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Fluoropolyol, a sorbent chemoselective oligomer, was deposited using a matrix-assisted laser-based deposition technique. Photochemical and/or photothermal modification of the oligomer that occurs for the UV-deposited films is shown by comparing films deposited with infrared (2.94 mum) and ultraviolet (UV) (193nm) radiation.

Background: Breast cancer represents one of the leading causes of death among women. Surgery can be effective, but once breast cancer has metastasized, it becomes extremely difficult to treat. Conventional therapies are associated with substantial toxicity and poor efficacy due to tumor heterogeneity, treatment resistance and disease relapse. Moreover, immune checkpoint blockade appears to offer limited benefit in breast cancer. The poor tumor immunogenicity and the immunosuppressive tumor microenvironment result in scarce T-cell infiltration, leading to a low response rate. Thus, there is considerable interest in the development of improved active immunotherapies capable of sensitizing a patient's immune system against tumor cells., Methods: We evaluated the in vitro anti-tumor activity of a personalized vaccine based on dendritic cells generated in the presence of interferon (IFN)-α and granulocyte-macrophage colony-stimulating factor (IFN-DC) and loaded with an oxidized lysate from autologous tumor cells expanded as 3D organoid culture maintaining faithful tumor antigenic profiles., Results: Our findings demonstrate that stimulation of breast cancer patients' lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients' own tumor cells., Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.

Background: Lateral lumbar interbody fusion (LLIF) is commonly used to address various lumbar pathologies. LLIF using the prone transpsoas (PTP) approach has several potential advantages, allowing simultaneous access to the anterior and posterior columns of the spine. The aim of this study was to report the 1-year outcomes of LLIF via PTP., Methods: This is a retrospective review of 97 consecutive patients who underwent LLIF via PTP. Radiographic parameters, including lumbar-lordosis, segmental-lordosis, anterior disc height, and posterior disc height, were measured on preoperative, initial-postoperative, and 1-year postoperative imaging. Patient-reported outcomes measures, including Oswestry Disability Index, visual analog scale (VAS), pain EQ5D, and postoperative complications, were reviewed., Results: Ninety-seven consecutive patients underwent 161 levels of LLIF. Fifty-seven percent underwent 1-level LLIF, 30% 2-level LLIF, 6% 3-level LLIF, and 7% 4-level LLIF. The most common level was L4 to L5 (35%), followed by L3 to L4 (33%), L2 to L3 (21%), and L1 to L2 (11%). Significant improvements were noted at initial and 1-year postoperative periods in lumbar-lordosis (2° ± 10°, P = 0.049; 3° ± 9°, P = 0.005), segmental-lordosis (6° ± 5°, P < 0.001; 5° ± 5°, P < 0.001), anterior disc height (8 mm ± 4 mm, P < 0.001; 7 mm ± 4 mm, P < 0.001), and posterior disc height (3 mm ± 2 mm, P < 0.001; 3 mm ± 2 mm, P < 0.001). Significant improvements were seen in Oswestry Disability Index at 6 weeks ( P = 0.002), 6 months ( P < 0.001), and 1 year ( P < 0.001) postoperatively; pain EQ5D at 6 weeks ( P < 0.001), 6 months ( P < 0.001), and 1 year ( P < 0.001) postoperatively; and leg and back visual analog scale at 2 weeks ( P < 0.001), 6 months ( P < 0.001), and 1 year ( P < 0.001) postoperatively. The average length of stay was 2.5 days, and the most common complications were ipsilateral hip flexor pain (46%), weakness (59%), and contralateral hip flexor pain (29%)., Conclusion: PTP is a novel way of performing LLIF. These 1-year data support that PTP is an effective, safe, and viable approach with similar patient-reported outcome measures and complications profiles as LLIF performed in the lateral decubitus position., Competing Interests: Declaration of Conflicting Interests : Dr. Singh is a consultant for AlphaTec, Stryker, and Spinewave. Dr. Moss is a consultant for AlphaTec, Stryker, Biederman, and Spinewave, and he receives royalties from AlphaTec, stock ownership in Spinal Simplicity, and Orthozon. Dr. Mallozzi is a consultant for AlphaTec and Spinewave., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2024 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

