Asian Screening Array and Next-Generation Sequencing Based Panels Applied to Preimplantation Genetic Testing for Monogenic Disorders Preclinical Workup in 294 Families: A Retrospective Analysis.

Objective: Currently, the most commonly used methods for linkage analysis of pre-implantation genetic testing for monogenic disorders (PGT-M) are next generation sequencing (NGS) and SNP array. We aim to investigate whether the application efficacy of Asian screening array (ASA) in PGT-M preclinical workup for the Chinese population is superior to NGS based single nucleotide polymorphism (SNP) panels.

Methods: We conducted a retrospective analysis by reviewing 294 couples from a single center over the past 4 years and compared the detection results between NGS-based SNP panels and ASA.

Preimplantation genetic testing for X-linked chronic granulomatous disease induced by a CYBB gene variant: A case report.

Introduction: X-linked recessive chronic granulomatous disease (XR-CGD) is a severe primary immunodeficiency principally caused by a CYBB (OMIM: 300481) gene variant. Recurrent fatal bacterial or fungal infections are the main clinical manifestations of XR-CGD.

Patient Concerns: In the current case, in vitro fertilization (IVF) associated with preimplantation genetic testing for monogenic disorder (PGT-M) was applied for a Chinese couple who had given birth to a boy with XR-CGD.

Preimplantation genetic testing in couples with balanced chromosome rearrangement: a four-year period real world retrospective cohort study.

Background: Couples with balanced chromosome rearrangement (BCR) are at high risk of recurrent miscarriages or birth defects due to chromosomally abnormal embryos. This study aimed to provide real-world evidence of the euploidy rate of blastocysts from couples with BCR using preimplantation genetic testing (PGT) and to guide pretesting genetic counselling.

Methods: A continuous four-year PGT data from couples with BCR were retrospectively analyzed.

A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation.

The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history.

Case report: Optical genome mapping revealed double rearrangements in a male undergoing preimplantation genetic testing.

Chromosome rearrangement is one of the main causes of abortion. In individuals with double chromosomal rearrangements, the abortion rate and the risk of producing abnormal chromosomal embryos are increased. In our study, preimplantation genetic testing for structural rearrangement (PGT-SR) was performed for a couple because of recurrent abortion and the karyotype of the male was 45, XY der (14; 15)(q10; q10).

Case Report: Preimplantation Genetic Testing for X-Linked Severe Combined Immune Deficiency Caused by Gene Variant.

Preimplantation genetic testing (PGT) has been increasingly used to prevent rare inherited diseases. In this study, we report a case where PGT was used to prevent the transmission of disease-caused variant in a SCID-X1 (OMIM:300400) family. SCID-X1 is an X-linked recessive inherited disease whose major clinical manifestation of immune deficiency is the significant reduction in the number of T-cells and natural killer cells.

Analysis of rare thalassemia genetic variants based on third-generation sequencing.

Thalassemia is a group of common hereditary anemias that cause significant morbidity and mortality worldwide. However, precisely diagnosing thalassemia, especially rare thalassemia variants, is still challenging. Long-range PCR and long-molecule sequencing on the PacBio Sequel II platform utilized in this study could cover the entire HBA1, HBA2 and HBB genes, enabling the diagnosis of most of the common and rare types of thalassemia variants.

Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth.

Methylmalonic acidemia combined with homocysteinemia and cobalamin C type (MMA-CblC, MIM # 277400) is a rare inherited disease with cobalamin metabolic disorder, which are caused by deficiency in the MMACHC gene. A couple with a proband child carried with compound heterozygous mutations of MMACHC (c.609G>A and c.

BRD4 inhibition sensitizes aggressive non-Hodgkin lymphomas to PI3Kδ inhibitors by suppressing PI3K reactivation and c-MYC expression.

Targeting phosphatidylinositol 3-kinase δ (PI3Kδ) is an important therapeutic strategy for indolent non-Hodgkin lymphomas (NHLs). However, we previously observed reactivation of phosphatidylinositol 3-kinase (PI3K) pathways in aggressive NHL cell lines following continuous exposure to PI3Kδ inhibitors (PI3Kδi), which limited their efficacy and suggests that more studies should be focused on this reactivation to improve current PI3Kδi-based treatments. Herein we conducted a drug synergy screening that combined a marketed PI3Kδi, idelalisib, with 14 well-characterized epigenetic drugs across several types of aggressive NHL cell lines.

