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Abstract Here we used cryo-electron microscopy (cryo-EM), double electron-electron resonance spectroscopy (DEER), and molecular dynamics (MD) simulations, to capture and characterize ATP- and substrate-bound inward-facing (IF) and occluded (OC) conformational states of the heterodimeric ATP binding cassette (ABC) multidrug exporter BmrCD in lipid nanodiscs. Supported by DEER analysis, the structures reveal that ATP-powered isomerization entails changes in the relative symmetry of the BmrC and BmrD subunits that propagates from the transmembrane domain to the nucleotide binding domain. The structures uncover asymmetric substrate and Mg2+ binding which we hypothesize are required for triggering ATP hydrolysis preferentially in one of the nucleotide-binding sites. MD simulations demonstrate that multiple lipid molecules differentially bind the IF versus the OC conformation thus establishing that lipid interactions modulate BmrCD energy landscape. Our findings are framed in a model that highlights the role of asymmetric conformations in the ATP-coupled transport with general implications to the mechanism of ABC transporters.

Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Background: Pancreatic neuroendocrine neoplasms (NENs) are tumors with histopathologic and prognostic heterogeneity that pose difficulties in establishing standards for diagnosis, classification, and treatment. Among NENs, well-differentiated neuroendocrine tumors (NETs) have been classified as grade 1, 2, and 3 in the most recently released World Health Organization classification. Although well-differentiated NETs are associated with relatively better prognosis, they have a potential for malignant behavior such as extrapancreatic spread, metastasis, or recurrence. The present study aimed to evaluate clinical and histomorphologic findings of patients with well-differentiated pancreatic NETs and to identify histopathologic findings effective in predicting nodal metastatic progression., Methods: The study group consisted of 54 patients diagnosed with well-differentiated NET. All preparations and blocks of the patients were examined for the following histopathologic parameters: tumor diameter, microscopic tumor growth pattern (solid, trabecular, acinar, and mixed), cellular features (clear, eosinophilic, oncocytic, peliotic, and pseudopapillary), stromal changes (calcification, lymphocytic infiltration, and stromal hyalinization), presence of necrosis, perineural invasion, lymphovascular invasion, mitotic activity, and Ki67 proliferative index., Results: Lymph node metastasis was present in 7 patients. Lymph node metastasis was significantly associated with tumor diameter of >2 cm ( p = 0.012), Ki67 proliferative index of >20% ( p = 0.022), grade 3 tumors ( p = 0.002), presence of dense stromal hyalinization ( p = 0.034), and mild lymphocytic infiltration ( p = 0.041)., Conclusion: The present study revealed that the new findings such as presence of dense stromal hyalinization and absence of remarkable lymphocytic infiltration could be predictive morphologic findings for the development of lymph node metastasis.

Introduction: Sclerosing adenosis is a form of adenosis characterized by lobulocentric architecture, glandular and stromal proliferation in which the stromal component compresses and distorts the glandular structures. Atypical epithelial proliferations such as atypical lobular hyperplasia, lobular carcinoma in situ, and ductal carcinoma in situ may accompany areas of sclerosing adenosis. We present a case of ductal carcinoma in situ and sclerosing adenosis with metastatic carcinoma on sentinel lymph node., Case Description: A 40-year-old woman presented with a palpable mass in her left breast. Radiologic studies showed a lesion suggesting malignancy in the left breast and atypical lymph node in the left axillary region. Left lumpectomy and sentinel lymph node biopsy was performed. Histopathologic examination revealed lobulocentric lesions with glandular proliferation and hyalinizing stroma in between. Foci of high-grade cribriform and solid type ductal carcinoma in situ were observed. Sentinel lymph node biopsy showed micrometastasis in one lymph node section. Based on these findings, the patient was diagnosed with high-grade ductal carcinoma in situ with sclerosing adenosis. However, the presence of micrometastasis in the lymph node suggested occult invasion that we were not able to detect., Conclusion: Ductal carcinoma in situ with sclerosing adenosis can mimic invasive carcinoma both radiologically and histologically. It should be kept in mind that there may be occult invasive carcinoma in patients with ductal carcinoma in situ whether the lesion is accompanied by sclerosing adenosis or not. Multiple sections and immunohistochemical studies can be of help.

