Polymorphisms of CARD9 Gene Predict Disease Progression and Renal Survival of Immunoglobulin A Nephropathy.

INTRODUCTION: A previous genome-wide association study has identified CARD9 (caspase recruitment domain family member 9) as a susceptibility gene for immunoglobulin A nephropathy (IgAN), which encodes an adapter protein and is related to mucosal immunity. This study aimed to investigate the association of CARD9 variants with the clinicopathological phenotypes and prognosis of IgAN. METHODS: Eight single nucleotide polymorphisms within CARD9 were genotyped using Sequenom MassARRAY iPLEX for 986 IgAN patients in this study. Logistic and linear regression analyses adjusted for age and gender were performed to evaluate the effects of CARD9 gene polymorphisms on clinicopathological phenotypes. The Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival. RESULTS: The T allele of rs10747047 was strongly associated with higher levels of serum creatinine (p = 0.005) and lower levels of estimated glomerular filtration rate (p = 0.005). The rs10870149-G and rs10870077-C alleles were associated with elevated 24-h urine protein excretion (p = 0.041 and 0.022, respectively) and more serious segmental glomerulosclerosis lesions (p = 0.005 and 0.041, respectively) in IgAN patients. Carriers with the T allele of rs10781533 and the C allele of rs3812552 also presented with severe segmental glomerulosclerosis lesions (p = 0.001 and 0.010, respectively). Additionally, rs10747047-C and rs10870077-C alleles were independently related to the poor prognosis of IgAN patients after adjustments for covariates (TT vs. CC hazard ratio [HR] = 0.138, 95% confidence interval [95% CI] = 0.022-0.871, p = 0.035; GG vs. CC HR = 0.321, 95% CI = 0.123, 0.836, p = 0.020, respectively). CONCLUSION: CARD9 variants are associated with disease severity and rapid disease progression for IgAN in a Chinese Han population.

Discovery of a novel 2-spiroproline steroid mimetic scaffold for the potent inhibition of 11ß-HSD1.

11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues, resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with a variety of ailments including metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a 3-point pharmacophore for 11ß-HSD1 that was utilized to design a 2-spiroproline derivative as a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of several leads, such as compounds 39 and 51. Importantly, deleterious hERG inhibition and pregnane X receptor induction were mitigated by the introduction of a 4-hydroxyl group to the proline ring system.

Discovery of 1'-(1-phenylcyclopropane-carbonyl)-3H-spiro[isobenzofuran-1,3'-pyrrolidin]-3-one as a novel steroid mimetic scaffold for the potent and tissue-specific inhibition of 11ß-HSD1 using a scaffold-hopping approach.

11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) has been identified as the primary enzyme responsible for the activation of hepatic cortisone to cortisol in specific peripheral tissues resulting in the concomitant antagonism of insulin action within these tissues. Dysregulation of 11ß-HSD1, particularly in adipose tissues, has been associated with metabolic syndrome and type 2 diabetes mellitus. Therefore, inhibition of 11ß-HSD1 with a small nonsteroidal molecule is therapeutically desirable. Implementation of a scaffold-hopping approach revealed a three-point pharmacophore for 11ß-HSD1 that was utilized to design a steroid mimetic scaffold. Reiterative optimization provided valuable insight into the bioactive conformation of our novel scaffold and led to the discovery of INCB13739. Clinical evaluation of INCB13739 confirmed for the first time that tissue-specific inhibition of 11ß-HSD1 in patients with type 2 diabetes mellitus was efficacious in controlling glucose levels and reducing cardiovascular risk factors.

Assessment of ecotoxicity of spent fluid catalytic cracking (FCC) refinery catalysts on Raphidocelis subcapitata and predictive models for toxicity.

The 17 spent fluid catalytic cracking refinery catalysts (SFCCCs) from different petroleum refineries were collected and the leachates of SFCCCs were prepared. The ecotoxicity of SFCCC leachates to Raphidocelis subcapitata was assayed. The results showed that the toxicity of the 17 SFCCCs differ greatly. Ji SFCCC was the most toxic to R. subcapitata with a 96 h EC50 value of 1.38%, while Ha SFCCC was the least toxic, with the EC50 value was >100%. The relationships between the toxicity of SFCCCs and the metal concentrations in leachates were analyzed. The concentration of Ni (p = 0.001), La (p = 0.001), Mn (p = 0.014), Ce (p = 0.017), Co (p = 0.018), and Ca (p = 0.031) in leachates showed significant correlation with EC50 values. The predictive model for the ecotoxicity of SFCCCs were established with the concentrations of Ni and La in leachates as: ln(EC50) = 0.817 + exp(1.356 - 1.736 × CNi - 0.262 × CLa) (R2 = 0.926). The main toxic ingredients of SFCCC to microalgae were identified for the first time in this work. The results and predictive model of this study are significance for toxicity determination and management of SFCCCs.

[Expert consensus on Tongsaimai Tablets/Capsules in treatment of peripheral vascular diseases in clinical practice].