In orthopedics, X-rays and computed tomography (CT) scans play pivotal roles in diagnosing and treating bone pathologies. Machine bulkiness and the emission of ionizing radiation remain the main problems associated with these techniques. The accessibility and low risks related to ultrasound handling make it a popular 2D imaging method. Indeed, 3D ultrasound assembles 2D slices into a 3D volume. This study aimed to implement a probe-tracking method for 6 DoF 3D ultrasound. The proposed method involves a dodecahedron with ArUco markers attached, enabling computer vision tracking of the ultrasound probe's position and orientation. The algorithm focuses on the data acquisition phase but covers the basic reconstruction required for data generation and analysis. In the best case, the analysis revealed an average error norm of 2.858 mm with a standard deviation norm of 5.534 mm compared to an infrared optical tracking system used as a reference. This study demonstrates the feasibility of performing volumetric imaging without ionizing radiation or bulky systems. This marker-based approach shows promise for enhancing orthopedic imaging, providing a more accessible imaging modality for helping clinicians to diagnose pathologies regarding complex joints, such as the shoulder, replacing standard infrared tracking systems known to suffer from marker occlusion problems.

In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors., (© 2024. The Author(s).)

Enhancing screening practices and developing scalable diagnostic tools are imperative in response to the increasing prevalence of youth mental health challenges. Structured lay psychiatric interviews have emerged as one such promising tool. However, there remains limited research evaluating structured psychiatric interviews, specifically their characterization of internalizing disorders in treatment-seeking youth. This study evaluates the relationship between the Development and Well-Being Assessment (DAWBA), a structured psychiatric interview, and established measures of pediatric anxiety and depression, including the Screen for Child Anxiety Related Disorders (SCARED), the Pediatric Anxiety Rating Scale (PARS), and the Mood and Feelings Questionnaire (MFQ). The study comprised two independent clinical samples of treatment-seeking youth: sample one included 55 youth with anxiety and 29 healthy volunteers (HV), while sample two included 127 youth with Major Depressive Disorder and 73 HVs. We examined the association between the DAWBA band scores, indicating predicted risk for diagnosis, the SCARED and PARS (sample one), and the MFQ (sample two). An exploratory analysis was conducted in a subset of participants to test whether DAWBA band scores predicted the change in anxiety symptoms (SCARED, PARS) across a 12-week course of cognitive behavioral therapy. The results revealed that the DAWBA significantly predicted the SCARED, PARS and MFQ measures at baseline; however, it did not predict changes in anxiety symptoms across treatment. These findings suggest that the DAWBA may be a helpful screening tool for indexing anxiety and depression in treatment-seeking youth but is not especially predictive of longitudinal trajectories in symptomatology across psychotherapy., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Anxiety disorders are among the most prevalent psychiatric disorders. Neuroimaging findings remain uncertain, and resting state functional magnetic resonance (rs-fMRI) connectivity is of particular interest since it is a scalable functional imaging modality. Given heterogeneous past findings for rs-fMRI in anxious individuals, we characterize patterns across anxiety disorders by conducting a systematic review and meta-analysis. Studies were included if they contained at the time of scanning both a healthy group and a patient group. Due to insufficient study numbers, the quantitative meta-analysis only included seed-based studies. We performed an activation likelihood estimation (ALE) analysis that compared patients and healthy volunteers. All analyses were corrected for family-wise error with a cluster-level threshold of p < .05. Patients exhibited hypo-connectivity between the amygdala and the medial frontal gyrus, anterior cingulate cortex, and cingulate gyrus. This finding, however, was not robust to potential file-drawer effects. Though limited by strict inclusion criteria, our results highlight the heterogeneous nature of reported findings. This underscores the need for data sharing when attempting to detect reliable patterns of disruption in brain activity across anxiety disorders., Competing Interests: Declaration of Competing Interest The authors report that they have no conflict of interest., (Published by Elsevier Ltd.)

