Androgen Receptor Expression Associates With Distinctive Clinicopathological and Molecular Features in ER-Positive and ER-Negative Breast Cancer

Background: Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression of breast cancer remains unclear. Methods: In this study, we analyzed the clinicopathological and molecular features associated AR loss in ER-positive and ER-negative breast cancer respectively, trying to elucidate the molecular correlation between AR and ER. Results: Our results showed that AR loss was associated with different clinicopathological characteristics in ER-positive and ER-negative breast cancer. Moreover, the expression of AR was correlated with different molecular features in ER-positive and ER-negative breast cancer.Conclusions: These results suggest that the role of AR in ER-positive breast cancer is distinctive from that in ER-negative breast cancer.

Androgen Receptor Expression Associates With Distinctive Clinicopathological and Molecular Features in ER-Positive and ER-Negative Breast Cancer

Background Androgen receptor (AR) expression is frequently observed in breast cancer, but its association with estrogen receptor (ER) expression of breast cancer remains unclear. Methods In this study, we analyzed the clinicopathological and molecular features associated AR loss in ER-positive and ER-negative breast cancer respectively, trying to elucidate the molecular correlation between AR and ER. Results Our results showed that AR loss was associated with different clinicopathological characteristics in ER-positive and ER-negative breast cancer. Moreover, the expression of AR was correlated with different molecular features in ER-positive and ER-negative breast cancer. Conclusions These results suggest that the role of AR in ER-positive breast cancer is distinctive from that in ER-negative breast cancer.

Metabolic profiling of cytotoxic metabolites from five Tabebuia species supported by molecular correlation analysis

Tabebuia is the largest genus among the family Bignoniaceae. Tabebuia species are known for their high ornamental and curative value. Here, the cytotoxic potential of extracts from the leaves and stems of five Tabebuia species was analyzed. The highest activity was observed for T. rosea (Bertol.) DC. stem extract against HepG2 cell line (IC50 4.7 µg/mL), T. pallida L. stem extract against MCF-7 cell line (IC50 6.3 µg/mL), and T. pulcherrima stem extract against CACO2 cell line (IC50 2.6 µg/mL). Metabolic profiling of the ten extracts using liquid chromatography–high-resolution mass spectrometry for dereplication purposes led to annotation of forty compounds belonging to different chemical classes. Among the annotated compounds, irridoids represent the major class. Principle component analysis (PCA) was applied to test the similarity and variability among the tested species and the score plot showed similar chemical profiling between the leaves and stems of both T. pulcherrima and T. pallida L. and unique chemical profiling among T. rosea (Bertol.) DC., T. argentea Britton, and T. guayacan (Seem.) Hemsl. leaf extracts and the stem extract of T. rosea (Bertol.) DC. Additionally, a molecular correlation analysis was used to annotate the bioactive cytotoxic metabolites in the extracts and correlate between their chemical and biological profiles.

Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements

An azole antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections related to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of ketoconazole are thoroughly studied by chemical shift anisotropy tensor and site-specific spin-lattice relaxation time measurements. The molecular correlation time at crystallographically different carbon sites is calculated by considering that the spin-lattice relaxation mechanism for the 13C nucleus is mainly governed by chemical shift anisotropy interaction and hetero-nuclear dipole-dipole coupling. The CSA parameters at the crystallographically distinct sites of ketoconazole are determined by two-dimensional phase adjusted spinning sideband (2D PASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment. The site-specific spin-lattice relaxation time is measured by the Torchia CP experiment. The spin-lattice relaxation rate is slow for all the carbon nuclei sites except C2, C3, C4, C5, and C26 carbon nuclei reside on the piperazine ring and the methyl group. It suggests the close-pack arrangement of the molecule due to π-π stacking interaction. The molecular correlation time of all the carbon atoms reside on the benzene ring, 1,3-dioxolane ring, imidazole ring, and the 2,4-dichlorobenzene ring is of the order of 10-4 s, while it is of the order of 10-7 s for carbon atoms reside on the piperazine ring. The CSA parameters of the carbon nuclei on the piperazine ring (C2, C3, C4, C5), and the methyl group (C26) are very low compared to other carbon nuclei. The CSA parameters are very high for carbon nuclei reside on the benzene ring, imidazole ring, and the 2,4-dichlorobenzene ring due to the presence of π-electrons. A huge variation of the spin-lattice relaxation time and the molecular correlation time are observed for numerous carbon nuclei situated on the side-chain of ketoconazole. The spin-lattice relaxation time varies from 500 s to 8 s, and the molecular correlation time varies in the range of 10-4s to 10-7s. These types of investigations portrayed the correlation between the structure and dynamics of the antifungal drug ketoconazole, which will help to develop the advanced antifungal drugs. Additionally, the CSA information of the drug molecules will be immensely useful for NMR crystallography.

