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OBJECTIVE:: To determine whether intestinal colonization with methicillin-resistant Staphylococcus aureus (MRSA) can be the source of surgical site infections (SSIs). BACKGROUND:: We hypothesized that gut-derived MRSA may cause SSIs via mechanisms in which circulating immune cells scavenge MRSA from the gut, home to surgical wounds, and cause infection (Trojan Horse Hypothesis). METHODS:: MRSA gut colonization was achieved by disrupting the microbiota with antibiotics, imposing a period of starvation and introducing MRSA via gavage. Next, mice were subjected to a surgical injury (30% hepatectomy) and rectus muscle injury and ischemia before skin closure. All wounds were cultured before skin closure. To control for postoperative wound contamination, reiterative experiments were performed in mice in which the closed wound was painted with live MRSA for 2 consecutive postoperative days. To rule out extracellular bacteremia as a cause of wound infection, MRSA was injected intravenously in mice subjected to rectus muscle ischemia and injury. RESULTS:: All wound cultures were negative before skin closure, ruling out intraoperative contamination. Out of 40 mice, 4 (10%) developed visible abscesses. Nine mice (22.5%) had MRSA positive cultures of the rectus muscle without visible abscesses. No SSIs were observed in mice injected intravenously with MRSA. Wounds painted with MRSA after closure did not develop infections. Circulating neutrophils from mice captured by flow cytometry demonstrated MRSA in their cytoplasm. CONCLUSIONS:: Immune cells as Trojan horses carrying gut-derived MRSA may be a plausible mechanism of SSIs in the absence of direct contamination. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Although antiestrogens have been available for breast cancer therapy since the early 1970s, neither their inconsistent anticancer capacity nor the developing antiestrogen resistance of tumors can be fully understood. Although clinical and experimental investigations revealed many tiny details concerning the link between estrogen signaling and tumor development, they yielded fairly controversial findings. Estrogen receptor (ER) overexpression in tumor cells induced by estrogen treatment was erroneously regarded as a promoter of DNA damage, genomic instability, and tumor growth. Similarly, compensatory ER overexpression caused by antiestrogen treatment or estrogen withdrawal was mistakenly evaluated as a key for rapid tumor growth attributed to acquired antiestrogen resistance. Nevertheless, ER upregulation induced by estrogen treatment is a physiologic process even in tumor cells, whereas in the case of antiestrogen administration, it is a contraregulatory action to defend the endangered estrogen signaling. Upregulation of estrogen signaling displays a unique dichotomy, ensuring the survival and safe proliferative activity of healthy cells, while inducing apoptotic death of malignant tumor cells. Analysis of the fairly controversial results justifies that whatever type of available endocrine therapies may be used, including estrogen, antiestrogen treatment, or oophorectomy, an extreme upregulation of ER signaling seems to be the crucial mechanism of successful prevention and treatment for breast cancer. The inconsistent therapeutic effects of antiestrogen administration may be explained by the different genetic capacities of patients for the compensatory upregulation of ER and aromatase enzyme expressions. The weaker the defensive counteraction against the inhibition of estrogen signaling, the poorer is the prognosis of the disease. De novo or acquired antiestrogen resistance of tumors may be associated with the missing capacity of patients for the extreme upregulation of estrogen signaling or with the exhaustion of defensive counteractions in cases that previously showed good reactivity. High-dose estrogen treatment is capable of restoring ER signaling and anticancer capacity even after heavy exposure to antiestrogen therapy. © 2015 Suba.

