Proteomic Analyses of the Effects of Drugs of Abuse on Monocyte-Derived Mature Dendritic Cells

Drug abuse has become a global health concern. Understanding how drug abuse modulates the immune system and how the immune system responds to pathogens associated with drug abuse, such hepatitis C virus (HCV) and human immunodeficiency virus (HIV-1), can be assessed by an integrated approach comparing proteomic analyses and quantitation of gene expression. Two-dimensional (2D) difference gel electrophoresis was used to determine the molecular mechanisms underlying the proteomic changes that alter normal biological processes when monocyte-derived mature dendritic cells were treated with cocaine or methamphetamine. Both drugs differentially regulated the expression of several functional classes of proteins including those that modulate apoptosis, protein folding, protein kinase activity, and metabolism and proteins that function as intracellular signal transduction molecules. Proteomic data were validated using a combination of quantitative, real-time PCR and Western blot analyses. These studies will help to identify the molecular mechanisms, including the expression of several functionally important classes of proteins that have emerged as potential mediators of pathogenesis. These proteins may predispose immunocompetent cells, including dendritic cells, to infection with viruses such as HCV and HIV-1, which are associated with drug abuse.     

Osteopontin: a marker for invasive oral squamous cell carcinoma but not for potentially malignant epithelial dysplasias

This study aimed to evaluate and correlate osteopontin (OPN) expression in oral squamous cell carcinoma (OSCC) and potentially malignant disorders including oral leukoplakia and oral submucous fibrosis (OSMF). Expression of OPN was investigated in 140 samples including OSCC, oral leukoplakia, and OSMF with or without dysplasia and normal oral mucosa. By using immunohistochemistry. Both intercellular and intracellular staining of the keratinocytes was considered to be positive, and intensity grading was assessed. Statistical analysis was done using analysis of variance. OPN positivity was detected in 85% cases of OSCC, 55% cases of oral leukoplakia, 35% cases of OSMF, and 60% cases of normal mucosa. These study highlights OPN as a biomarker for malignancy in the form of invasion but not to study progression from dysplasia to malignant transformation.     

Association of Helicobacter pylori with oral potentially malignant disorders and oral squamous cell carcinoma—a systematic review and meta-analysis

Objective

To assess any potential association between Helicobacter pylori and oral squamous cell carcinoma/oral potentially malignant disorders.

Materials and methods

Data mining was done using PubMed, Cochrane Library, and SCOPUS databases. The search included articles published up to May 2019. Newcastle-Ottawa scale was used to score the quality of the included articles. Data including the type of study, the sample population, the type of oral lesion, and the resulting statistical data were extracted.

Results

Out of 131 screened articles, only 15 articles fulfilled the eligibility criteria. Among the 15 studies, 9 focused on oral squamous cell carcinoma and 6 focused on oral potentially malignant disorders. Eight out of the 9 oral squamous cell carcinoma studies were included in the meta-analysis. Forest plot was generated using the odds ratio and confidence intervals calculated for each of the included studies. Due to the lack of sufficient studies, the meta-analysis was not performed for oral potentially malignant disorders.

Conclusion

Due to the contradictory results of the included studies, it was not possible to make any conclusive statement on the potential association of H. pylori with oral squamous cell carcinoma. The variations in the methodology, especially the differences in the sensitivity/specificity of the diagnostic modalities could be the cause for differential results.

Clinical relevance

Although the association of H. pylori with oral squamous cell carcinoma could not be confirmed, it is vital to reduce the excess oral microbial load, especially in patients exhibiting oral mucosal changes with no history of associated risk factors.

     

种植盾构术的研究进展

上前牙美学区在拔牙或即刻种植后,唇侧骨板因拔牙创伤或者血运降低,常发生唇侧牙槽骨的吸收塌陷,从而极大的影响前牙区的美学效果,甚至造成种植体的失败。为了避免唇侧软硬组织的吸收,获得更好的美学效果,近年来有学者提出了"盾构术"的概念,即在即刻种植手术中通过保留唇侧健康牙根片来保留牙周膜,从而避免唇侧骨板因为血运的减少而发生吸收。本文回顾了盾构术的相关文章,能帮助口腔临床医生更加全面的理解该技术。     

Internal target volume for post-hysterectomy vaginal recurrences of cervical cancers during image-guided radiotherapy

Objective:

The outcome of post-surgical recurrences of cervical cancer may be improved through radiation dose escalation, which hinges on accurate identification and treatment of the target. The present study quantifies target motion during course of image-guided radiotherapy (IGRT) for vault cancers.

