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In this paper, our main aim is to study periodic and potent elements of a ring. We specially study periodic elements of graded rings and generalize some classical results related to idempotent of polynomial rings. We show that a (von Neumann) quasi-inverse of a potent element is a root of unity. We study the isomorphism of potent elements and analyze some closure properties of the set Pot(R) of potent elements of a ring R. The potent elements of the endomorphism ring of a Fitting module are described, and we apply this to matrices over division rings. In the case of matrices over finite fields, we connect features of potent elements with the exponent of their minimal polynomials. [ABSTRACT FROM AUTHOR]

The antimicrobial resistance crisis is an ongoing major threat to public health safety. Low- and middle-income countries are particularly susceptible to higher fatality rates and the economic impact of antimicrobial resistance (AMR). As an increasing number of pathogens emerge with multi- and pan-drug resistance to last-resort antibiotics, there is an urgent need to provide alternative antibacterial options to mitigate disease transmission, morbidity, and mortality. As identified by the World Health Organization (WHO), critically important pathogens such as Klebsiella and Pseudomonas species are becoming resistant to last-resort antibiotics including colistin while being frequently isolated from clinical cases of infection. Antimicrobial peptides are potent amino acid sequences produced by many life forms from prokaryotic, fungal, plant, to animal species. These peptides have many advantages, including their multi-hit mode of action, potency, and rapid onset of action with low levels of resistance being evident. These innate defense mechanisms also have an immune-stimulating action among other activities in vivo, thus making them ideal therapeutic options. Large-scale production and formulation issues (pharmacokinetics, pharmacodynamics), high cost, and protease instability hinder their mass production and limit their clinical application. This review outlines the potential of these peptides to act as therapeutic agents in the treatment of multidrug-resistant infections considering the mode of action, resistance, and formulation aspects. Clinically relevant Gram-positive and Gram-negative pathogens are highlighted according to the WHO priority pathogen list.

The antimicrobial resistance crisis is an ongoing major threat to public health safety. Low- and middle-income countries are particularly susceptible to higher fatality rates and the economic impact of antimicrobial resistance (AMR). As an increasing number of pathogens emerge with multi- and pan-drug resistance to last-resort antibiotics, there is an urgent need to provide alternative antibacterial options to mitigate disease transmission, morbidity, and mortality. As identified by the World Health Organization (WHO), critically important pathogens such as Klebsiella and Pseudomonas species are becoming resistant to last-resort antibiotics including colistin while being frequently isolated from clinical cases of infection. Antimicrobial peptides are potent amino acid sequences produced by many life forms from prokaryotic, fungal, plant, to animal species. These peptides have many advantages, including their multi-hit mode of action, potency, and rapid onset of action with low levels of resistance being evident. These innate defense mechanisms also have an immune-stimulating action among other activities in vivo, thus making them ideal therapeutic options. Large-scale production and formulation issues (pharmacokinetics, pharmacodynamics), high cost, and protease instability hinder their mass production and limit their clinical application. This review outlines the potential of these peptides to act as therapeutic agents in the treatment of multidrug-resistant infections considering the mode of action, resistance, and formulation aspects. Clinically relevant Gram-positive and Gram-negative pathogens are highlighted according to the WHO priority pathogen list. [ABSTRACT FROM AUTHOR]