Suba Z.,The Surgical Center
Drug Design, Development and Therapy | Year: 2015

Currently available scientific evidence erroneously suggests that mutagenic weakness or loss of the BRCA1/2 genes may liberate the proliferative effects of estrogen signaling, which provokes DNA damage and genomic instability. Conversely, BRCA mutation seems to be an imbalanced defect, crudely inhibiting the upregulation of estrogen receptor expression and liganded transcriptional activity, whereas estrogen receptor-repressor functions become predominant. In BRCA-proficient cases, estrogen signaling orchestrates the activity of cell proliferation and differentiation with high safety, while upregulating the expression and DNA-stabilizing impact of BRCA genes. In turn, BRCA proteins promote estrogen signaling by proper estrogen synthesis via CYP19 gene regulation and by induction of the appropriate expression and transcriptional activity of estrogen receptors. In this exquisitely organized regulatory system, the dysfunction of each player may jeopardize genome stability and lead to severe chronic diseases, such as cancer development. Female organs, such as breast, endometrium, and ovary, exhibiting regular cyclic proliferative activity are particularly vulnerable in case of disturbances in either estrogen signaling or BRCA-mediated DNA repair. BRCA mutation carrier women may apparently be healthy or exhibit clinical signs of deficient estrogen signaling in spite of hyperestrogenism. Even women who enjoy sufficient compensatory DNA-defending activities are at risk of tumor development because many endogenous and environmental factors may jeopardize the mechanisms of extreme compensatory processes. Natural estrogens have numerous benefits in tumor prevention and therapy even in BRCA mutation carriers. There are no toxic effects even in sky-high doses and all physiologic cellular functions are strongly upregulated, while malignant tumor cells are recognized and killed in a Janus-faced manner. © 2015 Suba.

We previously demonstrated that pancreatic stellate cells within pancreatic ductal adenocarcinoma (PDAC) stroma secrete lumican and its presence is associated with prolonged survival of patients with localized PDAC. Here, we observed that extracellular lumican decreases PDAC tumour cell growth in xenograft and syngeneic orthotopic animal models, and induces growth inhibition of low-passage human PDAC cells in a species-specific manner. PDAC cells grown in variant culture conditions and exposed to extracellular lumican display typical characterizations of cancer cell in a quiescent state, such as growth inhibition, apoptosis, G0/G1 arrest and chemoresistance. Importantly, extracellular lumican is associated with diminished ERK1/2 phosphorylation and increased p38 phosphorylation within PDAC cells. We further demonstrated that extracellular lumican physically binds with EGFR to trigger EGFR internalization and downregulation of EGFR and its downstream signal molecule ERK. Lumican enhances casitas B-lineage lymphoma expression, which stabilized the TGFβ Type II receptor sensitizing PDAC cells to TGFβ-mediated activation of p38 and SMAD signals. These provide a mechanism for the shift in signalling and phenotypic changes we observed after prolonged exposure to lumican. Together, our findings demonstrate that stromal lumican restrains PDAC cell growth through mediating cell entry into a quiescent state.Oncogene advance online publication, 22 May 2017; doi:10.1038/onc.2017.125. © 2017 Macmillan Publishers Limited, part of Springer Nature.

Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER- breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers - included TNBCs - is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. © 2014 Suba.

Mittra I.,The Surgical Center
Preventive Medicine | Year: 2011

The incidence of breast cancer in developing countries is rapidly on the rise, and cancers are generally detected at advanced stages when a cure is not possible. If advanced cancers could be down-staged by earlier detection, many lives can be saved. However, can a screening program be successfully implemented in these countries? A high level of compliance at every level of a screening program is essential for its success. In the absence of a high level of awareness, compounded by a fatalistic attitude to life, the necessary level compliance may not be achieved. Furthermore, in view of a relatively low incidence, many women will have to be screened to detect a breast cancer; and hence a screening program may not be cost effective. It is not clear which is the best screening test to be employed; although clinical breast examination would seem appropriate, there is currently no randomized evidence that it would lead to mortality reduction. The most reasonable approach to breast cancer control in developing countries would be to provide the minimal level of cancer care that will reduce mortality and suffering, as well as to enlighten the population about the benefits of early detection using innovative approaches. © 2011 Elsevier Inc.

Spotnitz W.D.,The Surgical Center
World journal of surgery | Year: 2010

BACKGROUND: Fibrin sealant is a two-component topical hemostat, sealant, and tissue adhesive consisting of fibrinogen and thrombin that has been used in the United States as a blood bank- or laboratory-derived product since the 1980s and has been commercially available since 1998. METHODS/RESULTS: Initially, surgeons employed hospital-based materials because of the lack of availability of a commercially produced agent. At present, there are five U.S. Food and Drug Administration (FDA)-approved forms including products derived from pooled or autologous human plasma as well as bovine plasma. On-label indications include hemostasis, colonic sealing, and skin graft attachment. Recent clinical and experimental uses include tissue or mesh attachment, fistula closure, lymphatic sealing, adhesion prevention, drug delivery, and tissue engineering. CONCLUSIONS: The modern literature on fibrin sealant now exceeds 3000 articles and continues to expand. This brief review presents the history of this material, its present clinical use, and its future applications.

