Early breast cancer: concept and therapeutic review.

OBJECTIVE: Breast cancer treatment has evolved significantly over the years, both in terms of local and systemic approaches. Halsted's radical mastectomy gave way to modified mastectomies and to conservative surgeries, along with breast reconstruction and repair. Although the use of new drugs has directly increased the survival of patients submitted to adjuvant or neoadjuvant systemic therapies, the de-escalation of drugs may also be beneficial in numerous cases. Therefore, breast cancer treatment must be increasingly customized and assessed using a multidisciplinary approach. This study aimed to review the concept and therapy of early breast cancer. METHODS: A narrative review of the literature was carried out in the PubMed database in December 2022, where the keywords for the searches were as follows: early breast cancer, surgical treatment of breast cancer, systemic treatment of breast cancer, neoadjuvant chemotherapy in breast cancer, adjuvant treatment of luminal breast cancer, early triple negative tumor, and early positive Her-2 tumor. Articles that were historically important in the treatment of breast cancer and articles that impacted management with scientific relevance were selected for this review. DISCUSSION: As new evidence continues to update existing knowledge, breast cancer treatment is becoming increasingly personalized and must now take into account the different tumor variants and their clinical stages, the age of patients and relevant comorbidities, as well as personal expectations and desires. CONCLUSION: This literature review of current studies shows that the primary therapy for patients with early breast cancer continues to be surgery, although a customized and multidisciplinary approach is now required.

How well are Brazilian mastologists (breast surgeons) trained in breast reconstruction and oncoplastic surgery? A study of the impact of a breast reconstruction and oncoplastic surgery improvement course.

Introduction: The breasts are a female symbol, impacts self-image and self-esteem. Breast reconstructive and oncoplastic surgeries have an important role in minimizing injuries. In Brazil less than a third of public health system (SUS) users have access to immediate reconstructive surgery. The low rate of breast reconstructions has multiple causes and the deficiency in availability and surgeons' technical qualification play a role. In 2010, the Breast Reconstruction and Oncoplastic Surgery Improvement Course was created by professors of the Mastology Department of Santa Casa de São Paulo and State University of Campinas (UNICAMP). The objectives of this study were to evaluate the impact of the techniques learned on patients' management by the surgeons enrolled in the Course, as well as to characterize their profile. Methods: All students enrolled in the Improvement Course between 2010 and 2018 were invited to answer an online questionnaire. Students who did not agree to answer the questionnaire or answered them incompletely were excluded. Results: Total students included: 59. The mean age: 48.9 years, male (72%) with more than 5 years of Mastology practice (82.2%), from all regions of Brazil, 1.7% from the North, 33.9% from the Northeast, 44.1% from the Southeast, and 12% from the South. Most of the students considered they had little or no knowledge of breast reconstruction (74.6%) and 91,5% did not consider they had enough aptitude to perform breast reconstructions after finishing residency. After the Course, 96.6% considered themselves apt to perform such surgeries. Over 90% of the students considered the Course had impacted their practice and changed their surgical strategy view. Before the Course, 84.8% of the students stated that less than half of their patients who were operated on for breast cancer had breast reconstruction, compared to 30.5% after the Course. Conclusion: The Breast Reconstruction and Oncoplastic Surgery Improvement Course studied here positively impacted the mastologists' management of patients. New training centers worldwide can help a lot of women with breast cancer.

Dermoglandular advancement-rotation flap for conservative treatment of breast cancer - description of technique, objective and subjective assessments.

Objective: to describe and evaluate the dermoglandular advancement-rotation flap with no contralateral surgery as a technique for the conservative treatment of breast cancer when skin or a large proportion of gland requires resection. Patients/Methods: 14 patients with breast tumors with a mean size of 4.2 cm and need for skin resection. The resection area is included within an isosceles triangle, with its apex located on the areola, which is the pivot for rotation of a dermoglandular flap released through a lateral extension along that triangle base. Symmetry before and after radiotherapy was objectively assessed by authors using the BCCT.core software, as well as subjectively by three experts and patients themselves using the Harvard scale. Results: Experts considered the breast symmetry results to be excellent/good for 85.7% of patients in the early post-operative period and 78.6% in the late post-operative period. Excellent/good ratings provided by BCCT.core software amounted to 78.6% of cases in the early post-operative period and 92.9% in the late post-operative period. Symmetry was rated as excellent/good by 100% of patients. Conclusion: Dermoglandular advancement-rotation flap technique with no contralateral surgery provides good symmetry when a large proportion of skin or gland requires resection on breast conservative cancer treatment.

