Editorial Commentary: Both Femoral Acetabular Anteversion and Retroversion May Contribute to the Effect of Femoroacetabular Impingement: What's Your Version?

Femoral anteversion may be a protective factor for hip impingement, whereas hip arthroscopy outcomes are worse for patients with femoral retroversion. Changes in version also affect the location of impingement. The association of increased anteversion with cam lesions may also explain the high number of patients with asymptomatic cam lesions. Thus, some patients may have large α angles but be asymptomatic. Finally, although femoral version is important, it must be considered in the setting of the patient's acetabular morphology. There is a complex interplay of femoral and acetabular morphologies.

Glyceollins Trigger Anti-Proliferative Effects in Hormone-Dependent Aromatase-Inhibitor-Resistant Breast Cancer Cells through the Induction of Apoptosis.

Aromatase inhibitors (AIs) are standard treatment for estrogen-dependent postmenopausal breast tumors; however, resistance develops leading to tumor relapse and metastasis. We previously demonstrated that glyceollin inhibits proliferation, survival, and migration of hormone-independent letrozole-resistant breast cancer. Since many AI-resistant tumors remain hormone-dependent, identifying distinctions between estrogen-receptor-positive (ER+) and ER-negative (ER-) AI-resistant tumor response to therapy is critical. We hypothesize that treating ER+ letrozole-resistant T47D breast cancer cells (T47DaromLR) with a combination of 10 µM glyceollin and 0.5 µM lapatinib (a dual EGFR/HER2 inhibitor) will decrease cell proliferation through induction of apoptosis. The T47DaromLR cells were found to overexpress HER2 and MAPK while maintaining aromatase and ER levels compared to their letrozole-sensitive (T47Darom) counterparts. In the absence of estrogen stimulation, glyceollin ± lapatinib had no effect on the proliferation of the T47Darom cells, while glyceollin treatment caused 46% reduction in the proliferation of T47DaromLR cells, which was further diminished when combined with lapatinib. While neither agent influenced cell migration, glyceollin and lapatinib reduced S and G2/M phase cell entry and exclusively induced apoptosis by 1.29-fold in the T47DaromLR cells. Taken together, these results suggest that glyceollins and lapatinib may have potential as a novel combination therapeutic approach for hormone-dependent, letrozole-resistant tumors.

Dendritic Spine Density and Dynamics of Layer 5 Pyramidal Neurons of the Primary Motor Cortex Are Elevated With Aging.

It is well established that motor impairment often occurs alongside healthy aging, leading to problems with fine motor skills and coordination. Although previously thought to be caused by neuronal death accumulating across the lifespan, it is now believed that the source of this impairment instead stems from more subtle changes in neural connectivity. The dendritic spine is a prime target for exploration of this problem because it is the postsynaptic partner of most excitatory synapses received by the pyramidal neuron, a cortical cell that carries much of the information processing load in the cerebral cortex. We repeatedly imaged the same dendrites in young adult and aged mouse motor cortex over the course of 1 month to look for differences in the baseline state of the dendritic spine population. These experiments reveal increased dendritic spine density, without obvious changes in spine clustering, occurring at the aged dendrite. Additionally, aged dendrites exhibit elevated spine turnover and stabilization alongside decreased long-term spine survival. These results suggest that at baseline the aged motor cortex may exist in a perpetual state of relative instability and attempts at compensation. This phenotype of aging may provide clues for future targets of aging-related motor impairment remediation.

Editorial Commentary: Hip Femoroacetabular Impingement Emotional Impact and Mental Health: An Arthroscope Can't Fix Everything.

Arthroscopic treatment of femoroacetabular impingement is increasingly common with established clinical success. As with other chronic injuries, there is an emotional impact that can affect recovery, particularly in competitive athletes. As this emotional aspect of injury is more recognized, it will be important to determine comprehensive means of treating both an athlete's physical and mental health. It is important to establish preoperative expectations. For certain patients, psychological evaluation and treatment is indicated early in the diagnosis and recovery to ensure mental fitness, and this may be especially true for adolescents. A comprehensive and personalized approach to injury recovery is optimal.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Surgical management and outcomes of 12 cases of Wilms tumour with intracardiac extension from a single centre.