St. Andre A.,The Surgical Center
Critical Care Medicine | Year: 2015

Leaders of critical care services require knowledge and skills not typically acquired during their medical education and training. Leaders possess personality characteristics and evolve and adopt behaviors and knowledge in addition to those useful in the care of patients and rounding with an ICU team. Successful leaders have impeccable integrity, possess a service mentality, are decisive, and speak the truth consistently and accurately. Effective leaders are thoughtful listeners, introspective, develop a range of relationships, and nurture others. They understand group psychology, observe, analyze assumptions, decide, and improve the system of care and the performance of their team members. A leader learns to facilely adapt to circumstance, generate new ideas, and be a catalyst of change. Those most successful further their education as a leader and learn when and where to seek mentorship. Leaders understand their organization and its operational complexities. Leaders learn to participate and knowledgeably contribute to the fiscal aspects of income, expense, budget, and contracts from an institutional and department perspective. Clinician compensation must be commensurate with expectations and be written to motivate and make clear duties that are clinical and nonclinical. A leader understands and plans to address the evolving challenges facing healthcare, especially resource constraints, the emotions and requirements of managing the end of life, the complexities of competing demands and motivations, the bureaucracy of healthcare practice, and reimbursement. Responsibilities to manage and evolve must be met with intelligence, sensitivity, and equanimity. © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

Burger R.A.,The Surgical Center
Gynecologic Oncology | Year: 2011

Objective: To review the rationale for targeting the vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) pathways for anti-angiogenic therapy in patients with ovarian cancer and to summarize the currently available data with agents that block these pathways. Methods: Relevant papers and studies were identified by searches conducted on Medline using the terms angiogenesis, ovarian cancer, VEGF, PDGF, FGF, receptor, kinase, and inhibitor alone or in combination as well as by searches by drug name and by review of abstracts presented at recent oncology meetings. Results: The VEGF pathway is considered to be the key driver of angiogenesis, but the PDGF and FGF pathways also play important roles and may contribute to resistance to VEGF-specific blockade. Each pathway may also promote tumorigenesis; tumor cell overexpression of these growth factors and their receptors have been detected in ovarian tumor specimens, suggesting that autocrine loops may lead to tumor growth and progression. Selective inhibitors of the VEGF pathway (e.g., bevacizumab and VEGF Trap) as well as VEGF/PDGF pathway inhibitors (e.g., sorafenib and sunitinib) and VEGF/PDGF/FGF pathway inhibitors (e.g., cediranib, pazopanib, and BIBF 1120) have shown single-agent activity in women with ovarian cancer in phase II trials. Response rates of up to 21% have been reported with several agents in patients with recurrent ovarian cancer. Phase III trials with many anti-angiogenic agents in the treatment of ovarian cancer are currently ongoing. Conclusions: Anti-angiogenic agents may provide an improvement in the treatment of patients with recurrent ovarian cancer and may be useful when incorporated into first-line platinum/taxane therapy. It remains to be determined whether multitargeted agents will offer greater clinical benefit than specific VEGF pathway inhibitors. © 2010 Elsevier Inc.

Tool mount adaptors for interfacing a medical instrument with a medical insertion device are provided. The tool mount adaptor includes a collar for holding a medical instrument wherein the tool mount adaptor is releasably attachable to the medical insertion device. Cannula holder assemblies for a medical insertion device are also provided. The cannula holder assembly includes: (a) a cannula track; and (b) a cannula carriage slideably mounted on the cannula track comprising a cannula holder mount and a demobilizer. Medical insertion devices comprising the tool mount adaptors and/or cannula holder assemblies are also provided together with methods of using the medical insertion devices in diagnostic and/or therapeutic applications.

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