Early breast cancer: concept and therapeutic review

SUMMARY OBJECTIVE: Breast cancer treatment has evolved significantly over the years, both in terms of local and systemic approaches. Halsted's radical mastectomy gave way to modified mastectomies and to conservative surgeries, along with breast reconstruction and repair. Although the use of new drugs has directly increased the survival of patients submitted to adjuvant or neoadjuvant systemic therapies, the de-escalation of drugs may also be beneficial in numerous cases. Therefore, breast cancer treatment must be increasingly customized and assessed using a multidisciplinary approach. This study aimed to review the concept and therapy of early breast cancer. METHODS: A narrative review of the literature was carried out in the PubMed database in December 2022, where the keywords for the searches were as follows: early breast cancer, surgical treatment of breast cancer, systemic treatment of breast cancer, neoadjuvant chemotherapy in breast cancer, adjuvant treatment of luminal breast cancer, early triple negative tumor, and early positive Her-2 tumor. Articles that were historically important in the treatment of breast cancer and articles that impacted management with scientific relevance were selected for this review. DISCUSSION: As new evidence continues to update existing knowledge, breast cancer treatment is becoming increasingly personalized and must now take into account the different tumor variants and their clinical stages, the age of patients and relevant comorbidities, as well as personal expectations and desires. CONCLUSION: This literature review of current studies shows that the primary therapy for patients with early breast cancer continues to be surgery, although a customized and multidisciplinary approach is now required.

Management of early-stage triple-negative breast cancer: recommendations of a panel of experts from the Brazilian Society of Mastology.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogenous subtype involving different patterns of behavior and clinical course, demanding a complex, individualized sequence of treatment. The knowledge and attitudes of the affiliated members of the Brazilian Society of Mastology regarding TNBC were evaluated and a consensus regarding management and treatment was reached. METHODS: Affiliates completed a survey involving 44 objective questions. In addition, a specialist meeting was held with 27 experts and 3 ad hoc consultants. The panelists completed the survey before and after brainstorming. Answers achieving 70% of agreement were considered consensual. The chi-square test was used to compare answers between panelists and affiliates and the Kappa coefficient to calculate agreement. RESULTS: Consensus among the panelists increased from 26 (59.1%) to 32 questions (72.7%) following brainstorming (p = 0.17), including 7/10 questions on systemic treatment. Among the affiliates, consensus was achieved for 24 questions (54.5%), resulting in moderate agreement (κ = 0.445). Neoadjuvant chemotherapy should be indicated for almost all cases (except cT1a-b N0) and should include platinum agents. When indicated, immunotherapy is part of the standard of care. The panel reaffirmed the concept of no ink on tumor as indicative of adequate margins and the possibility of sentinel lymph node biopsy for cN1 patients who become cN0 following neoadjuvant therapy. Controversies remain on combining immunotherapy with capecitabine/olaparib in pertinent cases. CONCLUSION: Expert consensus was achieved for > 70% of the questions, with moderate agreement between panelists and affiliates. Educational interventions on systemic breast cancer treatment affected decision-making in 60% of the questions.

Rates and Predictors of Treatment Failure in Staphylococcus aureus Prosthetic Joint Infections According to Different Management Strategies: A Multinational Cohort Study-The ARTHR-IS Study Group.