Background: In monarchE and Postoperative Therapy with Endocrine and TS‐1 (POTENT) trials, abemaciclib and S‐1 have, respectively, shown to be effective as adjuvant therapies for luminal breast cancer (BC), although whether patients who meet the criteria are at high risk of recurrence compared to non‐eligible patients is still unknown. Here, we investigated recurrence risk according to the criteria of each trial in Japanese patients. Methods: We reviewed the records of 992 patients who received surgery at Chiba University Hospital for stage I–III BC from January 2017 to May 2022 and selected 553 analytic cohort patients and retrospectively analyzed the relapse‐free survival of the patients as the primary endpoint. High‐recurrence risk was defined according to monarchE trial and POTENT trial. Results: The 5‐year RFS for monarchE cohort 1 and cohort 2 eligible patients were 77.78% and 89.33%, respectively, which were significantly lower than monarchE non‐eligible patients (98.31%; p < 0.0001). However, the 5‐year RFS rate for POTENT eligible patients (90.51%) was lower than for POTENT non‐eligible patients (98.75%; p = 0.0001); excluding those who met the monarchE criteria, the prognosis of POTENT eligible patients had no significant differences from the prognosis of patients with POTENT non‐eligible BC (p = 0.3100). Conclusion: MonarchE criteria accurately identify patients who are prone to relapse. Moreover, although POTENT criteria also suggested a reasonable capacity for recurrence prediction, there was no significant difference in recurrence between POTENT non‐eligible patients and the patients who were POTENT but not monarchE eligible. This might offer justification for reconsidering the use of S‐1 in monarchE non‐eligible patients. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer remains the leading and deadly type of cancer worldwide. It was estimated to account for about 25% of the 7 million people that died as a result of cancer-related issues/mortality every year in the world. Non-small cell lung cancer (NSCLC) is the lethal/deadly class of lung cancer with nearly 1.5 million reported cases and less than 20% survival rate. Therefore, it becomes necessary to explore more effective NSCLC drugs. Result A computational approach was employed here to design ten new EGFRWT inhibitors using compound 18 as a template for the design identified with the best binding affinity and good pharmacokinetic properties previously reported in our work. The modeled inhibitory activities of these newly designed EGFRWT inhibitors (range from 7.746966 to 11.09261) were better than that of the hit compound with pIC50 of 7.5639 and gefitinib the positive control with pIC50 of 5.879426. The ligand-binding interaction between these newly designed EGFRWT inhibitors and the EGFR tyrosine kinase receptor as shown in Table 3 was investigated and elucidated using molecular docking protocol. Based on the molecular docking results, the binding affinities of these newly designed EGFRWT inhibitors were found to be between − 8.8 and − 9.5 kcal/mol. The designed compound SFD10 has the highest binding affinity of − 9.5 kcal/mol followed by compound SFD8 (with a binding affinity of − 9.3 kcal/mol), then by compound SFD9 and 4 (each with a binding affinity of − 9.3 kcal/mol). None of them was found to have more than one violation of the filtering criterion used in this study thereby showing good ADMET properties. Conclusion The modeled inhibitory activities and binding affinities of these newly designed EGFRWT inhibitors were found to be higher than that of the template compound and the control (gefitinib) used in this research. They were also seen to be non-toxic with good pharmacokinetic properties.

In the study of designing pharmacophore models for analgesic, a series of 4-[4–chloro-3- (trifluoromethyl)-phenyl]-4-piperidinol (TFMP) derivatives were synthesized and characterized by physical and spectral method (HR-EIMS, HR-FABMS, 1H-NMR, 13C-NMR, UV, and FT-IR). The analgesic action of the synthesized derivatives was estimated by means of Hot Plate Method. Most of the compounds displayed potent analgesic efficacy and an ultrashort to long duration of action. The results indicate that these compounds are useful as analgesics. In the presence of naloxone they displayed pain reliving effect. In conclusion, among active compounds 3 (188%), 5 (137%), 6 (162%), and 8 (107%) respectively, emerged as most effective analgesic and they depressed peripheral and centrally mediated pain by opioid independent systems. [ABSTRACT FROM AUTHOR]

