The Role of MicroRNA in Staphylococcal Enterotoxin B-Induced Inflammation and Acute Lung Injury

Staphylococcal enterotoxin B (SEB) is a potent activator of the Vβ8+T-cells leading to the proliferation of nearly 30% of the T-cell pool. As a consequence, excessive amounts of cytokine mediators are released leading to extensive tissue damage and sometimes toxic shock and death. Due to the ease with which SEB can be aerosolized anddisseminated, it is considered a biological weapon. In the current study, we investigated the pro-inflammatory effects of SEB in two mouse models of acute inflammatory lung injury. Specifically, while inflammatory cues are known to elicit changes in key transcriptional factors and gene expression, we explored for the first time, the role of microRNA following SEB exposure. We found that C57BL/6 mice exposed to a single dose (50 μg/mouse) of SEB demonstrated symptoms of pulmonary inflammation characterized by cellular infiltration, histopathological damage and the release of copious amounts of IFN-γ. Upon conducting microRNA microarray analysis and applying cutting-edge bioinformatics analysis, we identified the overexpression of miR-155 and the subsequent repression of its target gene Socs1 following SEB exposure. Further, through the use of miR-155-/- mice, we demonstrated the critical role for SEB-induced miR-155 in mediating damage. In a more severe model of acute inflammatory lung injury, C3H/HeJ mice were exposed to two smaller quantities (2 μg and 5μg/ mouse) of SEB given two hours apart. As a result, mice succumb to vascular leak, excessive cellular infiltration and exaggerated cytokine and chemokine release. Pulmonary damage is associated with the dysregulation of several miRNA. Those miRNA that were overexpressed were found to target key regulators of inflammation and those that were underexpressed allowed for the expression of pro-inflammatory genes demonstrating that several SEB-inducing miRNA act in concert to orchestrate inflammation. Therapeutic strategies to combat inhalation exposure to SEB are either lacking in their efficacy or with regards to acute inflammatory lung injury, limited to supportive care. As a result, we investigated the role of the marijuana cannabinoid- Delta-9-Tetrahydrocannabinol(THC), a known anti-inflammatory agent in the treatment of SEB-triggered inflammation. Interestingly, C3H/HeJ that succumbed to SEB toxicity, were completely protected by THC treatment. Upon investigation of the anti-inflammatory nature of THC, we demonstrated for the first time the ability of THC to modulate a prominent inflammatory miRNA cluster (miR-17-92) involved in activation of the PI3K/AKT signaling pathway THC, by acting as an inhibitor of this pathway, via the downregulation of the cluster, induces T-regulatory cells, reduces cellular proliferation and decreases IFN-γ production. Taken together, our studies highlight the importance of miRNA in SEB-induced inflammatory damage. Moreover, we provide further insight into the anti-inflammatory properties of THC and emphasize its potential as a powerful therapeutic agent

A Comparative Analysis of Biomarker Expression and Molecular Subtypes of Pure Ductal Carcinoma In Situ and Invasive Breast Carcinoma by Image Analysis: Relationship of the Subtypes with Histologic Grade, Ki67, p53 Overexpression, and DNA Ploidy

There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS). We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs) by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors

Bootcamp During Neoadjuvant Chemotherapy for Breast Cancer: A Randomized Pilot Trial

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Influence of Surgical Technique on Mastectomy and Reexcision Rates in Breast-Conserving Therapy for Cancer

Introduction. Breast conserving surgery (BCS) requires tumor excision with negative margins. Reexcision rates of 30–50% are reported. Ultrasound localization, intraoperative margin pathology, and specimen mammography have reduced reexcisions, but require new equipment. Cavity shave margin (CSM) is a technique, utilizing existing equipment, that potentially reduces reexcision. This study evaluates CSM reexcision impact. Methods. 522 cancers treated with BCS were reviewed. Patients underwent standard partial mastectomy (SPM) or CSM. Data collected included demographics, pathology, and treatments. Results. 455 SPMs were compared to 67 CSMs. Analysis revealed no differences in pathology, intraductal component, or neoadjuvant chemotherapy. Overall reexcision rate = 43%. Most reexcisions were performed for DCIS at margin. SPMs underwent 213 reexcisions (46.8%), versus 16/67 (23.9%) CSMs (P = 0.0003). Total mastectomy as definitive procedure was performed after more SPMs (P = 0.009). Multivariate analysis revealed CSM, % DCIS, tumor size, and race to influence reexcisions. Conclusions. CSM is a technique that reduces reexcisions and mastectomy rates

Prediction of post-operative necrosis after mastectomy: A pilot study utilizing optical diffusion imaging spectroscopy

<p>Abstract</p> <p>Introduction</p> <p>Flap necrosis and epidermolysis occurs in 18-30% of all mastectomies. Complications may be prevented by intra-operative detection of ischemia. Currently, no technique enables quantitative valuation of mastectomy skin perfusion. Optical Diffusion Imaging Spectroscopy (ViOptix T.Ox Tissue Oximeter) measures the ratio of oxyhemoglobin to deoxyhemoglobin over a 1 × 1 cm area to obtain a non-invasive measurement of perfusion (StO₂).</p> <p>Methods</p> <p>This study evaluates the ability of ViOptix T.Ox Tissue Oximeter to predict mastectomy flap necrosis. StO₂measurements were taken at five points before and at completion of dissection in 10 patients. Data collected included: demographics, tumor size, flap length/thickness, co-morbidities, procedure length, and wound complications.</p> <p>Results</p> <p>One patient experienced mastectomy skin flap necrosis. Five patients underwent immediate reconstruction, including the patient with necrosis. Statistically significant factors contributing to necrosis included reduction in medial flap StO₂(p = 0.0189), reduction in inferior flap StO₂(p = 0.003), and flap length (p = 0.009).</p> <p>Conclusion</p> <p>StO₂reductions may be utilized to identify impaired perfusion in mastectomy skin flaps.</p

Axillary lymph node dissection for breast cancer utilizing Harmonic Focus®

<p>Abstract</p> <p>Background</p> <p>For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus^®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus^®will decrease operative time and reduce post-operative complications.</p> <p>Methods</p> <p>Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study.</p> <p>Results</p> <p>Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups.</p> <p>Conclusion</p> <p>In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.</p

Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical. Therefore decreasing the variability, especially in a multicenter clinical trial setting, and establishing a minimum standard to ensure consistency in clinical trial data, without mandating axillary lymph node dissection, for all patients is necessary. The key elements which include proper staging and identification of nodal involvement at diagnosis, and appropriately targeted management of the axilla at the time of surgical resection are presented. The following protocols have been adopted as standard procedure by the I-SPY2 trial for management of axilla in patients with node positive disease, and present a framework for prospective clinical trials and practice

Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

[This corrects the article DOI: 10.1038/s41523-018-0074-6.]