A novel benzoxazinone derivative YLT-LL-11 inhibits diffuse large B-cell lymphoma growth via inducing cell cycle arrest and apoptosis.

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive B-cell non-Hodgkin's lymphoma (NHL) with high treatment difficulty and high relapse rate. The bromodomain and extra-terminal (BET) proteins play significant roles in supporting the transcription of known DLBCL oncogene MYC, which provides a way for the development of targeted therapeutic agents to address this kind of malignant tumor. Here, we reported a novel benzoxazinone derivative YLT-LL-11 as potential BRD4 inhibitor and further investigated the biological activities against DLBCL.

Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents.

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M.

Repositioning antipsychotic fluphenazine hydrochloride for treating triple negative breast cancer with brain metastases and lung metastases.

Triple negative breast cancer (TNBC) patients have a high risk of brain metastases. This deadly disease represents a major challenge for successful treatment, in part because of the poor ability of drugs to penetrate the blood-brain barrier. Antipsychotic drugs show good bioavailability in the brain, and some of them have exhibited anticancer effects in several cancer types.

Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis.

The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy.

YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect.

Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy.

The antipsychotic agent trifluoperazine hydrochloride suppresses triple-negative breast cancer tumor growth and brain metastasis by inducing G0/G1 arrest and apoptosis.

Women with aggressive triple-negative breast cancer (TNBC) are at high risk of brain metastasis, which has no effective therapeutic option partially due to the poor penetration of drugs across the blood-brain barrier. Trifluoperazine (TFP) is an approved antipsychotic drug with good bioavailability in brain and had shown anticancer effect in several types of cancer. It drives us to investigate its activities to suppress TNBC, especially the brain metastasis.

Author Correction: Structural and functional studies on Pseudomonas aeruginosa DspI: implications for its role in DSF biosynthesis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Structural characterization of a Δ, Δ-enoyl-CoA isomerase from Pseudomonas aeruginosa: implications for its involvement in unsaturated fatty acid metabolism.

Gene PA4980 from Pseudomonas aeruginosa encodes a putative enoyl-coenzyme A hydratase/isomerase that is associated with the function of the biofilm dispersion-inducing signal molecule cis-2-decenoic acid. To elucidate the role of PA4980 in cis-2-decenoic acid biosynthesis, we reported the crystal structure of its protein product at 2.39 Å.

Metabolism of SKLB-TB1001, a Potent Antituberculosis Agent, in Animals.

Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-d-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Here, the metabolites of the new DprE1 inhibitor SKLB-TB1001 and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) were studied.

Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles.

Nitrobenzothiazinone (BTZ) is a promising scaffold with potent activity against by inhibiting decaprenylphosphoryl-beta-d-ribose 2'-oxidase (DprE1). But unfavorable durability poses a challenge to further development of this class of agents. Herein, a series of BTZs bearing a variety of different substituents at the C-2 position were designed and synthesized.

Mechanistic insights into the allosteric regulation of aspartate kinase.

In plants and microorganisms, aspartate kinase (AK) catalyzes an initial commitment step of the aspartate family amino acid biosynthesis. Owing to various structural organizations, AKs from different species show tremendous diversity and complex allosteric controls. We report the crystal structure of AK from (PaAK), a typical α2β2 hetero-tetrameric enzyme, in complex with inhibitory effectors.

A novel benzothiazinethione analogue SKLB-TB1001 displays potent antimycobacterial activities in a series of murine models.

New chemotherapeutic compounds and regimens are needed to combat multidrug-resistant Mycobacterium tuberculosis. Here, we used a series of murine models to assess an antitubercular lead compound SKLB-TB1001. In the Mycobacterium bovis bacillus Calmette-Guérin and the acute M.

Synthesis and biological evaluation of N-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)benzenesulfonamide derivatives as new BET bromodomain inhibitors for anti-hematologic malignancies activities.

The bromodomain and extra-terminal proteins (BETs), in particular BRD4, has been reported to play important roles in cancer, inflammation, obesity, cardiovascular disease, and neurological disorders. In this paper, a series of benzomorpholinone derivatives were synthesized and biologically evaluated as BETs inhibitors. Detailed structure-activity relationship studies led to the discovery of several new potent compounds, of which 15h and 15i displayed [Formula: see text] values of 2.