PURPOSE: To review demographics, effect of preoperative chemotherapy on tumour thrombus, imaging, operative strategy, and outcomes of 12 patients presenting with intracardiac extension of Wilms tumour thrombus. METHODS: A retrospective audit was undertaken on patients with intracardiac extension of Wilms tumour. Patients were identified from the oncology database and information obtained on clinical presentation, stage, preoperative treatment, surgical procedures and complications, histology, and survival status. Ethics approval was obtained from the University of Cape Town Human Research Ethics Committee. RESULTS: From 1984 to 2016, 337 children with Wilms tumour were treated. Twelve (3.6%) had intracardiac extension of tumour thrombus, nine into the right atrium, and three into the right ventricle. Ultrasound, computerized tomography, magnetic resonance imaging, and echocardiograms were used to assess thrombus level. Patients were staged as stage III(8) and IV(4). All patients received preoperative chemotherapy. Thrombus retracted from the heart in two cases. One patient died preoperatively. Eleven underwent laparotomy, median sternotomy, and cardiopulmonary bypass (CPB). Four underwent cavectomy. Five required cavoatrial patches. Thrombus extending into the hepatic veins was extracted in five patients. There was one intraoperative complication and one perioperative death. Thrombus histology showed viable tumour in 9 of 11 patients. Three patients died of progressive disease. Seven patients are currently disease free. CONCLUSION: A combination of imaging is required to determine thrombus extent, and this facilitates surgical planning. Preoperative chemotherapy may cause thrombus regression, thus avoiding CPB. CPB offers appropriate conditions for safe tumour thrombus excision. Full management in centres with appropriately experienced staff and facilities for CPB is recommended.

Acute mobilization and migration of bone marrow-derived stem cells following anterior cruciate ligament rupture.

OBJECTIVE: Little is known regarding acute local and systemic processes following anterior cruciate ligament (ACL) rupture. No study has elucidated whether bone marrow-derived mesenchymal stem cells (MSCs) are mobilized into circulation and recruited to the injured joint. METHODS: In Part 1, Lewis rats were randomized to noninvasive ACL rupture (Rupture) or non-injured (Control) (n = 6/group). After 72 h, whole blood MSC concentration was assessed using flow cytometry. Synovial fluid and serum were assayed for stromal cell-derived factor (SDF)-1α and cartilage degeneration biomarkers, respectively. In Part 2, 12 additional rats were randomized and intravenously-injected with fluorescently-labeled allogenic MSCs. Cell tracking was performed using longitudinal, in vivo and ex vivo near-infrared (NIR) imaging and histology. Synovium SDF-1α and interleukin (IL)-17A immunostaining was performed. Serum was assayed for SDF-1α and 29 other cytokines. RESULTS: In Part 1, there was a significant increase in MSC concentration and synovial fluid SDF-1α in Rupture. No differences in cartilage biomarkers were observed. In Part 2, Rupture had significantly higher NIR signal at 24, 48, and 72 h, indicating active recruitment of MSCs to the injured joint. Ex vivo cell tracking demonstrated MSC localization in the synovium and myotendinous junction (MTJ) of the quadriceps. Injured synovia exhibited increased synovitis grade and higher degree of IL-17A and SDF-1α immunostaining. CONCLUSION: ACL rupture induced peripheral blood mobilization of MSCs and migration of intravenously-injected allogenic MSCs to the injured joint, where they localized in the synovium and quadriceps MTJ.

Burden of illness in systemic lupus erythematosus: results from a UK patient and carer online survey.

