What's new in molecular genetic pathology 2022: immune checkpoint inhibitor biomarkers and select solid tumors.

Predictive biomarker testing plays a critical role in targeted immuno-oncology, including the use of immune checkpoint inhibitors (ICI) for various solid tumors. Molecular advancements in cancers of the breast, kidney and brain have continued to propel tumor classification and precision therapy.

What's new in molecular genetic pathology 2021: solid tumors and NGS panel selection.

The linchpin of precision medicine is molecular genetic and genomic testing. Molecular biomarkers are important for establishing precise diagnoses and for predicting therapeutic responses that enable cancer patients to receive personalized and targeted treatment. Below are highlights of the current considerations in next generation sequencing (NGS) panel selection, and in molecular testing of solid tumors of the lung, digestive system, thyroid and soft tissue.

Identification of Antifungal Compounds against Multidrug-Resistant Candida auris Utilizing a High-Throughput Drug-Repurposing Screen.

is an emerging fatal fungal infection that has resulted in several outbreaks in hospitals and care facilities. Current treatment options are limited by the development of drug resistance. Identification of new pharmaceuticals to combat these drug-resistant infections will thus be required to overcome this unmet medical need.

MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis.

The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites.

Preparation and Evaluation of Potent Pentafluorosulfanyl-Substituted Anti-Tuberculosis Compounds.

The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100 nm.

SAR and identification of 2-(quinolin-4-yloxy)acetamides as cytochrome inhibitors.

A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of (Mtb). We report the results of a preliminary structure-activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library, while strains carrying single-nucleotide polymorphisms of the gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase () complex, were resistant to the library.

Learning curve for endobronchial ultrasound‑guided transbronchial needle aspiration: experience of a community‑based teaching hospital.

Endobronchial ultrasound‑guided transbronchial needle aspiration (EBUS‑TBNA) is a minimally invasive procedure. This procedure is useful for nodal staging of lung cancer and evaluating mediastinal lymphoma and granuloma. The present study was a retrospective analysis of our experience when EBUS‑TBNA was initially implemented.

Concomitant Kaposi sarcoma and multicentric Castleman's disease in a heart transplant recipient.

Post-transplant human herpes virus -8 (HHV-8)/Kaposi sarcoma herpes virus (KSHV) infection is associated with neoplastic and non-neoplastic diseases. Kaposi sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphomas (PEL) are the most common HHV-8-associated neoplastic complications described in solid organ transplant (SOT) patients. Concurrent KS and MCD have been previously described after transplantation only twice - once after liver transplantation and once after renal transplantation.

Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.

We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs.

Follow-up of breast papillary lesion on core needle biopsy: experience in African-American population.

Background: The optimal course of clinical follow-up after a diagnosis of breast papillary lesion on a core needle biopsy (CNB) remains elusive. In particular, no reports in literature have addressed this question in African-American population. We describe our experience with breast papillary lesions in a primarily African-American population.

Synthetic lethal screen identifies NF-κB as a target for combination therapy with topotecan for patients with neuroblastoma.

Background: Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma.

Methods: We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan.

The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells.

Brain tumor xenografts initiated from glioblastoma (GBM) CD133(+) tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, γH2AX and 53BP1 foci were quantified in CD133(+) cells and their differentiated (CD133(-)) progeny.

Systematic proteome analysis identifies transcription factor YY1 as a direct target of miR-34a.

MicroRNA 34a (miR-34a) is a potential tumor suppressor gene and has been identified as a miRNA component of the p53 network. To better understand the biological pathways involved in miR-34a action, a parallel global protein and mRNA expression profiling on miR-34a treated neuroblastoma cells (IMR32) was performed using isotope-coded affinity tags (ICAT) and Affymetrix U133plus2 microarray, respectively. Global profiling showed that miR-34a causes much smaller mRNA expression changes compared to changes at the protein level.

TIMP-2 modulates VEGFR-2 phosphorylation and enhances phosphodiesterase activity in endothelial cells.

In this study, we examine the effects of tissue inhibitor of metalloproteinases-2 (TIMP-2) on the phosphorylation status of specific phosphotyrosine residues on the vascular endothelial cell growth factor receptor-2 (VEGFR-2) cytoplasmic tail and examine the effects on associated downstream signaling pathways. To focus on metalloproteinase-independent mechanisms, we used the TIMP-2 analog known as Ala+TIMP-2 that is deficient in matrix metalloproteinase-inhibitory activity. Our experiments are designed to compare the effects of VEGF-A stimulation with or without Ala+TIMP-2 pretreatment, as well as basal responses in human microvascular endothelial cells.

Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y.

Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models.

Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined.

Therapeutic implications of T-cell clonopathy of unknown significance in chronic immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is typically considered an autoimmune disorder related to the production of autoantibodies; however, recent evidence indicates that cell-mediated cytotoxicity may be important pathogenetically in some cases. We describe seven patients with chronic ITP and concurrent T-cell clonopathy of unknown significance (TCUS), who failed various treatment regimens for ITP, including steroids, gamma globulins, splenectomy and rituximab, but had anecdotal success with azathioprine. These observations support the notion that ITP has heterogeneous biologic mechanisms, and that patients with persistent chronic ITP should be evaluated for T-cell clonality and considered for treatment options that are directed against cytotoxic T-cells.

Are clonal T-cell large granular lymphocytes to blame for unexplained haematological abnormalities?

Abnormalities diagnosed on routine blood work, such as mild neutropenia, anaemia, thrombocytopenia and relative lymphocytosis, often have obscure aetiologies. A series of 30 patients were evaluated for various unexplained haematological abnormalities between 1997 and 2005, and found to have circulating monoclonal T-cell large granular lymphocytes (T-LGL). These patients fit the diagnosis of T-cell clonopathy of unknown significance (TCUS), which may represent a clinical spectrum of clonal T-LGL proliferation.

Expression and function of Bapx1 during chick limb development.

The homeobox-containing transcription factor Bapx1 (also known as Nkx3.2) is crucial for development of the axial skeleton and parts of the chondrocranium. Here we describe the detailed expression of Bapx1 during chick limb development and show that in contrast to its expression in the axial skeleton, Bapx1 is expressed after the commitment to chondrogenesis.

B-cell lymphomas with coexpression of CD5 and CD10.

Coexpression of CD5 and CD10 is highly unusual in B-cell lymphomas and may pose a diagnostic challenge. We report 42 cases of B-cell lymphoma with simultaneous expression of CD5 and CD10. They made up approximately 0.

CD30-positive T-cell lymphomas co-expressing CD15: an immunohistochemical analysis.

The characteristic histologic features and immunophenotype are usually diagnostic and allow distinguishing CD30 positive T-cell lymphoma (including anaplastic large cell lymphoma) from classical Hodgkin's lymphoma. The latter differs by expression of CD15 and lack of CD45, pan-T antigens and ALK expression. We report nine cases of large cell hematopoietic neoplasms in which the neoplastic cells co-expressed CD30 and CD15, and had immunophenotypic and morphologic features of T-cell lymphoproliferative process.