INTRODUCTION: Guidelines have improved the management of prosthetic joint infections (PJI). However, it is necessary to reassess the incidence and risk factors for treatment failure (TF) of Staphylococcus aureus PJI (SA-PJI) including functional loss, which has so far been neglected as an outcome. METHODS: A retrospective cohort study of SA-PJI was performed in 19 European hospitals between 2014 and 2016. The outcome variable was TF, including related mortality, clinical failure and functional loss both after the initial surgical procedure and after all procedures at 18 months. Predictors of TF were identified by logistic regression. Landmark analysis was used to avoid immortal time bias with rifampicin when debridement, antibiotics and implant retention (DAIR) was performed. RESULTS: One hundred twenty cases of SA-PJI were included. TF rates after the first and all surgical procedures performed were 32.8% and 24.2%, respectively. After all procedures, functional loss was 6.0% for DAIR and 17.2% for prosthesis removal. Variables independently associated with TF for the first procedure were Charlson ≥ 2, haemoglobin < 10 g/dL, bacteraemia, polymicrobial infection and additional debridement(s). For DAIR, TF was also associated with a body mass index (BMI) > 30 kg/m2 and delay of DAIR, while rifampicin use was protective. For all procedures, the variables associated with TF were haemoglobin < 10 g/dL, hip fracture and additional joint surgery not related to persistent infection. CONCLUSIONS: TF remains common in SA-PJI. Functional loss accounted for a substantial proportion of treatment failures, particularly after prosthesis removal. Use of rifampicin after DAIR was associated with a protective effect. Among the risk factors identified, anaemia and obesity have not frequently been reported in previous studies. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov, registration no. NCT03826108.

Staphylococcus aureus is one of the most virulent bacteria and frequently causes prosthetic joint infections.Knowledge of the treatment of this type of infection has advanced in recent years, and treatment guidelines have led to improved management. Typically, the successful treatment of these infections has been determined by clinical cure, that is, the symptoms of infection have disappeared, but has not taken into account loss of function (such as significant difficulties walking), which is critical for the patient's quality of life. Our aim in this study was to evaluate the success of current management strategies for S. aureus prosthetic joint infection, including recovery of functionality, and the factors that predict why some of these infections are not cured, to identify areas for improvement.In a multinational cohort of 128 patients with S. aureus prosthetic joint infection, rates of treatment failure were found to be high, with significant rates of loss of function, especially when the prosthesis needed to be removed. Loss of function was less frequent when the infection was initially treated with surgical cleaning without removal of the prosthesis, even when this procedure failed at first. We found that anaemia and obesity were associated with lower treatment success, and that the probability of treatment success increased when surgical cleaning without prosthesis removal was performed early, and when the antibiotic rifampicin was used in combination with another antibiotic.

Preoperative and perioperative risk factors, and risk score development for prosthetic joint infection due to Staphylococcus aureus: a multinational matched case-control study.

OBJECTIVES: We aim to identify the preoperative and perioperative risk factors associated with post-surgical Staphylococcus aureus prosthetic joint infections (PJI) and to develop and validate risk-scoring systems, to allow a better identification of high-risk patients for more efficient targeted interventions. METHODS: We performed a multicenter matched case-control study of patients who underwent a primary hip and knee arthroplasty from 2014 to 2016. Two multivariable models by logistic regression were performed, one for the preoperative and one for perioperative variables; predictive scores also were developed and validated in an external cohort. RESULTS: In total, 130 cases and 386 controls were included. The variables independently associated with S. aureus-PJI in the preoperative period were (adjusted OR; 95% CI): body mass index >30 kg/m2 (3.0; 1.9 to 4.8), resident in a long-term care facility (2.8; 1.05 to 7.5), fracture as reason for arthroplasty (2.7; 1.4 to 5.03), skin disorders (2.5; 0.9 to 7.04), previous surgery in the index joint (2.4; 1.3 to 4.4), male sex (1.9; 1.2 to 2.9) and American Society of Anesthesiologists index score 3 to 4 (1.8; 1.2 to 2.9). The area under the receiver operating characteristic curve was 0.73 (95% CI 0.68 to 0.78). In perioperative model, the risk factors were the previous ones plus surgical antibiotic prophylaxis administered out of the first 60 minutes before incision (5.9; 2.1 to 16.2), wound drainage for >72 hours after arthroplasty (4.5; 1.9 to 19.4) and use of metal bearing material versus ceramic (1.9; 1.1 to 3.3). The area under the receiver operating characteristic curve was 0.78 (95% CI 0.72 to 0.83). The predictive scores developed were validated in the external cohort. DISCUSSION: Predictive scores for S. aureus-PJI were developed and validated; this information would be useful for implementation of specific preventive measures.