A Solid-State NMR Study of the Antibacterial Drug Cefpodoxime Proxetil

The structure-activity relationship of various molecular moieties of cefpodoxime proxetil is described by measuring Chemical shift anisotropy (CSA) tensor, spin-lattice relaxation time and molecular correlation time at twenty one crystallographically different carbon nuclei sites. Cefpodoxime proxetil molecule is associated with three rings, the aminothiazole ring, β-lactam ring, and the dihydrothiazine ring, which provide stability to the drug molecule towards β-lactamases and increase the affinity of the drug to PBPs receptors. A large variation of CSA parameters and motional degrees of freedom are observed among carbon nuclei reside on these three rings, which implies that the electronic environment, molecular conformation, and molecular dynamics are altered substantially within the ring. The substitution at the C7 position of the β-lactam ring (like acyl side chain, oxime group, and aminothiazole ring) is responsible for semi-synthetic incorporation. It also influences the antibacterial activity and the binding affinity of the drug with β-lactamase. A huge variation of the spin-lattice relaxation time and molecular correlation time is observed in this region. These types of description of the structure-activity relationship of the antibacterial drug cefpodoxime proxetil will be beneficial for developing the advanced antibacterial drugs, and it will also be useful in NMR crystallography.

Gastroblastoma: Cytologic Findings with Resection and Molecular Correlation

Casestudy Gastroblastoma is a rare tumor with biphasic components showing epithelial and mesenchymal differentiation. To date, <15 cases have been reported, with molecular confirmation of the recently identified MALAT1-GLI1 translocations only in a subset. Aspiration cytologic and small biopsy findings have not yet been reported. We present a case of gastroblastoma, arising in a 22-year-old female. Results A CT scan was performed, showing a 7 cm heterogeneous mass in the distal stomach and pancreas, clinically suspected to represent at gastrointestinal stromal tumor (GIST). She underwent two preoperative samples, including endoscopic ultrasound guided-fine needle aspiration and core biopsy, followed by a distal gastrectomy. Diff- Quik stained touch preparations performed on the core needle biopsy during rapid on-site evaluation showed a hypercellular neoplasm composed of large, three-dimensional aggregates of neoplastic cells in a background of numerous isolated single cells and bare nuclei. The neoplastic cells were bland with spindled to epithelioid nuclei, occasional nuclear grooves, and small nucleoli. Immunostains were only helpful in excluding GIST (CD117 and DOG1 negative). Distal gastrectomy showed a nodular/plexiform tumor with variably epithelioid to spindle cell cytology and solid to focally myxoid/microcystic architecture. Pancytokeratins CAM5.2 (patchy) and AE1/AE3 (very focal) were positive, with negative S100, SMA, Desmin, Melan-A, Inhibin, Calretinin, and Synaptophysin. Based on the age, location, histology and immunophenotype, gastroblastoma was suspected, and multiplex NGS-based fusion sequencing identified a MALAT1-GLI1 fusion. Staging studies were negative for metastasis at presentation. Conclusion Based on this experience, we recommend consideration of gastroblastoma for a gastric tumor in a young patient, especially if encountering a cytologic sample showing non-pleomorphic epithelioid and spindle cell cytology. Lack of expression of GIST, smooth muscle, neuroendocrine, and neural sheath-associated markers should particularly raise consideration of this rare neoplasm. While in this case molecular studies clinched the diagnosis upon resection, increasingly used GLI1 immunostain may be of use prospectively for diagnosis of limited samples.

Molecular Correlation between Larval, Deutonymph and Adult Stages of the Water Mite Arrenurus (Micruracarus) Novus

The systematics of many groups of organisms has been based on the adult stage. Morphological transformations that occur during development from the embryonic to the adult stage make it difficult (or impossible) to identify a juvenile (larval) stage in some species. Hydrachnidia (Acari, Actinotrichida, which inhabit mainly continental waters) are characterized by three main active stages—larval, deutonymph and adult—with intermediate dormant stages. Deutonymphs and adults may be identified through diagnostic morphological characters. Larvae that have not been tracked directly from a gravid female are difficult to identify to the species level. In this work, we compared the morphology of five water mite larvae and obtained the molecular sequences of that found on a pupa of the common mosquito Culex (Culex) pipiens with the sequences of 51 adults diagnosed as Arrenurus species and identified the undescribed larvae as Arrenurus (Micruracarus) novus. Further corroborating this finding, adult A. novus was found thriving in the same mosquito habitat. We established the identity of adult and deutonymph A. novus by morphology and by correlating COI and cytB sequences of the water mites at the larval, deutonymph and adult (both male and female) life stages in a particular case of ‘reverse taxonomy’. In addition, we constructed the Arrenuridae phylogeny based on mitochondrial DNA, which supports the idea that three Arrenurus subgenera are ‘natural’: Arrenurus, Megaluracarus and Micruracarus, and the somewhat arbitrary distinction of the species assigned to the subgenus Truncaturus.

Bridging the treatment gap in infant medulloblastoma: molecularly informed outcomes of a globally feasible regimen

Background Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. Methods In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. Results Twenty-nine children (range, 0.3–4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551–0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHβ, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633–1) and SHHβ having a PFS of 0.56 (95% CI: 0.42–1). Group 3 had a PFS of 0.50 (95% CI: 0.25–1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. Conclusions We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.