• Generating neutralizing mAbs against EV-As by co-immunization with EVA71 and CVA16. • An IgM antibody M20 shows potent and broad neutralizing ability against tetra-EV-A. • M20 binds to the GH loop of VP1, may be a candidate for universal vaccines design. To determine the potent and broad neutralizing monoclonal antibody (mAb) against enterovirus A (EV-A) in vitro and in vivo induced by enterovirus A71(EVA71) and coxsackievirus 16 (CVA16) co-immunization. The mAb was Generated by co-immunization with EVA71 and CVA16 through hybridomas technology. The characteristics and neutralizing ability of mAb were analysed in vitro and in mice. We screened three mAb, the IgM antibody M20 and IgG antibody B1 and C31. All three antibodies showed cross-reactivity against tetra-EV-As. However, M20 showed potent and broad neutralizing ability against tetra-EV-As than B1 and C31. Meanwhile, M20 provided cross-antiviral efficacy in tetra-EV-As orally infected mice. Moreover, M20 binds to a conserved neutralizing epitope within the GH loop of tetra-EV-As VP1. M20 and its property exhibited potent and broad antiviral activity against tetra-EV-As, and that is expected to be a potential preventive and therapeutic candidate against EV-As. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Virus-specific antibodies can be detected in infected patients approximately two weeks after symptom onset. In this study, we set up ELISA technology coating with purified SARS-CoV-2 S and N proteins to study the antibody response of 484 serum samples. We established a surrogate viral inhibition assay using SARS-CoV-2 S protein pseudovirus system to determine the neutralization potency of collected serum samples. Here, we report robust antibody responses to SARS-CoV-2 in 484 recovered patients varying from 154 to 193 days, with 92% of recovered patients displaying a positive virus-specific spike glycoprotein IgG (s-IgG) response, while the ratio of positive spike glycoprotein IgM (s-IgM) reached 63%. Furthermore, moderate to potent neutralization activities were also observed in 62% of patients, correlating significantly with s-IgG response. This study strongly supports the long-term presence of antibodies in recovered patients against SARS-CoV-2, although all serum samples were collected from individuals with mild or moderate symptoms.

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Virus-specific antibodies can be detected in infected patients approximately two weeks after symptom onset. In this study, we set up ELISA technology coating with purified SARS-CoV-2 S and N proteins to study the antibody response of 484 serum samples. We established a surrogate viral inhibition assay using SARS-CoV-2 S protein pseudovirus system to determine the neutralization potency of collected serum samples. Here, we report robust antibody responses to SARS-CoV-2 in 484 recovered patients varying from 154 to 193 days, with 92% of recovered patients displaying a positive virus-specific spike glycoprotein IgG (s-IgG) response, while the ratio of positive spike glycoprotein IgM (s-IgM) reached 63%. Furthermore, moderate to potent neutralization activities were also observed in 62% of patients, correlating significantly with s-IgG response. This study strongly supports the long-term presence of antibodies in recovered patients against SARS-CoV-2, although all serum samples were collected from individuals with mild or moderate symptoms. [ABSTRACT FROM AUTHOR]

It is well-known that idempotents lift modulo any nil one-sided ideal. While this is not true for periodic elements, it does hold true in many special cases. We investigate the connections between these special cases, as well as limitations. We also answer three questions from the literature. For example, we construct a nilpotent ideal where torsion-units lift, but periodic elements do not lift, modulo that ideal. [ABSTRACT FROM AUTHOR]