Substantial Reduction in Adjuvant Chemotherapy With the Use of the 21-Gene Test to Manage Early Breast Cancer in a Public Hospital in Brazil.

PURPOSE: We evaluated the impact of 21-gene test results on treatment decisions for patients with early-stage breast cancer treated under the public health care system in Brazil, Sistema Único de Saúde. METHODS: Eligible patients treated at Hospital Pérola Byington and Santa Casa de Misericórdia de São Paulo in Brazil were required to have the following characteristics: postsurgery with hormone receptor-positive, human epidermal growth factor 2-negative, node-negative and node-positive, and T1/T2 breast cancer and patients with these characteristics were candidates for adjuvant systemic therapy. Treatment recommendations, chemotherapy plus hormonal therapy (CT + HT) or HT alone, were captured before and after 21-gene test results. RESULTS: From August 2018 to April 2019, 179 women were enrolled. The mean age was 58 years (29-86 years), 135 (76%) were postmenopausal, and 58 (32%) had node-positive breast cancer. Most patients (61%) had a tumor > 2 cm, including 7% with tumors > 4 cm. Using Recurrence Score (RS) result cut points on the basis of the TAILORx trial, 40 (22%) had RS 0-10, 91 (51%) had RS 11-25, and 48 (27%) had RS 26-100. Before 21-gene testing, 162 of 179 (91%) patients were recommended for CT. After testing, 117 of 179 patients (65%) had changes in CT recommendation: 112 (63%) who were initially recommended CT received HT alone and five (3%) who were initially recommended HT alone received CT + HT. After 21-gene testing, 99% of physicians reported strong confidence in their treatment recommendations. CONCLUSION: The change in clinical practice at these public hospitals was greater than expected: 66% of initial treatment recommendations were changed to omit CT with 21-gene test results. Clinicopathologic features did not correlate well with 21-gene test results and did not adequately identify those most likely to benefit from CT.

Staphylococcal Protein A Induces Leukocyte Necrosis by Complexing with Human Immunoglobulins.

One of the defining features of Staphylococcus aureus is its ability to evade and impair the human immune response through expression of staphylococcal protein A (SpA). Herein, we describe a previously unknown mechanism by which SpA can form toxic immune complexes when in the presence of human serum, which leads to the loss of human leukocytes. Further, we demonstrate that these toxic complexes are formed specifically through SpA's interaction with intact human IgG and that, in the presence of purified IgG Fab and Fc fragments, SpA shows no such toxicity. The mechanism of action of this toxicity appears to be one mediated by necrosis and not by apoptosis, as previously hypothesized, with up to 90% of human B cells rapidly becoming necrotic following stimulation with SpA-IgG complexes. This phenomenon depends on the immunoglobulin binding capacity of SpA, as a nonbinding mutant of SpA did not induce necrosis. Importantly, immune sera raised against SpA had the capacity to significantly reduce the observed toxicity. An unprecedented toxic effect of SpA-IgG complexes on monocytes was also observed, suggesting the existence of a novel mechanism independent from the interaction of SpA with the B cell receptor. Together, these data implicate SpA in inducing indiscriminate leukocyte toxicity upon formation of complexes with IgG and highlight the requirement for vaccination strategies to inhibit this mechanism. IMPORTANCE Staphylococcus aureus is one of the largest health care threats faced by humankind, with a reported mortality rate within the United States greater than that of HIV/AIDS, tuberculosis, and viral hepatitis combined. One of the defining features of S. aureus as a human pathogen is its ability to evade and impair the human immune response through expression of staphylococcal protein A. Herein, we show that SpA induces necrosis in various immune cells by complexing with human immunoglobulins. Vaccination of mice with a nontoxigenic SpA mutant induced sera capable of inhibiting this mechanism. These observations shed new light on the toxic mechanisms of this key staphylococcal virulence factor and on protective modalities of SpA-based vaccination.

Oncoplastic mammaplasty with geometric compensation: Evolution of the technique, outcomes and follow-up in a multicentre retrospective cohort.