Monitoring shoulder kinematics, including the scapular segment, is of great relevance in the orthopaedic field. Among wearable systems, magneto-inertial measurement units (M-IMUs) represent a valid alternative for applications in unstructured environments. The aim of this systematic literature review is to report and describe the existing methods to estimate 3D scapular movements through wearable systems integrating M-IMUs. A comprehensive search of PubMed, IEEE Xplore, and Web of Science was performed, and results were included up to May 2023. A total of 14 articles was included. The results showed high heterogeneity among studies regarding calibration procedures, tasks executed, and the population. Two different techniques were described, i.e., with the x-axis aligned with the cranial edge of the scapular spine or positioned on the flat surface of the acromion with the x-axis perpendicular to the scapular spine. Sensor placement affected the scapular motion and, also, the kinematic output. Further studies should be conducted to establish a universal protocol that reduces the variability among studies. Establishing a protocol that can be carried out without difficulty or pain by patients with shoulder musculoskeletal disorders could be of great clinical relevance for patients and clinicians to monitor 3D scapular kinematics in unstructured settings or during common clinical practice.

Primary malignant brain tumors are the most common solid neoplasm in childhood. Despite recent advances, many children affected by aggressive or metastatic brain tumors still present poor prognosis, therefore the development of more effective therapies is urgent. Cancer stem cells (CSCs) have been discovered and isolated in both pediatric and adult patients with brain tumors (e.g., medulloblastoma, gliomas and ependymoma). CSCs are a small clonal population of cancer cells responsible for brain tumor initiation, maintenance and progression, displaying resistance to conventional anticancer therapies. CSCs are characterized by a specific repertoire of surface markers and intracellular specific pathways. These unique features of CSCs biology offer the opportunity to build therapeutic approaches to specifically target these cells in the complex tumor bulk. Treatment of pediatric brain tumors with classical chemotherapeutic regimen poses challenges both for tumor location and for the presence of the blood-brain barrier (BBB). Lastly, the application of chemotherapy to a developing brain is followed by long-term sequelae , especially on cognitive abilities. Novel avenues are emerging in the therapeutic panorama taking advantage of nanomedicine. In this review we will summarize nanoparticle-based approaches and the efficacy that NPs have intrinsically demonstrated and how they are also decorated by biomolecules. Furthermore, we propose novel cargoes together with recent advances in nanoparticle design/synthesis with the final aim to specifically target the insidious CSCs population in the tumor bulk.

