Observation of binding and polymerization of Fur repressor onto operator-containing DNA with electron and atomic force microscopes.

The Fur (ferric uptake regulation) protein is a global regulator that, in the presence of Fe2+, represses the expression of a number of iron-acquisition genes and virulence determinants such as toxins. Dark-field electron microscopy of positively stained Fur-DNA complexes in addition to atomic force microscopy allowed direct visualization of Fur interactions with the regulatory regions of aerobactin and hemolysin operons and provided complementary information about the structure of the complexes. According to the DNA used and the protein/DNA ratio, Fur binding to DNA results in partial or total covering of the fragments, indicating that the protein initiates polymerization along the DNA molecules at specific sites. Negative staining of Fur-DNA complexes revealed a well-ordered structure of the polymer suggesting a helical arrangement. Local rigidification of the DNA molecules resulting from Fur binding could be involved in the repression process.     

Case report: HIV negative isolated scrotal Kaposi's sarcoma

INTRODUCTION

Kaposi''s sarcoma (KS) is a rare angioproliferative disorder of the vascular endothelium. The development of KS requires Human Herpes Virus 8 (HHV-8) infection. An associated HIV infection is usually seen. Isolated scrotal KS has rarely been reported. In this article, we present a case of KS that primarily involved the scrotum in a HIV negative patient.

PRESENTATION OF CASE

A 71-year old male patient admitted to the outpatient department due to nodular lesions on the scrotum. The patient declared that these lesions were present for nearly 5 years. Past medical history revealed that he underwent left thoracotomy and upper lobectomy in 2006 for adenosquamous lung carcinoma. Then, he received a single cycle of adjuvant chemotherapy consisted of docetaxel and cisplatin. Physical examination revealed 3 black small nodules on the scrotum. The anti-HIV test was negative. All scrotal lesions were surgically excised. The pathological investigation revealed KS of the lymphangioma-like type.

DISCUSSION

The pathogenesis of KS has still not been clearly elucidated. However, it is known that all forms of KS are associated with HHV-8 infections. A defect in immune system was almost always necessary. Therefore, KS is usually associated with HIV infection. KS of the penis has been reported in HIV negative patients. Very few cases of scrotal KS have been presented. In a recent review, only 1 patient had scrotal KS out of 32 cases with HIV negative KS. In our case, the patient received a cycle of chemotherapy that might affect his immune system. The lymphangioma-like type is a common morphological sub-type. While lymph edemas are commonly observed in this sub-type, no edema in the lymphs was present in our case.

CONCLUSION

Classical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients.     

Using economics alongside clinical trials: Why we cannot choose the evaluation technique in advance

When drafting protocols for the use of economic evaluation alongside clinical trials, it is common to have to specify which type of economic evaluation is going to be carried out. Will it be a cost-benefit analysis (CBA), cost-effectiveness analysis (CEA) or a cost-utility analysis (CUA)? It is our contention that prior specification of the appropriate economic technique is not possible, in the majority of cases, until data on effectiveness and cost are actually available. In this letter, we aim to demonstrate the thinking behind our contention and to illustrate this with two case studies; one of a recent randomised trial, the other of a trial currently in progress.     

Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempt to computationally screen for possible medications for COVID-19 via rapidly estimating the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twenty-seven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.

Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV-2 Mpro can be promising inhibitors.     

Benefit of continuous positive airway pressure on work quality in patients with severe obstructive sleep apnea

Sleep and Breathing - The objective of this prospective study was to assess the effect of CPAP therapy on job productivity and work quality for patients with severe obstructive sleep apnea (OSA). A...     

Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication

Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8⁺ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.     

Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria

Summary  Mitochondria and peroxisomes are ubiquitous subcellular organelles, which fulfil an indispensable role in the cellular metabolism of higher eukaryotes. Moreover, they are highly dynamic and display large plasticity. There is growing evidence now that both organelles exhibit a closer interrelationship than previously appreciated. This connection includes metabolic cooperations and cross-talk, a novel putative mitochondria-to-peroxisome vesicular trafficking pathway, as well as an overlap in key components of their fission machinery. Thus, peroxisomal alterations in metabolism, biogenesis, dynamics and proliferation can potentially influence mitochondrial functions, and vice versa. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interrelationship with a particular emphasis on organelle dynamics and its implication in diseases. Competing interests: None declared Presented at the Annual Symposium of the SSIEM, Lisbon, Portugal, 2–5 September 2008     

Performance-Based Contracts and Provider Efficiency

This paper examines the form of performance-based contract which is relatively new to healthcare systems. Economic theories on contracting are reviewed to provide theoretical support for potential impacts of performance-based contracting (PBC) on improving efficiency of the healthcare system. Implementation issues of PBC in healthcare practice are briefly discussed with examples in the literature reviewed. In addition, various economic incentives of PBC on provider behaviour are discussed, including its primary intended incentive on improving system efficiency, as well as incentives of risk selection on patients, improved matching between providers and patients, and gaming on reporting. In summary, with a simple and economically valid idea of ‘rewarding good performance’ behind it, PBC is a potentially powerful contracting tool that could improve accountability, introduce competition, and improve the efficiency of healthcare resource allocation. In practice, PBC has been implemented and tested in various settings. Some preliminary evidence suggests that the implementation of incentive regulation such as PBC could increase healthcare outputs including access, quantity and effectiveness as well as reduce costs of care. However, it also introduces complicated incentives on providers which makes the evaluation of the effect of PBC on healthcare systems a challenging task, both theoretically and empirically. Furthermore, there are various practical issues, such as measurement of performance, which remain unsolved and make the implementation of PBC controversial. In the meantime, development of PBC in healthcare systems should remain cautious. More research on outcome evaluation and treatment effectiveness is needed to establish the link between financial incentives and healthcare outcomes.