BACKGROUND AND OBJECTIVES: To report on the outcomes and evolution of an oncoplastic mammaplasty referred to as geometric compensation mammaplasty. METHODS: Seventy-three patients with malignant tumours were operated on and followed up in five centres in two countries. Preoperative markings were performed using a Wise pattern. The resection of affected skin was geometrically compensated using another area of preserved skin. RESULTS: Mean pathological tumour size was 30.42 ± 21.98 mm. Twenty tumours (30.77%) were locally advanced and 15 (20.55%) were multicentric. Twenty-two patients (34.38%) were submitted to neoadjuvant chemotherapy. Cosmetic results were considered good or excellent in 59 cases (80.82%). Margins were positive in two cases (2.74%). Complications were partial wound dehiscence (n = 11; 15.07%), fat necrosis (n = 9; 12.33%), skin necrosis (n = 5; 6.85%), seromas (n = 5; 6.85%), enlarged scars (n = 7; 9.59%) and infection (n = 2; 2.74%). There were three cases of local recurrence (4.29%), two of bone metastasis (2.86%) and three of metachronous contralateral breast cancer (4.35%). No deaths were recorded within a mean follow-up of 35.33 ± 28.21 months. CONCLUSIONS: The technique allowed breast conservation in situations requiring a large resection of skin in difficult positions, with a high rate of free margins, correction of ptosis, satisfactory symmetry and few complications.

Autologous Breast Reconstruction With the Latissimus Dorsi Muscle With Immediate Fat Grafting: Long-term Results and Patient Satisfaction.

OBJECTIVE: The aim of this study was to describe a variation of the breast reconstruction technique with myocutaneous flap of the fat-grafted latissimus dorsi muscle and its outcomes and evaluation of patient satisfaction. METHOD: This prospective cohort study included 18 patients and 19 reconstructed breasts, with 1 bilateral case. There were 7 cases of late reconstruction and 11 cases of immediate reconstruction. The flap was prepared with fat at the time of surgery, which was injected before its preparation. The evaluation of the results regarding shape, volume, and symmetry was performed through a satisfaction scale completed by patients and 2 physicians from 12 to 18 months after reconstruction. RESULTS: On average, 171.31 mL of fat was injected (100-275 mL); the average time of unilateral surgery was 3 hours 42 minutes (3 hours to 4 hours 30 minutes). After a mean follow-up of 26.38 months (13-38 months), we did not observe complications of this new technique. In the evaluation performed by patients regarding the shape, volume, and symmetry, more than 80% rated the outcome as excellent and good, and the evaluations by the medical team were also satisfactory. In the comparative analysis between immediate and late reconstruction, patients who underwent immediate reconstruction were more satisfied. CONCLUSIONS: This reconstruction technique with autologous fat injection was effective, with satisfactory and long-lasting results, and without the requirement for implants to set breast shape and volume.

Pilus Assembly in Gram-Positive Bacteria.

Pili of Gram-positive bacteria are unique structures on the bacterial surface, assembled from covalently linked polypeptide subunits. Pilus assembly proceeds by transpeptidation reactions catalyzed by sortases, followed by covalent anchoring of the filament in the peptidoglycan layer. Another distinctive property is the presence of intramolecular isopeptide bonds, conferring extraordinary chemical and mechanical stability to these elongated structures. Besides their function in cell adhesion and biofilm formation, this section discusses possible application of pilus constituents as vaccine components against Gram-positive pathogens.

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination.

Induction of persistent protective immune responses is a key attribute of a successful vaccine formulation. MF59 adjuvant, an oil-in-water emulsion used in human vaccines, is known to induce persistent high-affinity functional Ab titers and memory B cells, but how it really shapes the Ag-specific B cell compartment is poorly documented. In this study, we characterized the Ab- and Ag-specific B cell compartment in wild-type mice immunized with HlaH35L, a Staphylococcus aureus Ag known to induce measurable functional Ab responses, formulated with MF59 or aluminum salts, focusing on germinal centers (GC) in secondary lymphoid organs. Taking advantage of single-cell flow cytometry analyses, HlaH35L-specific B cells were characterized for the expression of CD38 and GL-7, markers of memory and GC, respectively, and for CD80 and CD73 activation markers. We demonstrated that immunization with MF59-, but not aluminum salt-adjuvanted HlaH35L, induced expanded Ag-specific CD73(+)CD80(-) GC B cells in proximal- and distal-draining lymph nodes, and promoted the persistence of GC B cells, detected up to 4 mo after immunization. In addition to increasing GC B cells, MF59-adjuvanted HlaH35L also increased the frequency of T follicular helper cells. This work extends previous knowledge regarding adaptive immune responses to MF59-adjuvanted vaccines, and, to our knowledge, for the first time an adjuvant used in human licensed products is shown to promote strong and persistent Ag-specific GC responses that might benefit the rational design of new vaccination strategies.