Purpose: To prospectively observe opioid consumption in patients undergoing knee arthroscopy and to create an evidence-based guideline for opioid prescription., Methods: This prospective multicenter observational study enrolled patients undergoing outpatient knee arthroscopy for meniscal repair, meniscectomy, or chondroplasty. Patients were provided with a pain journal to record postoperative opioid consumption, Numeric Pain Rating Scale (NPRS) pain scores, and Likert scale satisfaction scores for 1 week postoperatively. State databases were reviewed for additional opioid prescriptions., Results: One hundred patients were included in this study. Patients were prescribed a median of 5 pills (37.5 oral morphine equivalent [OME]). Median postoperative opioid consumption was 0 pills, with a mean of 0.6 pills (4.4 OME), and 74% of patients did not consume any opioid medication postoperatively. All patients consumed ≤5 pills (37.5 OME), and no patient required a refill. Patients reported a mean daily NPRS value of 1.9 out of 10 and a mean Likert score of 4.4 out of 5., Conclusion: We found that current opioid prescribing habits exceed the need for postoperative pain management. Overall, all patients consumed ≤5 opioid pills, and 92% of patients discontinued opioids by the second postoperative day. In spite of the low prescription quantity, patients reported high satisfaction rates and low NPRS pain scores and required no refills. Therefore, we recommend that patients undergoing knee arthroscopy are prescribed no more than 5 oxycodone 5-mg pills., Level of Evidence: II, prospective prognostic cohort investigation., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background: Cognitive bias (CB) is increasingly recognized as an important source of medical error and up to 75% of errors in internal medicine are thought to be cognitive in origin (O'Sullivan ED, Schofield SJ. Cognitive bias in clinical medicine. J R Coll Physicans Edinb. 2018;48;225-232). However, primary data regarding the true incidence of bias is lacking. A prospective evaluation of CB in the management of surgical cases with complications has not been reported. This study reports the incidence and distribution of various types of CBs, and evaluates their impact on management errors and standard of care (SOC)., Methods: A prospectively collected series of 736 general surgical cases with complications from three university hospitals was analyzed. Surgical residents evaluated cases for 22 types of CBs (Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003;78:775-780). Supervising quality officers validated all quality assessments. Data were assessed for the incidence of CBs, error assessments (diagnostic, technical, judgment, system, communication, therapeutic, and professionalism), and SOC., Results: CB was attributed in 32.7% (241/736) of all cases with complications. The most common CBs identified, both singly and in groups, were anchoring, confirmation, omission, commission, overconfidence, premature closure, hindsight, diagnosis momentum, outcome, and ascertainment bias. The attribution of CB was correlated to a statistically significant increase in the incidence of management errors by the surgical team and lower SOC assessments., Conclusions: CBs are identified in the management of cases with complications and are associated with an increase in management errors and a degradation in SOC. Insight into the types of CBs and their association with the type and severity of management errors may prove useful in improving quality care., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The Accreditation Council for Graduate Medical Education has defined six core competencies (CCs) that every successful physician should possess. However, the assessment of CC achievement among trainees is difficult. This project was designed to prospectively evaluate the impact of resident identification of CC as a component of morbidity review on error identification and standard of care (SOC) assessments. The platform was assessed for its reliability as a measure of resident critical analysis of complication causality across postgraduate year (PGY)., Materials and Methods: A total of 1945 general surgery cases with complications were assessed for error identification and SOC management between January 1, 2016, and December 31, 2018. CC identification was additionally assessed between January 1, 2019, and December 31, 2019, and included 708 general surgery cases. Data were evaluated for error assessments and overall SOC management. PGY4 and 5 residents were compared for number of cases and complications reviewed, severity, error causation, and CC relevance., Results: Study groups were equivalent by Clavien-Dindo scores. Error identification significantly increased in all categories: diagnostic (P < 0.001), technical (P < 0.05), judgment (P < 0.001), system (P < 0.001), and communication (P < 0.001). Overall SOC assessments validated by a supervising surgical quality officer were unchanged. An increased exposure to cases with severe complications, error causation, and CC relevance was noted across PGY., Conclusions: The addition of CC assessment into morbidity review appears to improve the critical thinking of evaluating residents by increasing the identification of management errors. Used as an element of prospective self-assessment, teaching residents to identify CC principles in cases with complications may assist in learner progression toward clinical competence and critical thinking., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pitching velocity is one of the most important metrics used to evaluate a baseball pitcher's effectiveness. The relationship between age and pitching velocity after a lighter ball baseball training program has not been determined., Purpose/hypothesis: The purpose of this study was to examine the relationship between age and pitching velocity after a lighter ball baseball training program. We hypothesized that pitching velocity would significantly increase in all adolescent age groups after a lighter baseball training program, without a significant difference in magnitude of increase based on age., Study Design: Cohort study; Level of evidence, 2., Methods: Baseball pitchers aged 10 to 17 years who completed a 15-week training program focused on pitching mechanics and velocity improvement were included in this study. Pitchers were split into 3 groups based on age (group 1, 10-12 years; group 2, 13-14 years; group 3, 15-17 years), and each group trained independently. Pitch velocity was assessed at 4 time points (sessions 3, 10, 17, and 25). Mean, maximum, and mean change in pitch velocity between sessions were compared by age group., Results: A total of 32 male baseball pitchers were included in the analysis. Mean/maximum velocity increased in all 3 age groups: 3.4/4.8 mph in group 1, 5.3/5.5 mph in group 2, and 5.3/5.2 mph in group 3. While mean percentage change in pitch velocity increased in all 3 age groups (group 1, 6.5%; group 2, 8.3%; group 3, 7.6%), the magnitude of change was not significantly different among age groups. Program session number had a significant effect on mean and maximum velocity, with higher mean and maximum velocity seen at later sessions in the training program ( P = .018). There was no interaction between age and program session within either mean or maximum velocity ( P = .316 and .572, respectively)., Conclusion: Age had no significant effect on the magnitude of increase in maximum or mean baseball pitch velocity during a velocity and mechanics training program in adolescent males., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: P.N.C. has received educational support from Tornier and Active Medical, consulting fees from Arthrex and DePuy, and royalties from DePuy. M.E.B. has received educational support from Arthrex and Smith & Nephew, grant support from Arthrex, and hospitality payments from Stryker. A.A.R. has received research support from Aesculap/B. Braun, Arthrex, Histogenics, Medipost, Major League Baseball, NuTech, OrthoSpace, Smith & Nephew, and Zimmer; has received consulting fees and speaking fees from Arthrex; has received royalties from Arthrex, Saunders/Mosby-Elsevier, and SLACK; and is a board or committee member for Atreon Orthopaedics. B.J.E. has received educational support from Arthrex, DePuy, and Smith & Nephew. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Background: Major depressive disorder (MDD) is the leading cause of years lived with disability; however, little is known about its etiology to inform treatment. For a subset of MDD patients, appetite change and/or bodily inflammation may play a role in exacerbating symptoms. The goal of this study is to examine whether, relative to healthy comparisons (HC), MDD individuals with increased versus decreased appetite symptoms show a differential relationship between diet quality and inflammation., Methods: Unmedicated current MDD (n = 61) varying in appetite change (decrease (MDD-DE): n = 39; increase (MDD-IN): n = 22) and HC (n = 42) completed 24-hour dietary recall and state depression/anxiety measures. Healthy eating and dietary inflammatory indices were calculated from dietary reports. Blood samples measured five inflammation-related biomarkers. Analyses investigated between- and within-group differences in the Healthy Eating Index (HEI), the Dietary Inflammatory Index (DII), inflammation-related blood biomarkers, and symptom severity., Results: While both MDD-DE and MDD-IN exhibited lower HEI scores than HC, only MDD-IN showed higher plasma interleukin-1 receptor antagonist (IL-1RA) and interleukin-6 (IL-6) levels than HC. In contrast, MDD-DE exhibited higher DII scores than MDD-IN and HC. Within MDD-DE, greater symptom severity was associated with lower HEI and higher DII., Limitations: Modest sample sizes and the cross-sectional study design limited power to detect within-MDD effects., Conclusions: Although MDD, regardless of appetite change, is linked to poorer dietary quality, depression severity was related to dietary characteristics only in subjects who reported appetite loss. Thus, increasing the quality of dietary intake could be a treatment target for some individuals with depression., Competing Interests: Declaration of Competing Interest None of the authors have financial or personal conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