Methods:

All patients underwent planning CT simulation after bladder-filling protocol. A daily pre-treatment megavoltage CT was performed. All translations and rotations were recorded. Post-registration displacement of gross tumour volume (GTV) and centre of mass (COM) of GTV was independently recorded by two observers for fractions one to seven. Day 1 image sets served as reference images against which the displacements of COM were measured. We calculated the displacements of common volume (CV) and encompassing volume (EV) of GTV for both the observers.

Results:

A total of 90 image data sets of 15 patients were available for evaluation. Individual patient GTV and average GTV by both the observers were comparable. The average shifts for EV were 2.4 mm [standard deviation (SD) ±1.2] in the mediolateral, 4.2 mm (SD ±2.8) in the anteroposterior and 4.0 mm (SD ±2.1) in superoinferior directions. Similarly, the average shifts for CV were 1.9 mm (SD ±0.6) in the mediolateral, 3.7 mm (SD ±2.7) in the anteroposterior and 4.4 mm (SD ±2.7) in superoinferior directions. Using Stroom''s/van Herk''s formula, the minimum recommended margins would be 4.5/5.2, 8.2/9.4 and 7.3/8.3 mm, respectively, for lateral, anteroposterior and superoinferior directions.

Conclusion:

Differential directional internal margin is recommended in patients undergoing IGRT for post-surgical recurrence of cervical cancers.

Advances in knowledge:

Internal organ motion of vault cancers can be accounted for by a directional margin to the gross tumour.     

Circumspect descent prevails in solving random constraint satisfaction problems

We study the performance of stochastic local search algorithms for random instances of the K-satisfiability (K-SAT) problem. We present a stochastic local search algorithm, ChainSAT, which moves in the energy landscape of a problem instance by never going upwards in energy. ChainSAT is a focused algorithm in the sense that it focuses on variables occurring in unsatisfied clauses. We show by extensive numerical investigations that ChainSAT and other focused algorithms solve large K-SAT instances almost surely in linear time, up to high clause-to-variable ratios alpha; for example, for K = 4 we observe linear-time performance well beyond the recently postulated clustering and condensation transitions in the solution space. The performance of ChainSAT is a surprise given that by design the algorithm gets trapped into the first local energy minimum it encounters, yet no such minima are encountered. We also study the geometry of the solution space as accessed by stochastic local search algorithms.     

Allosteric switch regulates protein–protein binding through collective motion

Many biological processes depend on allosteric communication between different parts of a protein, but the role of internal protein motion in propagating signals through the structure remains largely unknown. Through an experimental and computational analysis of the ground state dynamics in ubiquitin, we identify a collective global motion that is specifically linked to a conformational switch distant from the binding interface. This allosteric coupling is also present in crystal structures and is found to facilitate multispecificity, particularly binding to the ubiquitin-specific protease (USP) family of deubiquitinases. The collective motion that enables this allosteric communication does not affect binding through localized changes but, instead, depends on expansion and contraction of the entire protein domain. The characterization of these collective motions represents a promising avenue for finding and manipulating allosteric networks.Intermolecular interactions are one of the key mechanisms by which proteins mediate their biological functions. For many proteins, these interactions are enhanced or suppressed by allosteric networks that couple distant regions together (1). The mechanisms by which these networks function are just starting to be understood (2–4), and many of the important details have yet to be uncovered. In particular, the role of intrinsic protein motion and kinetics remains particularly poorly characterized. A number of structural ensembles representing ubiquitin motion have been recently proposed (5–9). Additionally, it has been suggested that through motion at the binding interface, its free state visits the same conformations found in complex with its many binding partners (5, 10). However, it remains an unanswered question if the dynamics that enable this multispecificity are only clustered around the canonical binding interface or whether this motion is allosterically coupled to the rest of the protein, especially given the presence of motion at distal sites (11).     

Secondary rifampin resistance following multi-drug therapy--a case report

This is the first report of secondary resistance to rifampin following MDT in a patient with prolonged, but irregular treatment. Repeated mouse foot-pad studies demonstrated resistance to dapsone after several years of monotherapy, and following subsequent MDT the studies demonstrated the development of resistance to rifampin.