Objective The objective of this study was to assess the impact of systemic lupus erythematosus (SLE) on patients and carers. Methods Adults with SLE and carers of SLE patients completed a UK-specific online survey covering many aspects of the disease. Surveys were developed in collaboration with an NHS lupus unit and a lupus patient organization. Results A total of 121 patients and 31 carers completed the surveys. Of the 70% of patients initially misdiagnosed with another condition, 59% received treatment for the misdiagnosis. Fatigue was the most debilitating symptom, experienced daily by 79% of patients. The proportion of patients not reporting flares to healthcare providers varied with flare severity: mild flares (43%), moderate flares (15%) and severe flares (5%). Most patients (89%) reported reduced ability to socialize, and 76% had changed employment; of these, 52% stopped working completely. Over one-half (52%) of carers in paid employment missed time from work, and 55% of carers reported a worsened financial status. Most carers (87%) experienced interference with social activities. Conclusion SLE is commonly misdiagnosed and has a considerable impact on the physical, social and financial status of patients and carers. Increased awareness of the disease among healthcare providers and employers of patients and their carers is needed.

Prenatal diagnosis and prognosis of accelerated idioventricular rhythm.

OBJECTIVES: As postnatal identification of accelerated idioventricular rhythm (AIVR) relies on specific electrocardiographic patterns, prenatal diagnosis of this condition is challenging and its true incidence is unknown. The objectives of this study were to evaluate the performance of prenatal ultrasonography in identifying intrauterine cardiocirculatory events linked to specific electrocardiographic signs of postnatal AIVR, including left or right ventricular origin, and to assess the prenatal prognosis of this arrhythmia. METHODS: We reviewed Doppler tracings from the superior vena cava/ascending aorta (SVC/Ao), ductus venosus (DV), ductus arteriosus (DA) and aortic isthmus (AoI), as well as simultaneous M-mode recordings of septal and left ventricular wall motions of fetuses diagnosed with AIVR from January 2004 to December 2014. RESULTS: Three cases of AIVR were identified among 27 912 fetuses. SVC/Ao Doppler flow recordings revealed atrioventricular dissociation (ventricular rates within 20% of atrial rates) in all three fetuses and episodes of isorhythmic atrioventricular dissociation in one, while M-mode confirmed normal left ventricular shortening fraction in all cases. Fusion beats were observed on AoI tracing in one fetus, while simultaneous recordings of AoI and DA revealed signs of right bundle branch block in one case and left bundle branch block in the other two. On DV Doppler recordings, retrograde a-waves in the presence of simultaneous atrial and ventricular contractions were observed in all three fetuses, leading to an increase in central venous pressure in all and hydrops fetalis in two cases without evidence of ventricular dysfunction. CONCLUSIONS: Echocardiographic criteria required for postnatal diagnosis of AIVR can be documented in utero using specific ultrasonographic approaches. During fetal life, AIVR may not be a benign entity. Hydrops fetalis is frequently associated with AIVR because of increase in central venous pressure related to simultaneous atrioventricular contractions; thus, the ultrasonographic investigation protocol of fetuses with unexplained hydrops fetalis should aim at ruling out AIVR and include Doppler flow recordings in SVC/Ao, DV, AoI, DA and umbilical vein. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Differences in Blood Pressure in Infants After General Anesthesia Compared to Awake Regional Anesthesia (GAS Study-A Prospective Randomized Trial).