How parents manifest symptoms of anxiety or depression may affect how children learn to modulate their own distress, thereby influencing the children's risk for developing an anxiety or mood disorder. Conversely, children's mental health symptoms may impact parents' experiences of negative emotions. Therefore, mental health symptoms can have bidirectional effects in parent-child relationships, particularly during moments of distress or frustration (e.g., when a parent or child makes a costly mistake). The present study used simultaneous functional magnetic resonance imaging (fMRI) of parent-adolescent dyads to examine how brain activity when responding to each other's costly errors (i.e., dyadic error processing) may be associated with symptoms of anxiety and depression. While undergoing simultaneous fMRI scans, healthy dyads completed a task involving feigned errors that indicated their family member made a costly mistake. Inter-brain, random-effects multivariate modeling revealed that parents who exhibited decreased medial prefrontal cortex and posterior cingulate cortex activation when viewing their child's costly error response had children with more symptoms of depression and anxiety. Adolescents with increased anterior insula activation when viewing a costly error made by their parent had more anxious parents. These results reveal cross-brain associations between mental health symptomatology and brain activity during parent-child dyadic error processing., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Classification of mammary microcalcifications is based on radiological and histological characteristics that are routinely evaluated during the diagnostic path for the identification of breast cancer, or in patients at risk of developing breast cancer. The main aim of this study was to explore the relationship between the imaging parameters most commonly used for the study of mammary microcalcifications and the corresponding histological and chemical properties. To this end, we matched the radiographic characteristics of microcalcifications to breast lesion type, histology of microcalcifications and elemental composition of microcalcifications as obtained by energy dispersive x ray (EDX)-microanalysis. In addition, we investigated the properties of breast cancer microenvironment, under the hypothesis that microcalcification formation could result from a mineralization process similar to that occurring during bone osteogenesis. In this context, breast lesions with and without microcalcifications were compared in terms of the expression of the main molecules detected during bone mineralization (BMP-2, BMP-4, PTX3, RANKL OPN and RUNX2). Our data indicate that microcalcifications classified by mammography as "casting type" are prevalently made of hydroxyapatite magnesium substituted and are associated with breast cancer types with the poorest prognosis. Moreover, breast cancer cells close to microcalcifications expressed higher levels of bone mineralization markers as compared to cells found in breast lesions without microcalcifications. Notably, breast lesions with microcalcifications were characterized by the presence of breast-osteoblast-like cells. In depth studies of microcalcifications characteristics could support a new interpretation about the genesis of ectopic calcification in mammary tissue. Candidating this phenomenon as an integral part of the tumorigenic process therefore has the potential to improve the clinical management of patients early during their diagnostic path.

