Orbital swelling as a first symptom in breast carcinoma diagnosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>The frequency of intra-orbital metastasis in systemic cancer is a controversial topic. Of all metastatic tumors to the orbit of the eye, breast carcinoma is considered to be the most prevalent. Orbital findings typically present themselves after the diagnosis of the primary tumor, with an average delay of three to six years. In spite of that, this study reports a case in which orbital manifestation was the initial symptom in breast carcinoma diagnosis.</p> <p>Case presentation</p> <p>A 66-year-old Italian Caucasian woman presented with a swelling located on the lower orbit of her right eye.</p> <p>Conclusions</p> <p>Previous cases report orbital manifestations discovered secondary to breast cancer. This case demonstrates that orbital symptoms may be the primary presentation of the disease. Orbital metastasis originating from breast cancer predicts widespread metastatic disease in other organs. In the presence of an ambiguous infiltrative orbital process, diagnostic examination of the breast is recommended.</p

3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis

Initiation of protein-primed (-) strand DNA synthesis in hepatitis B virus (HBV) requires interaction of the viral reverse transcriptase with epsilon (ε), a cis-acting regulatory signal located at the 5’ terminus of pre-genomic RNA (pgRNA), and several host-encoded chaperone proteins. Binding of the viral polymerase (P protein) to ε is necessary for pgRNA encapsidation and synthesis of a short primer covalently attached to its terminal domain. Although we identified small molecules that recognize HBV ε RNA, these failed to inhibit protein-primed DNA synthesis. However, since initiation of HBV (-) strand DNA synthesis occurs within a complex of viral and host components (e.g., Hsp90, DDX3 and APOBEC3G), we considered an alternative therapeutic strategy of allosteric inhibition by disrupting the initiation complex or modifying its topology. To this end, we show here that 3,7-dihydroxytropolones (3,7-dHTs) can inhibit HBV protein-primed DNA synthesis. Since DNA polymerase activity of a ribonuclease (RNase H)-deficient HBV reverse transcriptase that otherwise retains DNA polymerase function is also abrogated, this eliminates direct involvement of RNase (ribonuclease) H activity of HBV reverse transcriptase and supports the notion that the HBV initiation complex might be therapeutically targeted. Modeling studies also provide a rationale for preferential activity of 3,7-dHTs over structurally related α-hydroxytropolones (α-HTs)

A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules

Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small-molecule–protein interactions

A Collective Variable for the Rapid Exploration of Protein Druggability

An efficient molecular simulation methodology has been developed for the evaluation of the druggability (ligandability) of a protein. Previously proposed techniques were designed to assess the druggability of crystallographic structures and cannot be tightly coupled to molecular dynamics (MD) simulations. By contrast, the present approach, JEDI (<u>J</u>ust <u>E</u>xploring <u>D</u>ruggability at protein <u>I</u>nterfaces), features a druggability potential made of a combination of empirical descriptors that can be collected “on-the-fly” during MD simulations. Extensive validation studies indicate that JEDI analyses discriminate druggable and nondruggable protein binding site conformations with accuracy similar to alternative methodologies, and at a fraction of the computational cost. Since the JEDI function is continuous and differentiable, the druggability potential can be used as collective variable to rapidly detect cryptic druggable binding sites in proteins with a variety of MD free energy methods. Protocols for applications to flexible docking problems are outlined

Breast cancer surgery during the COVID-19 pandemic: An observational clinical study of the breast surgery clinic at ospedale policlinico san martino - Genoa, Italy

Background: COVID-19 pandemic required a marked re-allocation of healthcare resources, including at Breast Units. A patient-tailored program was developed to assess its efficacy regarding prevention of COVID-19 infection among patients with breast cancer undergoing surgery and healthcare workers (HCWs). Patients and Methods: From March 9th to April 9th 2020, 91 patients were selected for elective surgery by means of: i) Prehospital screening aimed at avoiding hospitalization of symptomatic or suspicious COVID-19 patients, and ii) prioritisation of surgical procedure according to specific disease features. Results: Eighty-five patients (93.4%) were fit for surgery, while five patients (5.5%) were temporarily excluded through 'telephone triage'; another two patients were excluded at in-hospital triage. A total of 71 out of 85 patients (83.5%) were diagnosed with invasive cancer, most of whom were undergoing breast-conserving surgery (61 out of 85 patients, 71.8%). The mean in-hospital stay was 2.2 days (SD=0.7 days). After hospital discharge, no patient needed re-admission due to post-operative complications; moreover, no COVID-19 infection among patients or HCWs was detected. Conclusion: Safe breast cancer surgery was accomplished for both patients and HCWs by means of a careful preoperative selection of patients and in-hospital preventative measures. This screening program can be transferred to high-volume Breast Units and it may be useful in implementing European Community recommendations for prevention of COVID-19 infection

Development and validation of RVFV antiviral screen.

A. Identification of optimal mAb for the detection of RVFV by mAb staining of a serial dilution of RVFV strain MP-12 in an FFA. B. Impact of cell number on the sensitivity of antiviral compound screen. C. Evaluation of the sensitivity of the antiviral compound screen based upon the evaluation of ribavirin and β-D-N4-Hydroxycytidine N4-Hydroxycytidine (NHC/EIDD-1931), a known antiviral for RVFV. Data is presented as focus forming units. These data are the cumulation of three independent experiments with technical duplicates.</p

Primary screening data.

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Antiviral effect of compounds on bunyavirus replication.

Vero cells were infected with either RVFV ZH501 (A) or LACV (B) then treated with decreasing concentrations of antiviral compound. Viral growth was measured by FFA. Data represents three independent experiments completed with biological replicates. Error bars represent standard deviation.</p

Experimental methods for compound generation and validation of compounds.

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EC₅₀ against LACV and ZIKV replication.

EC50 against LACV and ZIKV replication.</p