Raghuram Kandimalla,1 Suvakanta Dash,2 Ashim Chandra Bhowal,3 Sanjeeb Kalita,1 Narayan Chandra Talukdar,1 Sarathi Kundu,3 Jibon Kotoky1,4 1Drug Discovery Lab, Institute of Advanced Study in Science and Technology, 2Girijananda Choudhury Institute of Pharmaceutical Sciences, 3Soft Nano Laboratory, Institute of Advanced Study in Science and Technology, 4National Institute of Pharmaceutical Education and Research, Guwahati, India Abstract: In this study, a glycogen–gold nanohybrid was fabricated to enhance the potency of a promising hepatoprotective agent silymarin (Sly) by improving its solubility and gut permeation. By utilizing a facile green chemistry approach, biogenic gold nanoparticles were synthesized from Annona reticulata leaf phytoconstituents in combination with Sly (SGNPs). Further, the SGNPs were aggregated in glycogen biopolymer to yield the therapeutic nanohybrids (GSGNPs). Transmission electron microscopy, UV–Vis spectroscopy, X-ray diffraction, and Fourier transform infrared spectroscopy analysis confirmed the successful formation and conjugation of both SGNPs and GSGNPs. The fabricated nanohybrids showed significant protection against CCl4-induced hepatic injury in Wistar rats and maintained natural antioxidant (superoxide dismutase and catalase) levels. Animals treated with GSGNPs (10 mg/kg) and SGNPs (20 mg/kg) retained usual hepatic functions with routine levels of hepatobiliary enzymes (aspartate transferase, alanine transaminase, alkaline phosphatase, and lactate dehydrogenase) and inflammatory markers (interleukin-1β and tumor necrosis factor-α) with minimal lipid peroxidation, whereas those treated with 100 mg/kg of Sly showed the similar effect. These results were also supported by histopathology of the livers where pronounced hepatoprotection with normal hepatic physiology and negligible inflammatory infiltrate were observed. Significant higher plasma Cmax supported the enhanced bioavailability of Sly upon GSGNPs treatment compared to SGNPs and free Sly. Graphite furnace atomic absorption spectrophotometry analysis also substantiated the efficient delivery of GSGNPs over SGNPs. The fabricated therapeutic nanohybrids were also found to be biocompatible toward human erythrocytes and L929 mouse fibroblast cells. Overall, due to increased solubility, bioavailability and profuse gut absorption; GSGNPs demonstrated tenfold enhanced potency compared to free Sly. Keywords: silymarin, Annona reticulata, glycogen–gold, nanohybrid, potency, hepatoprotection

[Display omitted] Protein kinases constitute the largest group within the kinase family, and mutations and translocations of protein kinases due to genetic alterations are intimately linked to the pathogenesis of numerous diseases. Bruton's tyrosine kinase (BTK) is a member of the protein kinases and plays a pivotal role in the development and function of B cells. BTK belongs to the tyrosine TEC family. The aberrant activation of BTK is closely associated with the pathogenesis of B-cell lymphoma. Consequently, BTK has always been a critical target for treating hematological malignancies. To date, two generations of small-molecule covalent irreversible BTK inhibitors have been employed to treat malignant B-cell tumors, and have exhibited clinical efficacy in hitherto refractory diseases. However, these drugs are covalent BTK inhibitors, which inevitably lead to drug resistance after prolonged use, resulting in poor tolerance in patients. The third-generation non-covalent BTK inhibitor Pirtobrutinib has obtained approval for marketing in the United States, thereby circumventing drug resistance caused by C481 mutation. Currently, enhancing safety and tolerance constitutes the primary issue in developing novel BTK inhibitors. This article systematically summarizes recently discovered covalent and non-covalent BTK inhibitors and classifies them according to their structures. This article also provides a detailed discussion of binding modes, structural features, pharmacological activities, advantages and limitations of typical compounds within each structure type, providing valuable references and insights for developing safer, more effective and more targeted BTK inhibitors in future studies. [ABSTRACT FROM AUTHOR]