BACKGROUND: The General Anesthesia compared to Spinal anesthesia (GAS) study is a prospective randomized, controlled, multisite, trial designed to assess the influence of general anesthesia (GA) on neurodevelopment at 5 years of age. A secondary aim obtained from the blood pressure data of the GAS trial is to compare rates of intraoperative hypotension after anesthesia and to identify risk factors for intraoperative hypotension. METHODS: A total of 722 infants ≤60 weeks postmenstrual age undergoing inguinal herniorrhaphy were randomized to either bupivacaine regional anesthesia (RA) or sevoflurane GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born at <26 weeks of gestation. Moderate hypotension was defined as mean arterial pressure measurement of <35 mm Hg. Any hypotension was defined as mean arterial pressure of <45 mm Hg. Epochs were defined as 5-minute measurement periods. The primary outcome was any measured hypotension <35 mm Hg from start of anesthesia to leaving the operating room. This analysis is reported primarily as intention to treat (ITT) and secondarily as per protocol. RESULTS: The relative risk of GA compared with RA predicting any measured hypotension of <35 mm Hg from the start of anesthesia to leaving the operating room was 2.8 (confidence interval [CI], 2.0-4.1; P < .001) by ITT analysis and 4.5 (CI, 2.7-7.4, P < .001) as per protocol analysis. In the GA group, 87% and 49%, and in the RA group, 41% and 16%, exhibited any or moderate hypotension by ITT, respectively. In multivariable modeling, group assignment (GA versus RA), weight at the time of surgery, and minimal intraoperative temperature were risk factors for hypotension. Interventions for hypotension occurred more commonly in the GA group compared with the RA group (relative risk, 2.8, 95% CI, 1.7-4.4 by ITT). CONCLUSIONS: RA reduces the incidence of hypotension and the chance of intervention to treat it compared with sevoflurane anesthesia in young infants undergoing inguinal hernia repair.

Sawfishes stealth revealed using computational fluid dynamics.

Detailed computational fluid dynamics simulations for the rostrum of three species of sawfish (Pristidae) revealed that negligible turbulent flow is generated from all rostra during lateral swipe prey manipulation and swimming. These results suggest that sawfishes are effective stealth hunters that may not be detected by their teleost prey's lateral line sensory system during pursuits. Moreover, during lateral swipes, the rostra were found to induce little velocity into the surrounding fluid. Consistent with previous data of sawfish feeding behaviour, these data indicate that the rostrum is therefore unlikely to be used to stir up the bottom to uncover benthic prey. Whilst swimming with the rostrum inclined at a small angle to the horizontal, the coefficient of drag of the rostrum is relatively low and the coefficient of lift is zero.

A phase III randomized trial of adding topical nitroglycerin to first-line chemotherapy for advanced nonsmall-cell lung cancer: the Australasian lung cancer trials group NITRO trial.

BACKGROUND: We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. PATIENTS AND METHODS: Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. RESULTS: Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86-1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79-1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82-1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. CONCLUSION: The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. CLINICAL TRIALS NUMBER: Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Formation of Ultrarelativistic Electron Rings from a Laser-Wakefield Accelerator.

Ultrarelativistic-energy electron ring structures have been observed from laser-wakefield acceleration experiments in the blowout regime. These electron rings had 170-280 MeV energies with 5%-25% energy spread and ∼10 pC of charge and were observed over a range of plasma densities and compositions. Three-dimensional particle-in-cell simulations show that laser intensity enhancement in the wake leads to sheath splitting and the formation of a hollow toroidal pocket in the electron density around the wake behind the first wake period. If the laser propagates over a distance greater than the ideal dephasing length, some of the dephasing electrons in the second period can become trapped within the pocket and form an ultrarelativistic electron ring that propagates in free space over a meter-scale distance upon exiting the plasma. Such a structure acts as a relativistic potential well, which has applications for accelerating positively charged particles such as positrons.

Evaluation of a multidimensional cystic fibrosis transition program: a quality improvement initiative.

The adequate preparation of cystic fibrosis (CF) youth for the transfer from pediatric to adult-based health care services is essential to meet the needs of this changing population. This paper describes the evolution of a transition clinic for patients with CF into a multidimensional quality improvement transition initiative. Three transition interventions (a patient transition clinical pathway; collaboration with the adult clinic; and a tool to measure transfer readiness) were sequentially implemented and evaluated. Each was found to be a valuable addition to a comprehensive transition protocol and today are endorsed as part of transition best practices.

Using proliferative markers and Oncotype DX in therapeutic decision-making for breast cancer: the B.C. experience.

