Chemical constituents from Amentotaxus yunnanensis and Torreyayunnanensis

In a chemical study of taxonomically related Taxaceae plants of Yunnan Province, China, seven compounds, including a new amentoflavone biflavonoid, 2,3-dihydro-7,7' '-dimethoxyamentoflavone (1), were isolated from Amentotaxus yunnanensis, and 12 isolates were obtained from Torreya yunnanensis. From the latter plant, a new abietane diterpene, torreyayunnin (7), is reported for the first time. The known isolates from A. yunnanensis have been identified as sequoiaflavone (3), sotetsuflavone (4), 7,7' '-dimethoxyamentoflavone (5), lutein, beta-sitosterol, and sequoyitol. Amentoflavone (2), sotetsuflavone (4), sciadopitysin (6), 12-hydroxydehydroabietinol, meridinol, balanophonin, (+)-pinoresinol monomethyl ether, (+)-pinoresinol monomethyl ether glucoside, erythro-1-(4-hydroxy-3-methoxyphenyl)-2-[4-[2-formyl-(E)-vinyl]-2- methoxyphenoxy]propane-1,3-diol, threo-1-(4-hydroxy-3-methoxyphenyl)-2- [4-[2-formyl-(E)-vinyl]-2-methoxyphenoxy] propane-1,3-diol, and (E)-2-butenedioic acid were identified as known isolates from T. yunnanensis. The presence of the amentoflavone biflavonoids (1, 3-5) in A. yunnanensis supports its placement in the Taxaceae. The occurrence of the biflavonoid sotetsuflavone (4) in both A. yunnanensis and T. yunnanensis suggests that these two genera are closely related. The identification and structural elucidation of these isolates were based on spectral data analysis including 1D and 2D NMR.     

A review of Kallmann syndrome: genetics, pathophysiology, and clinical management

Kallmann syndrome is a genetic disorder with the hallmarks of anosmia and hypogonadotrophic hypogonadism. It has a male preponderance. With the elucidation of the genetic pathways involved, affected females and inheritance patterns are becoming more clearly identified. It is an eminently treatable disorder, but it must first be recognized by the physician. With treatment, favorable reproductive outcomes can be attained in addition to maturation of secondary sex characteristics.     

A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.     

Preclinical Safety and Pharmacology of Hematide™, a Peptidic Erythropoiesis Stimulating Agent (ESA), in Rats and Monkeys

The pharmacology, toxicokinetics, and safety of Hematide^TM, a synthetic peptidic erythropoiesis-stimulating agent (ESA), were characterized. Hematide was given intravenously (0, 0.5, 5, and 50 mg/kg) weekly for five weeks with a 6- (rat) and 12-week (monkey) recovery period. The pharmacological action of Hematide resulted in polycythemia. Histopathology consistent with drug-induced exaggerated pharmacology was observed primarily in rats. Secondary sequelae resulting from pronounced polycythemia was considered the cause of deaths in rats and a single high-dose monkey. Toxicokinetic analysis indicated prolonged exposure. In conclusion, Hematide is a potent ESA and the safety and efficacy profile support clinical development.     

Endometrial evaluation with transvaginal US and hysterosonography in asymptomatic postmenopausal women with breast cancer receiving tamoxifen

PURPOSE: To determine performance characteristics of transvaginal ultrasonography (US) and hysterosonography for diagnosing endometrial abnormality in asymptomatic postmenopausal women with breast cancer receiving tamoxifen. MATERIALS AND METHODS: The authors prospectively examined 138 women receiving tamoxifen by using transvaginal US, hysterosonography, and office hysteroscopy. The combined hysteroscopic-histopathologic diagnosis was the reference standard. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios of transvaginal US and hysterosonography were calculated. RESULTS: All 138 women underwent transvaginal US; 104, successful hysterosonography; and 117, successful hysteroscopy. Uterine abnormality was present in 47 (40.2%) of 117 women: 45 with polyps and two with submucosal fibroids. Receiver operating characteristic curve analysis revealed 6 mm to be the optimal endometrial thickness cutoff for diagnosing endometrial abnormalities. When a thickness greater than 6 mm or a focal endometrial finding was considered abnormal, transvaginal US had a sensitivity of 85.1% and a specificity of 55.7%. In 92 women who completed transvaginal US, hysterosonography, and hysteroscopy, hysterosonography was more specific (79.2%; P =.008) but not significantly more sensitive (89.7%; P =.508) than transvaginal US. When women with abnormal transvaginal US findings were further examined with hysterosonography, the sequential combination of transvaginal US and hysterosonography was more specific (77.1%) than transvaginal US alone (P <.001), without a significant decrease in sensitivity (78.7%; P =.25). CONCLUSION: In asymptomatic postmenopausal women receiving tamoxifen, 6 mm is the optimal endometrial thickness cutoff for diagnosing endometrial abnormalities with transvaginal US. Further examination with hysterosonography can improve specificity by reducing the high false-positive rate of transvaginal US.     

Isolation of the human insulin-like growth factor genes: insulin-like growth factor II and insulin genes are contiguous.

Overlapping recombinant clones that encompass the insulin-like growth factor (IGF) I and II genes have been isolated from a human genomic DNA library. Each gene is present once per haploid genome; the IGF-I gene spans greater than 35 kilobase pairs (kbp) and the IGF-II gene is at least 15 kbp. The exon-intron organization of these genes is similar, each having four exons, which is one more than the related insulin gene. Comparison of the restriction endonuclease cleavage maps of the IGF-II and insulin genes, including their flanking regions and hybridization with an IGF-II cDNA probe, revealed that they are adjacent to one another. The IGF-II and insulin genes have the same polarity and are separated by 12.6 kbp of intergenic DNA that includes a dispersed middle repetitive Alu sequence. The order of the genes is 5'-insulin-IGF-II-3'.