The hypolipidemicactivity of aqueous extract for flowers of Hibiscussabdariffa L. was evaluated inhypercholesterolemicrats. Thirty two male adult rats were divided into four groups, each one involved eight rats. First group fed normal diet (normal group). The second group fed with high cholesterol diet (HCD) and received oral administration of 2 ml sterile water (control group). the third and fourth groups fed with high cholesterol diet(HCD) and received oral administration of aqueous extract of flowers of H. sabdariffa, 200 and 400 mg/kg respectively in 2 mL of sterile water for 21 days. The animals were sacrificed; Biochemical analysis of blood serum were performed for lipid profile and liver enzymes.The extract induces a significant decrease in serum cholesterol, triglycerides and Bloodlevels of AST, ALT, ALP. The results concluded that Hibiscus sabdariffaextract aqueous (200, 400 mg/kg) have potent hypolipidemicactivity inhypercholesterolemic rats. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C Virus is the leading cause of death in liver-related diseases globally. The identification of innovative drug targets and inexpensive therapeutic agents remain a high priority for chronic HCV infection management. In the last few decades, the availability of highly effective interferon-free regimens for HCV treatment is the only possible option for cure of the large number of chronic HCV patients. Direct acting antiviral drugs, such as Sovaldi, are expensive and their efficacy varies from genotype to genotype. In addition, these drugs are advised in combination with ribavirin and interferon, which makes the treatment costly. Thiazolide derivatives are recently emerging antiviral agents that may change current and future therapies for liver complications caused by HBV and HCV. Nitazoxanides are synthetic nitrothiazolyl-salicylamide derivative of thiazolide, which have been used as anti-HCV drugs. The derivatives of thiazolides were randomly screened for anti-HCV and anti-HBV activity in a biological system, yet the stability and other properties of thesecompoundswere not tested. Representing chemicalcompoundswith Hosoya-polynomial produces closed forms of many topological indices, which correlate with the chemical properties of the material under investigation. These indices are used in the development of quantitative structure-activity relationships (QSARs), in which the biological activity and other properties of molecules like boiling point, stability, strain energy, radius of gyration, and viscosity are correlated with their structures.In this paper, Hosoya-polynomials and Weiner indices of some derivatives of thiazolides were determined. Graphs of Hosoya polynomial for these derivatives were also plotted. Objectives: In this study, therefore, it was attempted to extend the research to check the stability and other properties of thiazolide derivatives using the Hosoya-polynomial and Wiener index. Methods: In the first step, Hosoya polynomials of some famous classes of thiazolides were computed, followed by computation of F Wiener indices of thiazolide derivatives. Distance-based graph invariants were used as a structure-descriptor for predicting various physicochemical properties of organic compounds. The Weiner index of 8 derivatives of thiazolidines was computed, including RM-4832, RM-4848, RM-4850, RM-4851, RM-4852, RM-4850, Tizoxanide, and Nitazoxanide. Results: These indices indicate the physiochemical properties of these compounds in relation to stability in the given biological environment. The Wiener indices of the studied compounds ranged from 374 to 684. Out of 8 analyzed compounds, 3 showed Wiener indices of 374. RM-4863 had a maximum index value of 684. Graphs were also drawn for Hosoya polynomials of all these thiazole derivatives. Conclusions: The results confirmed that RM-4863 is a stable physiochemical compound, which might be used as an effective drug for treating viral infections, including HCV and HBV. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinases 4/6 play an important role in regulation of cell cycle, and overexpress in a variety of cancers. Up to now, new CDK inhibitors still need to be developed due to its poor selectivity. Herein we report a novel series of 4-(2,3-dihydro-1 H -benzo[ d ]pyrrolo[1,2- a ]imidazole-7-yl)- N -(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine anologues as potent CDK 4/6 inhibitors based on LY2835219 (Abemaciclib). Compound 10d , which exhibits approximate potency on CDK4/6 (IC 50  = 7.4/0.9 nM), has both good pharmacokinetic characters and high selectivity on CDK1 compared with LY2835219. Overall, compound 10d could be a promising candidate and a good starting point as anticancer drugs. [ABSTRACT FROM AUTHOR]