BACKGROUND: Proliferative scoring of breast tumours can guide treatment recommendations, particularly for estrogen receptor (er)-positive, her2-negative, T1-2, N0 disease. Our objectives were to □ estimate the proportion of such patients for whom proliferative indices [mitotic count (mc), Ki-67 immunostain, and Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.) recurrence score (rs)] were obtained.□ compare the indices preferred by oncologists with the indices available to them.□ correlate Nottingham grade (ng) and its subcomponents with Oncotype dx.□ assess interobserver variation. METHODS: All of the er-positive, her2-negative, T1-2, N0 breast cancers diagnosed from 2007 to 2011 (n = 5110) were linked to a dataset of all provincial breast cancers with a rs. A 5% random sample of the 5110 cancers was reviewed to estimate the proportion that had a mc, Ki-67 index, and rs. Correlation coefficients were calculated for the rs with ng subcomponent scores. Interobserver variation in histologic grading between outside and central review pathology reports was assessed using a weighted kappa test. RESULTS: During 2007-2011, most cancers were histologically graded and assigned a mc; few had a Ki-67 index or rs. The ng and mc were significantly positively correlated with rs. The level of agreement in histologic scoring between outside and central pathology reports was good or very good. Very few cases with a low mc had a high rs (1.8%). CONCLUSIONS: Patients with low ng and mc scores are unlikely to have a high rs, and thus are less likely to benefit from chemotherapy. In the context of limited resources, that finding can guide clinicians about when a rs adds the most value.

Pathogenetic role of glomerular CXCL13 expression in lupus nephritis.

Podocytes maintain the structure and function of the glomerular filtration barrier. However, podocytes have recently been implicated in the innate immune response, and their function as non-haematopoietic antigen-presenting cells was highlighted. We have shown previously that excessive expression of the chemokine CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, we found that CXCL13 is elevated significantly in the serum of patients with SLE-nephritis. In this study, we were able to show for the first time that (i) CXCL13 is expressed locally in glomeruli in a model for SLE-nephritis in mice and that (ii) incubation of human podocytes with CXCL13 induces receptor stimulation of CXCR5 with activation of signalling pathways, resulting in (iii) secretion of proinflammatory cytokines and chemokines in culture supernatant. This cytokine/chemokine cocktail can lead to (iv) a neutrophil respiratory burst in isolated human granulocytes. Taken together, our results provide further evidence that CXCL13 is involved in the pathogenesis of glomerulonephritis and that podocytes can play an active role in local proinflammatory immune responses. Thus, CXCL13 could be a direct target for the therapy of glomerulonephritis in general and for SLE-nephritis in particular.

Prognostic value of systemic inflammation-based markers in advanced pancreatic cancer.

BACKGROUND: The prognostic significance of various systemic inflammation-based markers has been explored in different cancers. These markers can be used to assist with decision-making in oncology clinics. AIM: The aim of this study was to investigate the prognostic significance of three systemic inflammation-based factors: neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and modified Glasgow Prognostic Score (mGPS) in patients with advanced pancreatic cancer. METHODS: Data were collected retrospectively for advanced pancreatic cancer patients treated between 1 January 2008 and 31 December 2012 at the Royal Perth Hospital. The ratios were dichotomised as <5 versus ≥5 for NLR and <200 versus ≥200 for PLR. Modified Glasgow Prognostic Scores were scored as: mGPS '0' = both C-reactive protein (CRP) and albumin normal, mGPS '1' = elevated CRP < 10 mg/L and mGPS '2' = both elevated CRP > 10 mg/L and albumin < 35 g/L. Univariate and multivariate analyses were carried out. RESULTS: Data were evaluable for 124 patients. Median survivals based on the three inflammation-based prognostic markers evaluated were: NLR <5 versus ≥5 = 8.5 months versus 2.6 months respectively (P = 0.0007; hazard ratio (HR) 1.81), PLR <200 versus ≥200 = 9.1 months versus 4 months respectively (P = 0.007; HR 1.64) and mGPS score 1, 2, 3 = 8.3 months, 9.6 months and 1.8 months respectively (P = 0.0004). Besides Eastern Cooperative Oncology Group performance status, NLR, PLR and mGPS were significant independent prognostic markers both on univariate as well as multivariate analysis. CONCLUSIONS: Our findings suggest that the NLR, PLR and mGPS derived from routine blood tests can be used as clinically meaningful biomarkers to stratify advanced pancreatic cancer patients into different prognostic groups.