Despite the screening program, breast cancer is the commonest cause of cancer death in women in the industrialized world. In this study, we investigate the correlation among poorly differentiated carcinoma, epithelial to mesenchymal transition (EMT) phenomenon, and expression of NF-kB, Sonic Hedgehog (SHH), K-RAS, and PTX3 in breast cancer in 100 breast biopsies. Samples were classified as follows: 30 benign lesions (BL), 30 ductal infiltrating carcinomas low grade (MLG1), and 40 ductal infiltrating carcinomas high grade (MLG3). Expression of vimentin, CD44, β-catenin, NF-kB, SHH, K-RAS, CD44, and PTX3 was studied by immunohistochemistry. The different rate of cells with vimentin, nuclear β-catenin, and CD44 expression in MLG3 as compared with MLG1 and BL suggested that the process of de-differentiation of breast cancer cells could be related to the EMT. Our results showed a significant increase in NF-kB signal in MLG3 (2.33 ± 0.77) with respect to MLG1 (1.26 ± 0.55) and BL (0.86 ± 0.52). SHH expression appeared low in BL (1.00 ± 0.41) and homogenously widespread in MLG1 (1.23 ± 0.63) and MLG3 (1.56 ± 0.54). An important increase in K-RAS signal was observed in MLG3 compared to that in BL (2.20 ± 0.69 vs 0.82 ± 0.59). As regards PTX3, we observed a strong expression in MLG3 (2.00 ± 0.78) with respect to BL (0.58 ± 0.55) and MLG1 (1.53 ± 0.76). The recurring expression of NF-kB, SHH, K-RAS, and PTX3 in vimentin- and CD44-positive breast cancer cells allows to speculate that breast cells acquire the ability to express these molecules in concomitance to EMT phenomenon.

Gastroesophageal reflux disease (GERD) is a very common disorder with increasing prevalence. It is estimated that up to 20%-25% of Americans experience symptoms of GERD weekly. Excessive reflux of acidic often with alkaline bile salt gastric and duodenal contents results in a multitude of symptoms for the patient including heartburn, regurgitation, cough, and dysphagia. There are also associated complications of GERD including erosive esophagitis, Barrett's esophagus, stricture and adenocarcinoma of the esophagus. While first line treatments for GERD involve mainly lifestyle and non-surgical therapies, surgical interventions have proven to be effective in appropriate circumstances. Anti-reflux operations are aimed at creating an effective barrier to reflux at the gastroesophageal junction and thus attempt to improve physiologic and mechanical issues that may be involved in the pathogenesis of GERD. The decision for surgical intervention in the treatment of GERD, moreover, requires an objective confirmation of the diagnosis. Confirmation is achieved using various preoperative evaluations including: ambulatory pH monitoring, esophageal manometry, upper endoscopy (esophagogastroduodenoscopy) and barium swallow. Upon confirmation of the diagnosis and with appropriate patient criteria met, an anti-reflux operation is a good alternative to prolonged medical therapy. Currently, minimally invasive gastro-esophageal fundoplication is the gold standard for surgical intervention of GERD. Our review outlines the many factors that are involved in surgical decision-making. We will review the prominent features that reflect appropriate anti-reflux surgery and present suggestions that are pertinent to surgical practices, based on evidence-based studies.