A series of twelve furanochalcones ( F1 - F12 ) was synthesized and investigated for their human monoamine oxidase inhibitory activities. Among the series, compound (2 E , 4 E )-1-(furan-2-yl)-5-phenylpenta-2, 4-dien-1-one ( F1 ), which was analyzed by single-crystal X-ray diffraction, showed potent and selective MAO-B inhibitory activity with an inhibition constant ( K i ) value of 0.0041 μM and selectivity index of (SI) 172.4, and exhibited competitive inhibition. Introduction of a cinnamyl group to the furanochalcone significantly increased the inhibitory activity. In the dilution-recovery experiments, the residual activities of MAO-A and MAO-B by F1 under the diluted condition fully recovered as compared with the undiluted condition, indicating F1 is a reversible inhibitor. The K i value of F1 is the lowest among the values of chalcone derivatives and furthermore lower than that (0.0079 μM) of the reversible MAO-B inhibitor, lazabemide, a marketed drug. Molecular docking study against hMAO-B provided the binding site interactions of the lead compound, including strong π-π stacking between the phenyl system and FAD nucleus. [ABSTRACT FROM AUTHOR]

Azaindoles are an important class of nitrogen-containing heterocyclics and were identified as the most active and potent classes of compounds with a wide range of biological and pharmacological activities. They were extensively used as pharmaceuticals. Although the number of drugs is available in the market even though the search for new molecules is ever demanding. In present work, various Azaindoles were synthesized and characterized using physical and spectral data. Finally, the Azaindole derivatives were screened for their In vitro cytotoxic activity. Some of the molecules exhibited very good potency when compared with respective standards. The approach is very challenging and was found difficult to get a molecule with potency. Even though, the present molecules were provided novel leads against Cancer and also insights into structural features required to be considered while designing the molecules with Azaindole core structures for cytotoxic studies. [ABSTRACT FROM AUTHOR]

Cell cycle consists of different types of phases, transition from G1, S, G2, M. Inhibition of associated CDKs like CDK9/Cyclin T1 complex, which are indirectly involved in the Cell cycle progression in the form of transcription elongation, reduces diverse diseases such as Cardiac Hypertrophy, Alzheimer’s, Cancer, AIDS and Inflammation. Glide tool of the Schrodinger software has been used for performing Structure Based Virtual Screening and Docking against Drug Bank and MDPI database. The best hits were identified which go and bind in the active site of the target where ATP binds for the activity. The ADMET, MM-GBSA and DFT analysis is also done for the same. Compound 4-{4-[4-(3-aminopropoxy)phenyl]-1H-pyrazol-5-yl}-6-chlorobenzene-1,3-diol ( DB08045 ) was found to be more potent, novel and selective as an inhibitor. Hopefully compound ( DB08045 ) could be used as an anti-cancer agent for the treatment of life-threatening diseases. [ABSTRACT FROM AUTHOR]

The optimisation of the azanaphthyridine series of Spleen Tyrosine Kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over hERG activity. A good pharmacokinetic profile was achieved by modification of the p K a . Morpholine compound 32 is a potent SYK inhibitor showing moderate selectivity, good oral bioavailability and good efficacy in the rat Arthus model but demonstrated a genotoxic potential in the Ames assay. [ABSTRACT FROM AUTHOR]

Let R be a ring, J(R) the Jacobson radical of R and P the set of potent elements of R. We prove that if R satisfies (∗) given x, y in R there exist integers m=m(x,y)>1 and n=n(x,y)>1 such that xmy=xyn and if each x∈R is the sum of a potent element and a nilpotent element, then N and P are ideals and R=N⊕P. We also prove that if R satisfies (∗) and if each x∈R has a representation in the form x=a+u, where a∈P and u∈J(R) ,then P is an ideal and R=J(R)⊕P.

Efficient delivery of siRNA to cancer cells after systemic administration poses a significant challenge. While many methods of nucleic acid delivery have been described, encapsulation of siRNA in lipid nanoparticles (LNPs) represents the most clinically advanced delivery approach. Currently, there are two siRNA-LNP-based treatments (ALN-VSP and TKM-PLK1) in clinical trials targeting solid tumors, with additional studies ongoing for noncancer diseases. The consensus from these clinical studies is that siRNA-LNP represents safe and potent silencing systems. Improvements in LNP technology through development of more potent and biocompatible ionizable cationic lipids along with targeting lipids to mediate delivery of LNPs specifically to cancer cells are on the horizon. In combination with genomic screening, it is possible that within the next 5 years the pathogenic drivers of individual cancers will be identified and siRNA-based personalized medicines will be formulated to achieve successful treatment of cancer and other genetic diseases. [ABSTRACT FROM AUTHOR]