Alternativas para o tratamento não hormonal de mulheres no climatério / Alternatives to non-hormonal treatment of climacteric women

Objetivo: Analisar as opções de tratamento não hormonal da mulher climatérica. Material e método: Estudo e análise dos trabalhos e capítulos de livro que mostrem avaliação adequada das opções de tratamento não hormonal das mulheres climatéricas, considerando as indicações, benefícios e tolerabilidade com os diferentes tratamentos. Resultados e conclusões: A revisão apresentou evidências de que medidas gerais (dieta, atividade física e ocupacional) são recomendáveis para todas as mulheres climatéricas. Para alívio dos sintomas vasomotores, o tratamento com mais índices de sucesso é realizado com antidepressivos, outras opções como cinarizina ou hipotensores podem beneficiar secundariamente as mulheres que devam utilizá-los por indicações clínicas. A fitoterapia, acupuntura e homeopatia ainda não apresentam evidências conclusivas...

Oncoplastic mammaplasty with geometric compensation--a technique for breast conservation.

OBJECTIVE: To describe a technique of oncoplastic mammaplasty, referred to as geometric compensation, which is suitable for tumors close to the skin in areas not included in the classic preoperative drawings for mammaplasty. MATERIALS AND METHODS: Seventeen patients with malignant tumors were included. Preoperative markings followed the "Wise-pattern" technique. The resection of affected skin was geometrically compensated with another area of preserved skin. RESULTS: The mean age of the patients was 52.88 ± 12.14 years. Mean pathological tumor size was 43.82 ± 31.39 mm. There were 7 (41.18%) locally advanced tumors. Six patients (35.29%) were submitted to neoadjuvant and the remainder to adjuvant chemotherapy. Radiotherapy was indicated in all cases. Fifteen patients (88.24%) received hormone therapy. Ptosis was corrected in all cases. The aesthetic result was rated excellent in seven cases (41.18%), good in 7 (41.18%), and fair in three cases (17.65%). Surgical margins were free. A seroma developed in one case (5.88%), small fat necrosis in three (17.65%), and enlarged scar in one (5.88%). There were no recurrences within 28.24 ± 18.02 months. CONCLUSIONS: The technique allowed breast conservation in situations requiring large resection of affected skin, with free surgical margins, correction of ptosis, satisfactory symmetry, and few complications.

Staphylococcal Esx proteins modulate apoptosis and release of intracellular Staphylococcus aureus during infection in epithelial cells.

The opportunistic pathogen Staphylococcus aureus is one of the major causes of health care-associated infections. S. aureus is primarily an extracellular pathogen, but it was recently reported to invade and replicate in several host cell types. The ability of S. aureus to persist within cells has been implicated in resistance to antimicrobials and recurrent infections. However, few staphylococcal proteins that mediate intracellular survival have been identified. Here we examine if EsxA and EsxB, substrates of the ESAT-6-like secretion system (Ess), are important during intracellular S. aureus infection. The Esx proteins are required for staphylococcal virulence, but their functions during infection are unclear. While isogenic S. aureus esxA and esxB mutants were not defective for epithelial cell invasion in vitro, a significant increase in early/late apoptosis was observed in esxA mutant-infected cells compared to wild-type-infected cells. Impeding secretion of EsxA by deleting C-terminal residues of the protein also resulted in a significant increase of epithelial cell apoptosis. Furthermore, cells transfected with esxA showed an increased protection from apoptotic cell death. A double mutant lacking both EsxA and EsxB also induced increased apoptosis but, remarkably, was unable to escape from cells as efficiently as the single mutants or the wild type. Thus, using in vitro models of intracellular staphylococcal infection, we demonstrate that EsxA interferes with host cell apoptotic pathways and, together with EsxB, mediates the release of S. aureus from the host cell.

