dependent kinases (Cdk). Three homologs exist in humans: Cdc25A, Cdc25B, and Cdc25C. Cdc25A and Cdc25B have oncogenic properties and are overexpressed in some types of tumors.

Napthalimidobenzamide DB-51630: a novel DNA binding agent inducing p300 gene expression and exerting a potent anti-cancer activity.

Control of gene expression by small molecule compounds is a novel therapeutic strategy for cancer and usually it requires the presence of specific molecular recognition. The development of the compounds preferentially binding to the specific DNA sequence is one of the potential but very difficult approaches in this strategy. We designed and synthesized novel napthalimidobenzamide derivatives and analyzed their binding preferences to oligonucleotides by EtBr-displacement assay with DNA sequences, being essential fragments of the genes.

TAS-108, a novel oral steroidal antiestrogenic agent, is a pure antagonist on estrogen receptor alpha and a partial agonist on estrogen receptor beta with low uterotrophic effect.

Purpose: Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 compared with other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant.

Experimental Design: The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) alpha and beta were compared in the reporter assay systems.

Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase.

A series of novel 6-methylene-bridged uracil derivatives have been optimized for clinical use as the inhibitors of human thymidine phosphorylase (TP). We describe their synthesis and evaluation. Introduction of a guanidino or an amidino group enhanced the in vitro inhibitory activity of TP comparing with formerly reported inhibitor 1.

Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: discovery of novel orally active inhibitors of human thymidine phosphorylase.

A series of novel 6-methylene-bridged uracil derivatives have been prepared as inhibitors of human thymidine phosphorylase (TP). To enhance the in vivo antitumor activity of fluorinated pyrimidine 2'-deoxyribonucleosides such as 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd), a potent TP inhibitor preventing their degradation to an inactive compound, has become a target of medicinal chemistry. We present here the synthesis and evaluation of novel human TP inhibitors.

gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor.

UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, gamma-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro.

Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex.

Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules.

A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells.

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity.

Substrate phage as a tool to identify novel substrate sequences of proteases.

Combinatorial phage peptide libraries have been used to identify the ligands for specific target molecules. These libraries are also useful for identification of the specific substrates of various proteases. A substrate phage library has a random peptide sequence at the N-terminus of the phage coat protein and an additional tag sequence that enables attachment of the phage to an immobile phase.

Specific distribution of TOP-53 to the lung and lung-localized tumor is determined by its interaction with phospholipids.

We have investigated the mechanism of TOP-53 distribution to the lung and lung-localized tumor. In contrast to etoposide (VP-16), TOP-53 contains a basic aminoalkyl group that may predispose it to interact specifically with phospholipids, consequently leading to an increase of drug accumulation in the tissues. Therefore, we have studied its interaction with phospholipids in vitro using an organic solvent-water partition system.

UFT and its metabolites inhibit cancer-induced angiogenesis. Via a VEGF-related pathway.

Treatment with UFT for spontaneous lung metastasis of murine renal carcinoma (RENCA) after resection of the primary tumor has resulted in significant prolongation of the life span of tumor-bearing animals. UFT inhibited the growth of metastatic nodules in the lung, apparently via decreased density of microvessels in the metastatic foci. Subsequent experiments used dorsal air sac assay to directly trace newly forming microvessels.

Anticancer effect of 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) against A549 non-small cell lung cancer cell line is related to its anti-invasive activity.

We examined the effects of TAC-101 on the invasion and metastasis of human non-small cell lung cancer (NSCLC) cell lines. TAC-101 showed an ability to inhibit in vitro invasiveness of NSCLC at a non-cytotoxic concentration range of 3-10 microM; such concentration levels were easily achievable following oral administration of therapeutically effective doses. The inhibition of cell invasion at 10 microM of TAC-101 accounted for 58-69% when compared with control cells.

Establishment and characterization of 6-[[2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103)-resistant cell lines.

6-2-(Dimethylamino)ethylămino-3-hydroxy-7H-indeno2, 1-cquinolin-7-one dihydrochloride (TAS-103) is a novel anticancer agent that was developed to target both topoisomerase (Topo) I and Topo II. To elucidate its mechanism of action, we have established and characterized TAS-103-resistant cells, derived from mouse leukemia (P388), human colon cancer (DLD-1), and human lung adenocarcinoma (A549) cell lines, by exposure to stepwisely increasing concentrations of TAS-103 in the culture medium. P388 / TAS cells showed only cross-resistance to VP-16 and adriamycin (ADR).

Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59).

Purpose: We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in antiestrogen therapy for breast cancer patients and to assess its tissue-selective estrogenic/antiestrogenic activity.

Methods: Using DP-TAT-59, a major and active metabolite of TAT-59, an in vitro cell growth inhibition test was performed. Antitumor activity was determined using TAT-59 against human tumor xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen-resistant cell lines, R-27 and FST-1.

Identification of substrate sequences for membrane type-1 matrix metalloproteinase using bacteriophage peptide display library.

Membrane type-1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of progelatinase A (proMMP-2) which is associated with tumor invasion and metastasis, and also known to have an ability to digest extracellular matrix components. To clarify substrate specificity of MT1-MMP, we have searched for amino acid sequences cleaved by this protease using the hexamer substrate phage library consisting of a large number of randomized amino acids sequences. The consensus substrate sequences for MT1-MMP were deduced from the selected clones and appeared to be P-X-G/P-L at the P3-P1' sites.

UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice.

UFT, an anticancer agent that is composed of tegafur (FT) and uracil at a molar ratio of 1:4, is widely used in clinical practice in Japan to treat cancer patients requiring a long-term chemotherapy, and it is associated with few side effects, if any. In this study, we have evaluated the inhibitory effect of UFT against RENCA cell-induced angiogenesis by a dorsal air sac assay. Marked angiogenesis is induced by implantation of a chamber containing RENCA cells into mice.