Abstract: P2X receptors are ion channels gated by ATP. In rodents these channels are modulated by zinc and copper. Zinc is co-released with neurotransmitter at some synapses and can modulate neuronal activity, but the role of copper in the brain is unclear. Rat P2X2 receptors show potentiation by 2–100 μM zinc or copper in the presence of a submaximal concentration of ATP but are inhibited by zinc or copper at concentrations above 100 μM. In contrast, human P2X2 (hP2X2) receptors show no potentiation and are strongly inhibited by zinc over the range of 2–100 μM. The effect of copper on hP2X2 is of interest because there are human brain disorders in which copper concentration is altered. We found that hP2X2 receptors are potently inhibited by copper (IC50 = 40 nM). ATP responsiveness recovered extremely slowly after copper washout, with full recovery requiring over 1 h. ATP binding facilitated copper binding but not unbinding from this inhibitory site. A mutant receptor in which the first six extracellular cysteines were deleted, C(1–6)S, showed normal copper inhibition, however reducing agents dramatically accelerated recovery from copper inhibition in wild type hP2X2 and the C(1–6)S mutant, indicating that the final two disulfide bonds are required to maintain the high affinity copper binding site. Three histidine residues required for normal zinc inhibition were also required for normal copper inhibition. Humans with untreated Wilson's disease have excess amounts of copper in the brain. The high copper sensitivity of hP2X2 receptors suggests that they are non-functional in these patients. [Copyright &y& Elsevier]

Background: Abuse of topical corticosteroids (TC), especially over the face, is prevalent worldwide, including in India. Data about the magnitude of this problem in our country is lacking. Aims: The aims of this study were to ascertain the demographics, magnitude and clinical features of TC misuse on the face in the dermatology outpatient department (OPD) attendees in order to raise awareness about this problem and to analyze its causes. Methods: This was a prospective multicenter questionnaire-based clinical study conducted at 12 dermatology centers nationwide. Patients with relevant facial dermatoses reporting to the investigator were asked about their current use of over-the-counter topical formulations and a structured questionnaire applied in case the same was confirmed to be TC. Results: A total of 2926 patients with facial dermatoses were screened, of which 433 (14.8%) were using TC. TC was used as a fairness/general purpose cream or aftershave in 126 (29%) and in 104 (24%) for acne. Steroid combinations were used by 258 (59.6%). Potent and superpotent TC were significantly (P = 0.05) more frequently used by the rural/suburban population. The younger age groups used more potent formulations. A non-physician recommendation for TC use was obtainable in 257 (59.3%) patients. Of these, 232 (90.3%) were for potent/ super-potent steroids. Among 176 physician prescriptions, 78 (44.3%) were from nondermatologists. All non-physician prescriptions and 146 (83%) physician prescriptions for TC were inappropriately refilled. Adverse effects were seen in 392 (90.5%) TC users. Acne/ exacerbation of acne was the most common adverse effect. Conclusions: TC misuse in patients with facial dermatoses is quite common, and most of this use is unwarranted. Use as a fairness cream is the most common indication in this cohort. Limitations: This was an OPD-based study and, therefore, it may or may not accurately reflect the community data. [ABSTRACT FROM AUTHOR]

Abstract: Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD). [Copyright &y& Elsevier]

Abstract: A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model. [Copyright &y& Elsevier]

Abstract: A series of OX2R/OX1R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity. [Copyright &y& Elsevier]

Abstract: A pro-p group G is a PF-group if it has central series of closed subgroups with trivial intersection satisfying and . In this paper, we prove that a finitely generated pro-p group G is a p-saturable group, in the sense of Lazard, if and only if it is a torsion free PF-group. Using this characterization, we study certain families of subgroups of p-saturable groups. For example, we prove that any normal subgroup of a p-saturable group contained in the Frattini is again p-saturable. [Copyright &y& Elsevier]