Objective: Phyllodes tumors are biphasic tumors consisting of epithelial and stromal components that account for less than 1% of all breast tumors. According to the World Health Organization (WHO) phyllodes tumors are classified into three categories as benign, borderline and malignant. It has been reported that these tumors are usually benign and both the stromal component and the epithelial component may progress to malignancy. In this descriptive study, it was aimed to present the cases of phyllodes tumor and to evaluate the clinicopathological features of these tumors in the light of the literature., Materials and Methods: In our study, 55 cases of phyllodes tumor diagnosed between 2005-2018 in the Department of Medical Pathology were retrospectively studied. A total of 55 cases were included in the study., Results: All cases were female with a mean age of 39.7+15.2 years. Fifty-seven tumors diagnosed in 55 cases were classed as benign in 20 cases (35.1%), borderline in 14 cases (24.6%) and malignant phyllodes tumors in 23 cases (40.3%). Ductal carcinoma in situ (solid and cribriform type) were detected in one case with malignant phyllodes tumor, whereas invasive ductal carcinoma was detected in one case. Bilateral ductal carcinoma in situ was present in the patient with invasive ductal carcinoma., Conclusion: These tumors which rapidly grow into large masses can be clinically and pathologically confused with benign lesions, macroscopic and microscopic evaluation of concomitant in situ-invasive carcinomas should be considered. Phyllodes tumors have an important role in breast surgery and pathology., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2020 Turkish Federation of Breast Diseases Associations.)

We report a new correlated phase of two-dimensional charged carriers in high magnetic fields, manifested by an anisotropic insulating behavior at low temperatures. It appears in a large range of low Landau level fillings 1/3≲ν≲2/3 in hole systems confined to wide GaAs quantum wells when the sample is tilted in magnetic field to an intermediate angle. The parallel field component (B_{∥}) leads to a crossing of the lowest two Landau levels, and an elongated hole wave function in the direction of B_{∥}. Under these conditions, the in-plane resistance exhibits an insulating behavior, with the resistance along B_{∥} about 10 times smaller than the resistance perpendicular to B_{∥}. We interpret this anisotropic insulating phase as a two-component, striped Wigner crystal.

We observe geometric resonance features of composite fermions on the flanks of the even-denominator ν=1/2 fractional quantum Hall state in high-mobility two-dimensional electron and hole systems confined to wide GaAs quantum wells and subjected to a weak, strain-induced, unidirectional periodic potential modulation. The features provide a measure of how close to ν=1/2 the system stays single-component and supports a composite fermion Fermi sea before transitioning into a ν=1/2 fractional quantum Hall state, presumably, the two-component Ψ331 state.

In two-dimensional electron systems confined to GaAs quantum wells, as a function of either tilting the sample in a magnetic field or increasing density, we observe multiple spin-polarization transitions of the fractional quantum Hall states at filling factors ν=4/5 and 5/7. The number of observed transitions provides evidence that these are fractional quantum Hall states of interacting two-flux composite fermions. Moreover, the fact that the reentrant integer quantum Hall effect near ν=4/5 always develops following the transition to full spin polarization of the ν=4/5 fractional quantum Hall state links the reentrant phase to a pinned ferromagnetic Wigner crystal of composite fermions.

We observe the fractional quantum Hall effect (FQHE) at the even-denominator Landau level filling factor ν=1/2 in two-dimensional hole systems confined to GaAs quantum wells of width 30 to 50 nm and having bilayerlike charge distributions. The ν=1/2 FQHE is stable when the charge distribution is symmetric and only in a range of intermediate densities, qualitatively similar to what is seen in two-dimensional electron systems confined to approximately twice wider GaAs quantum wells. Despite the complexity of the hole Landau level structure, originating from the coexistence and mixing of the heavy- and light-hole states, we find the hole ν=1/2 FQHE to be consistent with a two-component, Halperin-Laughlin (Ψ331) state.