Aims: Cytokeratin 19 (CK19) mRNA copy number predicts the probability of tumour load in axillary lymph nodes (ALN) and can help in decision-making regarding the axillary dissection. The purpose of this study was to define a new cut-off of CK19 mRNA copy number using the one-step nucleic acid amplification (OSNA) assay on metastatic sentinel lymph nodes (SLN) in order to identify cases at risk of having one or more positive ALN., Methods: 1296 SLN from 1080 patients were analysed with the OSNA assay. 194 patients with positive SLN underwent ALN dissection and the mean value of CK19 copy number (320 000) of their SLN was set as initial cut-off. Receiver operative characteristics curve identify a best cut-off of 7700 (sensitivity 78%, specificity 57%). A comparison between our and the traditional cut-off (5000) was performed., Results: The cut-off of 7700 successfully identifies patients with positive ALN (p=0.001, false- negative cases: 17%). In the range between 5000 and 7700, one patient with positive ALN would not undergo axillary dissection, whereas eight patients with negative ALN would be correctly identified., Conclusions: We suggest that the level of CK19 mRNA copy number could be the only parameter to consider in the intraoperative management of the axilla., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Mammary microcalcifications have a crucial role in breast cancer detection, but the processes that induce their formation are unknown. Moreover, recent studies have described the occurrence of the epithelial-mesenchymal transition (EMT) in breast cancer, but its role is not defined. In this study, we hypothesized that epithelial cells acquire mesenchymal characteristics and become capable of producing breast microcalcifications., Methods: Breast sample biopsies with microcalcifications underwent energy dispersive X-ray microanalysis to better define the elemental composition of the microcalcifications. Breast sample biopsies without microcalcifications were used as controls. The ultrastructural phenotype of breast cells near to calcium deposits was also investigated to verify EMT in relation to breast microcalcifications. The mesenchymal phenotype and tissue mineralization were studied by immunostaining for vimentin, BMP-2, β2-microglobulin, β-catenin and osteopontin (OPN)., Results: The complex formation of calcium hydroxyapatite was strictly associated with malignant lesions whereas calcium-oxalate is mainly reported in benign lesions. Notably, for the first time, we observed the presence of magnesium-substituted hydroxyapatite, which was frequently noted in breast cancer but never found in benign lesions. Morphological studies demonstrated that epithelial cells with mesenchymal characteristics were significantly increased in infiltrating carcinomas with microcalcifications and in cells with ultrastructural features typical of osteoblasts close to microcalcifications. These data were strengthened by the rate of cells expressing molecules typically involved during physiological mineralization (i.e. BMP-2, OPN) that discriminated infiltrating carcinomas with microcalcifications from those without microcalcifications., Conclusions: We found significant differences in the elemental composition of calcifications between benign and malignant lesions. Observations of cell phenotype led us to hypothesize that under specific stimuli, mammary cells, which despite retaining a minimal epithelial phenotype (confirmed by cytokeratin expression), may acquire some mesenchymal characteristics transforming themselves into cells with an osteoblast-like phenotype, and are able to contribute to the production of breast microcalcifications.

The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in all vertebrate species. In humans, the expression of Stil regulates cancer cell proliferation and survival. In this study, we examined the function of Stil in neural progenitor cell proliferation and neural differentiation using the mammalian dopaminergic (DA) PC12 cells. Stil is expressed in both proliferating and differentiated PC12 cells. The RNAi-mediated knockdown of Stil expression yielded a decreased proliferation rate of PC12 cells, whereas the overexpression of Stil transcript increased PC12 cell proliferation. The up- and down-regulation of the Sonic hedgehog (Shh) pathway by pharmacological approaches targeting Smoothened (Smo) demonstrated that Stil functions in the Shh pathway for PC12 proliferation. Smo antagonist cyclopamine decreased the proliferation rate of PC12 cells, whereas the overexpression of Stil rescued the cyclopamine-induced decrease in cell proliferation. Oppositely, the application of Smo agonist purmorphamine increased the rate of PC12 cell proliferation. However, the proliferation defect caused by Stil knockdown remained evident after activating the Shh pathway by purmorphamine. The expression of Stil is not required for PC12 cell neural differentiation. In PC12 cells transfected with Stil shRNA plasmids, the outgrowth of neurites persisted after treatment with nerve growth factor (NGF), whereas overexpression of Stil did not increase neurite growth in response to NGF induction. Together, the results from this study suggest a novel role for the oncogene Stil in neural progenitor cells through the Shh pathway, and further introduces Stil as a bio-marker for DA cells., (Copyright © 2013. Published by Elsevier Inc.)