Tongsaimai Tablets/Capsules are composed of Lonicerae Japonicae Flos, Angelicae Sinensis Radix, Achyranthis Bidentatae Radix, Codonopsis Radix, Dendrobii Caulis, Astragali Radix, Scrophulariae Radix, and Glycyrrhizae Radix et Rhizoma, and are effective in promoting blood circulation, removing blood stasis, supplementing Qi, and nourishing Yin. It is widely used in the treatment of peripheral vascular diseases. With 40 years of clinical application, it has accumulated substantial research data and application experience. Its good clinical efficacy and pharmacoeconomic benefits in improving the clinical symptoms of peripheral vascular diseases have been confirmed by relevant research. Meanwhile, this drug has also been recommended by many expert consensus, guidelines, and teaching materials, serving as one of the most commonly used Chinese patent medicines in clinical practice. To further improve the understanding of the drug among clinicians and properly guide its clinical medication, the China Association of Chinese Medicine took the lead and organized experts to jointly formulate this expert consensus. Based on the questionnaire survey of clinicians and the systematic review of research literature on Tongsaimai Tablets/Capsules with clinical problems in the PICO framework, the consensus, combined with expert experience, concludes recommendations or consensus suggestions by GRADE system with the optimal evidence available through the nominal group technique. This consensus defines the indications, usage, dosage, course of treatment, medication time, combined medication, and precautions of Tongsaimai Tablets/Capsules in the treatment of peripheral vascular diseases, and explains the safety of its clinical application. It is recommended for clinicians and pharmacists in the peripheral vascular department(vascular surgery), traditional Chinese medicine surgery(general surgery), and endocrinology department of hospitals at all levels in China.

Tea consumption is associated with cognitive impairment in older Chinese adults.

OBJECTIVE: To explore the association between tea consumption and cognitive impairment (CoI). METHODS: 4579 adults (≥60 years) from the Weitang Geratric Diseases Study were assessed for characteristics of tea consumption and cognitive function by administering questionnaires and the Abbreviated Mental Test (AMT), respectively. We divided the subjects into normal cognitive function group (AMT score ≥8) and CoI group (AMT score ≤7).   The association between tea consumption and risk of CoI was determined by logistic regression models. RESULTS: The least-squared means of the AMT scores for the subjects who seldom consumed tea were less favorable than those who habitually consumed tea. An inverse association was found between tea consumption (of any type) and prevalence of CoI (odds ratio = 0.74, 95% confidence interval = 0.57-0.98, P = 0.032). Interestingly, the protective correlation of tea was more obvious in never smokers (odds ratio = 0.63), but vanished in current/former smokers (odds ratio = 1.10). In never smokers, frequency of tea consumption was significantly associated with CoI (P for trend = 0.010). CONCLUSION: Habitual tea consumption is suggested to be associated with a decreased risk of CoI among elders in Suzhou, and a higher frequency of tea consumption was associated with a lower prevalence of CoI among never smokers.

New Iridoid Glycosides with Antidepressant Activity Isolated from Cyperus rotundus.

Based on bioactive screening results, two new iridoid glycosides, named rotunduside G (1) and rotunduside H (2), were isolated from the rhizomes of Cyperus rotundus, together with four known ones, negundoside (3), nishindaside (4), isooleuropein (5) and neonuezhenide (6). Their structures were elucidated on the basis of spectroscopic methods and from literature values. In mice models of despair, 1 and 2 showed significant antidepressant activity.

Effect of jet airflow deflection on cleaning performance of filter cartridge.

Pleated cartridge filters are widely used to remove dust in industrial processes. However, pulse-jet cleaning is not uniform on the filter cartridges. The phenomenon of pulsed jet airflow deflection exists during pulse jet cleaning, which causes a large impact on the local area of filter cartridge and shortens the service life of the filter cartridge. But perhaps due to the lack of effective testing methods, the impact of pulsed jet deflection on dust cleaning is often ignored. Under more comprehensive conditions, such as jet pressures, jet distance, and jet-hole diameter, the influence of the pulsed jet airflow deflection on the cleaning performance of the filter cartridge has been discussed systematically, by testing the peak static pressure on the side wall of the filter cartridge. The experimental results show that the sidewall peak static pressure of the face-flow surface of the filter cartridge is greater than that of the back-flow surface due to deflection, and the difference between the two is proportional to the jet-hole diameter and jet pressure. After installing the diversion nozzle, the results show that the peak static pressures of the face-flow and back-flow surfaces are basically the same. Therefore, it is proved that the diversion nozzle can effectively correct the jet airflow deflection.

Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2.

Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-ß superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease. Thus, selective inhibition of ALK2 has emerged as a promising strategy for the treatment of multiple disorders. Herein, we report the discovery of a novel pyrazolopyrimidines series as highly potent, selective, and orally bioavailable inhibitors of ALK2. Structure-based drug design and systematic structure-activity relationship studies were employed to identify potent inhibitors displaying high selectivity against other ALK subtypes with good pharmacokinetic profiles.

The relationship between peak pressure and parameters of pulse-jet cleaning in a sintered plastic filter.