Abstract: We have prepared a series of cathepsin K inhibitors bearing the keto-1,3,4-oxadiazole warhead capable of forming a hemithioketal complex with the target enzyme. By modifying binding moieties at the P1, P2, and prime side positions of the inhibitors, we have achieved selectivity over cathepsins B, L, and S, and have achieved sub-nanomolar potency against cathepsin K. This series thus represents a promising chemotype that could be used in diseases implicated by imbalances in cathepsin K activity such as osteoporosis. [Copyright &y& Elsevier]

Abstract: A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of other receptors. [Copyright &y& Elsevier]

Abstract: Highly potent and novel derivatives of doxorubicin were linked to monoclonal antibodies (mAbs) for site-specific drug delivery. Drug linker 5 consisted of a dipeptide linker attached directly to the daunosamine nitrogen of the n-butyldiacetate doxorubicin derivative 2a. Upon hydrolysis of the peptide linker and acetate groups, the free daunosamine nitrogen is able to form the highly potent 2-pyrrolinodoxorubicin (3a). The second approach involved the use of an oxazolidine carbamate (13) to mask an activating aldehyde group until proteolytic hydrolysis releases 3a. Both drug linkers were shown to be substrates for the lysosomal enzyme cathepsin B. Each molecule was conjugated to the mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) to give potent drug conjugates against renal cell carcinoma and anaplastic large cell lymphoma cell lines, respectively. The activities were immunologically selective, since antigen negative cell lines were much less sensitive to treatment with the drug conjugates. The approaches described here for attaching highly potent doxorubicin derivatives to mAbs are novel and allow for control of drug stability while covalently bound to the delivery agent. [Copyright &y& Elsevier]

A novel series of aminopyrimidine IKK2 inhibitors have been developed which show excellent in vitro inhibition of this enzyme and good selectivity over the IKK1 isoform. The relative potency and selectivity of these compounds has been rationalized using QSAR and structure-based modelling. [Copyright &y& Elsevier]

Abstract: During an effort to search for more potent growth hormone secretagogues, we discovered a class of compounds of which the best compound 8 was 7-fold more active in vitro than the best compound in the series we revealed before [Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng, K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett. 1997, 7, 2319.]. Animal studies show that compound 8 can stimulate growth hormone release at the oral dose as low as 0.06mpk. Chemistry and biological studies are discussed. [Copyright &y& Elsevier]

Mutation or abnormal expression of protein tyrosine kinases (PTKs) is one of the main causes of cancer. Fibroblast growth factor receptors (FGFRs) are a subfamily of tyrosine kinase receptors, which have four subtypes including FGFR1, FGFR2, FGFR3 and FGFR4. Their abnormal expression in cells is considered to be the main cause of tumorigenesis, so inhibiting FGFRs is thought to be important targets for cancer treatment. This article mainly summarizes the recent development of FGFR inhibitors in the past 5 years, and hopes to guide the future research on the design and synthesis of FGFR inhibitors. Image 1 • Cancer is recognized as most serious public health problem, and is considered to be the leading cause of death in the world. • The abnormal expression of fibroblast growth factor receptors (FGFRs) in cells is considered to be the main cause of tumorigenesis. • Inhibiting FGFRs is thought to be important targets for cancer treatment. • Recent development of FGFR inhibitors in the past 5 years has been summarized to guide the future research on the design and synthesis of FGFR inhibitors. [ABSTRACT FROM AUTHOR]

Let R be a ring (not necessarily with identity) and let E denote the set of idempotents of R. We prove that R is a direct sum of a J-ring (every element is a power of itself) and a nil ring if and only if R is strongly π-regular and E is contained in some J-ideal of R. As a direct consequence of this result, the main theorem of [1] follows.