Structure and protective efficacy of the Staphylococcus aureus autocleaving protease EpiP.

Despite the global medical needs associated with Staphylococcus aureus infections, no licensed vaccines are currently available. We identified and characterized a protein annotated as an epidermin leader peptide processing serine protease (EpiP), as a novel S. aureus vaccine candidate. In addition, we determined the structure of the recombinant protein (rEpiP) by X-ray crystallography. The crystal structure revealed that rEpiP was cleaved somewhere between residues 95 and 100, and we found that the cleavage occurs through an autocatalytic intramolecular mechanism. The protein expressed by S. aureus cells also appeared to undergo a similar processing event. To determine whether the protein acts as a serine protease, we mutated the hypothesized catalytic serine 393 residue to alanine, generating rEpiP-S393A. The crystal structure of this mutant protein showed that the polypeptide chain was not cleaved and was not interacting stably with the active site. Indeed, rEpiP-S393A was shown to be impaired in its protease activity. Mice vaccinated with rEpiP were protected from S. aureus infection (34% survival, P=0.0054). Moreover, the protective efficacy generated by rEpiP and rEpiP-S393A was comparable, implying that the noncleaving mutant could be used for vaccination purposes.

Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine.

Helicobacter pylori colonizes the gastric mucosa of more than 50% of the human population, causing chronic inflammation, which however is largely asymptomatic. Nevertheless, H. pylori-infected subjects can develop chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Chronic exposure to the pathogen and its ability to induce epithelial to mesenchymal transition (EMT) through the injection of cytotoxin-associated gene A into gastric epithelial cells may be key triggers of carcinogenesis. By deregulating cell-cell and cell-matrix interactions as well as DNA methylation, histone modifications, expression of micro RNAs, and resistance to apoptosis, EMT can actively contribute to early stages of the cancer formation. Host response to the infection significantly contributes to disease development and the concomitance of particular genotypes of both pathogen and host may turn into the most severe outcomes. T regulatory cells (Treg) have been recently demonstrated to play an important role in H. pylori-related disease development and at the same time the Treg-induced tolerance has been proposed as a possible mechanism that leads to less severe disease. Efficacy of antibiotic therapies of H. pylori infection has significantly dropped. Unfortunately, no vaccine against H. pylori is currently licensed, and protective immunity mechanisms against H. pylori are only partially understood. In spite of promising results obtained in animal models of infection with a number of vaccine candidates, few clinical trials have been conducted so far and with no satisfactory outcomes. However, prophylactic vaccination may be the only means to efficiently prevent H. pylori-associated cancers.

Interaction between cyclooxygenase-2 and insulin-like growth factor in breast cancer: A new field for prevention and treatment.

The objective of this study was to evaluate the correlation between cyclooxygenase-2 (COX-2) and markers of cell proliferation and apoptosis, including, Bcl-2, Bax, Ki-67 and the type I insulin-like growth factor (IGF) receptor (IGF1-R) in ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC), present in the same surgical specimen. A total of 110 cases were evaluated using tissue microarrays. Cases were classified in scores from 0 to 3 according to pre-defined methods. The results showed that the positivity rates were COX-2 in 87% of cases in DCIS and IDC; Bcl-2 in 55% of cases in DCIS and IDC; Bax in 23% of cases in IDC and 19% in DCIS, IGF-1 in 24% of cases in DCIS and IDC; and Ki-67 in 81% of cases in DCIS and IDC. We also observed a positive correlation between the expression of COX-2 and IGF1-R (p=0.045). Our results demonstrate a positive correlation between the expression of COX-2 and IGF1-R in DCIS and IDC, demonstrating that they are involved in breast cancer carcinogenesis. Further studies are required to prove the effectiveness of COX-2 and IGF1-R inhibitors for the prevention and treatment of breast cancer, as well as to explain their mechanism of action.