Sintered plastic filters are recently favored in industrial filtration systems because of their advantage of high filtration precision and long service life. In order to embody experimental characterization of pulse-jet cleaning of sintered plastic filters, tests were concluded on a self-made pulse-jet cleaning experimental platform. The cleaning characteristics of sintered plastic filters were investigated with varied pulse-jet parameters of tank pressure, nozzle diameter, and jet distance (the distance between nozzle and filter opening). The relationship between pressure distribution and pulse-jet cleaning parameters was established. The results showed that peak positive pressure on the corresponding sintered plastic filter inner wall increased with the increasing tank pressure. With the increasing jet distance, peak pressure first increased, then decreased, and with the increasing nozzle diameter, the optimum jet distance decreased gradually. At the optimum jet distance, the peak pressure with a nozzle diameter of 6 mm was the best, which was confirmed through the jet flow photographed by schlieren. The mathematical model obtained by curve fitting was s = (d - a)/2tan0.37275d2-1.33545d+35.950052. These results indicated that there was a direct relationship between the peak pressure and the parameters of pulse-jet cleaning in a sintered plastic filter. It provided theoretical support and application foundation for industrial dust-cleaning design.Implications: Sintered plastic filter is a new generation of high efficiency dust collector. Generally, its characteristics can be divided into three major categories as follows. 1) In terms of materials, the sintered plastic filter is made of PE substrate and coated with PTFE membrane, which makes it have stable chemical properties and can be used in high humidity, high oil, and other special situations. 2) In terms of dust cleaning, sintered plastic filter has high dust-cleaning efficiency of ultra-fine dust because of the unique membrane, which is not only limited to the surface of the filter plate, but also penetrates into the interior of the interstice. 3) In terms of structure, the sintered plastic filter is a rigid wavy porous structure filter of nine cavities formed by special sintering process of polymer material. This filter elements of integrated rigid design make its physical structure strong, not easy to deform and damage, and with a longer service life than traditional filters (bag filters and pleated fabric filter cartridges). In order to embody experimental characterization of pulse-jet cleaning of sintered plastic filters, tests were concluded on a self-made pulse-jet cleaning experimental platform described in this article. The cleaning characteristics of sintered plastic filters were investigated with varied pulse-jet parameters of tank pressure, nozzle diameter, and jet distance (the distance between nozzle and filter opening). The relationship between pressure distribution and pulse-jet cleaning parameters was established. These results indicated that there was a direct relationship between the peak pressure and the parameters of pulse-jet cleaning in a sintered plastic filter. It provided theoretical support and application foundation for industrial dust-cleaning design.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound 38 (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles. Pemigatinib has received accelerated approval from the U.S. Food and Drug Administration for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. Additional clinical trials are ongoing to evaluate pemigatinib in patients with FGFR alterations.

Interference from familiar natural distractors is not eliminated by high perceptual load.

A crucial prediction of perceptual load theory is that high perceptual load can eliminate interference from distractors. However, Lavie et al. (Psychol Sci 14:510-515, 2003) found that high perceptual load did not eliminate interference when the distractor was a face. The current experiments examined the interaction between familiarity and perceptual load in modulating interference in a name search task. The data reveal that high perceptual load eliminated the interference effect for unfamiliar distractors that were faces or objects, but did not eliminate the interference for familiar distractors that were faces or objects. Based on these results, we proposed that the processing of familiar and natural stimuli may be immune to the effect of perceptual load.

N'-[(1E)-1-(3,5-Dichloro-2-hy-droxy-phen-yl)propyl-idene]-4-meth-oxy-benzohydrazide monohydrate.

The title compound, C(17)H(16)Cl(2)N(2)O(3)·H(2)O, displays a trans conformation with respect to the C=N double bond. The dihedral angle between the two benzene rings is 30.77 (5)° and there is one intra-molecular N-H⋯O hydrogen bond. In the crystal, mol-ecules are linked by hydrogen bonding to the water molecules of crystallization, which acts as both an acceptor and a donor, into a three-dimensional network.

N'-[(E)-1-(3,5-Dichloro-2-hy-droxy-phen-yl)ethyl-idene]-4-meth-oxy-benzo-hydrazide monohydrate.

The title compound, C(16)H(14)Cl(2)N(2)O(3)·H(2)O, displays a trans conformation with respect to the C=N double bond. The dihedral angle between the two benzene rings is 4.98 (12)°. Intra-molecular O-H⋯N and O-H⋯O hydrogen bonds occur. The crystal structure is stabilized by inter-molecular O-H⋯O and N-H⋯O hydrogen bonds. In addition, there are π-π inter-actions between the chemically distinct benzene rings of inversion-related mol-ecules [centroid-centroid separation = 3.715 (1) Å].

A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity.

TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage-mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. In vivo, the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4+ and CD8+ T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient-derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.

Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition.

A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.

INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ).

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations.

A series of beta-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, -2, -3, and -9. This was achieved by exploiting subtle differences within the otherwise highly conserved S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.

Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.

Discovery of a potent, selective, and orally active human epidermal growth factor receptor-2 sheddase inhibitor for the treatment of cancer.

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.