Provision of home mechanical ventilation and sleep services for England survey.

The Department of Health is promoting the generation of specialist networks to manage long term ventilatory weaning and domiciliary non-invasive ventilation patients. Currently the availability of these services in England is not known. We performed a short survey to establish the prevalence of sleep and ventilation diagnostic and treatment services. The survey focussed on diagnostic services and Home Mechanical Ventilation (HMV) provision, and was divided into (a) availability of diagnostics, (b) funding, and (c) patient groups. This survey has confirmed that the majority of Home Mechanical Ventilation set-ups are currently for Obesity Related Respiratory Failure and Chronic Obstructive Pulmonary Disease. We have found that there is variable provision of diagnostic services, with the majority of units offering overnight oximetry (95%) but only 55% of responders providing a home mechanical ventilation service. Even more interestingly, less than two thirds of units charged their primary care trust for this service. These data may assist in the development of regional networks and specialist home mechanical ventilation centres.

Impact of anaesthetics and surgery on neurodevelopment: an update.

Accumulating preclinical and clinical evidence suggests the possibility of neurotoxicity from neonatal exposure to general anaesthetics. Here, we review the weight of the evidence from both human and animal studies and discuss the putative mechanisms of injury and options for protective strategies. Our review identified 55 rodent studies, seven primate studies, and nine clinical studies of interest. While the preclinical data consistently demonstrate robust apoptosis in the nervous system after anaesthetic exposure, only a few studies have performed cognitive follow-up. Nonetheless, the emerging evidence that the primate brain is vulnerable to anaesthetic-induced apoptosis is of concern. The impact of surgery on anaesthetic-induced brain injury has not been adequately addressed yet. The clinical data, comprising largely retrospective cohort database analyses, are inconclusive, in part due to confounding variables inherent in these observational epidemiological approaches. This places even greater emphasis on prospective approaches to this problem, such as the ongoing GAS trial and PANDA study.

Novel Therapeutic Combination Targets the Growth of Letrozole-Resistant Breast Cancer through Decreased Cyclin B1.

As breast cancer cells transition from letrozole-sensitive to letrozole-resistant, they over-express epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and human epidermal growth factor receptor 2 (HER2) while acquiring enhanced motility and epithelial-to-mesenchymal transition (EMT)-like characteristics that are attenuated and reversed by glyceollin treatment, respectively. Interestingly, glyceollin inhibits the proliferation and tumor progression of triple-negative breast cancer (TNBC) and estrogen-independent breast cancer cells; however, it is unlikely that a single phytochemical would effectively target aromatase-inhibitor (AI)-resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib and glyceollin induced apoptosis in hormone-dependent AI-resistant breast cancer cells, we hypothesized that combination therapy would also be beneficial for hormone independent letrozole-resistant breast cancer cells (LTLT-Ca) compared to AI-sensitive breast cancer cells (AC-1) by decreasing the expression of proteins associated with proliferation and cell cycle progression. While glyceollin + lapatinib treatment caused comparable inhibitory effects on the proliferation and migration in both cell lines, combination treatment selectively induced S and G2/M phase cell cycle arrest of the LTLT-Ca cells, which was mediated by decreased cyclin B1. This phenomenon may represent a unique opportunity to design novel combinatorial therapeutic approaches to target hormone-refractory breast tumors.