Introduction: Surgery is currently the definitive treatment for early-stage breast cancer. However, the rate of positive surgical margins remains unacceptably high. The human sodium iodide symporter (hNIS) is a naturally occurring protein in human thyroid tissue, which enables cells to concentrate radionuclides. The hNIS has been exploited to image and treat thyroid cancer. We therefore investigated the potential of a novel oncolytic vaccinia virus GLV1h-153 engineered to express the hNIS gene for identifying positive surgical margins after tumor resection via positron emission tomography (PET). Furthermore, we studied its role as an adjuvant therapeutic agent in achieving local control of remaining tumors in an orthotopic breast cancer model., Methods: GLV-1h153, a replication-competent vaccinia virus, was tested against breast cancer cell lines at various multiplicities of infection (MOIs). Cytotoxicity and viral replication were determined. Mammary fat pad tumors were generated in athymic nude mice. To determine the utility of GLV-1h153 in identifying positive surgical margins, 90% of the mammary fat pad tumors were surgically resected and subsequently injected with GLV-1h153 or phosphate buffered saline (PBS) in the surgical wound. Serial Focus 120 microPET images were obtained six hours post-tail vein injection of approximately 600 μCi of 124I-iodide., Results: Viral infectivity, measured by green fluorescent protein (GFP) expression, was time- and concentration-dependent. All cell lines showed less than 10% of cell survival five days after treatment at an MOI of 5. GLV-1h153 replicated efficiently in all cell lines with a peak titer of 27 million viral plaque forming units (PFU) ( <10,000-fold increase from the initial viral dose ) by Day 4. Administration of GLV-1h153 into the surgical wound allowed positive surgical margins to be identified via PET scanning. In vivo, mean volume of infected surgically resected residual tumors four weeks after treatment was 14 mm3 versus 168 mm3 in untreated controls (P < 0.05)., Conclusions: This is the first study to our knowledge to demonstrate a novel vaccinia virus carrying hNIS as an imaging tool in identifying positive surgical margins of breast cancers in an orthotopic murine model. Moreover, our results suggest that GLV-1h153 is a promising therapeutic agent in achieving local control for positive surgical margins in resected breast tumors.

Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.

Vacuum-assisted breast biopsy (VABB) is now available for non-palpable lesions. The present study describes the results obtained from 226 consecutive VABBs performed at "L. Sacco" Hospital, Milan, from November 2005 to July 2007 (198 stereotactic and 28 ultrasonographic procedures). Adequate tissue samples for histopathological evaluation were obtained in 225 cases (99.6%). The diagnoses were as follows: 9 normal tissues (4%), 97 benign (43%), 25 "probably benign" (11%), 4 "suspicious for malignancy" (2%) and 90 malignant (40%, 53 in situ and 37 infiltrating carcinoma). Of the 90 malignant cases, 38 (42.2%) underwent subsequent surgical excision in our Unit; 84.2% (32/38) had concordant histopathological findings. In conclusion, VABB is an accurate and safe technique for diagnosis of non-palpable lesions, and in experienced hands avoids unnecessary surgical procedures.

Quadruplex structures arise from four coplanar G bases arranged in a Hoogsteen base pairing motif to create a central pore that can coordinate cations. The termini of eukaryotic chromosomes contain structures, known as telomeres, which are capable of forming quadruplex structures. Quadruplexes have been implicated in a variety of disease states, including cancer. The literature seems to agree that the human telomeric repeat containing four stretches of three guanines displays conformational states that are different in the presence of Na+ and K+ and an unknown number of species involved in the quadruplex to single strand transition. Using circular dichroism spectroscopy, differential scanning calorimetry, and singular-value decomposition, the number of species present in the dissociation process is assessed. The results indicate that three species exist in equilibria during the melting process. We present a model for the heat-induced denaturation from the folded to the unfolded state, whereby the hybrid parallel-antiparallel quadruplex undergoes a transition to an unknown intramolecular intermediate followed by a transition to a single strand.

Three-hundred fifty consecutively autopsied AIDS patients in Milan, Italy, were studied to determine the frequencies of clinical and postmortem diagnoses of mycobacterial diseases, to evaluate the clinical histories of those patients with mycobacterial diseases, and to investigate the reasons for nondiagnosis of mycobacterial diseases during life. Seventy-eight patients (22.3%) had mycobacterial diseases. In 64 cases (18.3%) the diagnosis was made antemortem and in 50 (14.2%) at autopsy; there were 36 cases of concordant clinical and postmortem diagnoses. Nontuberculous mycobacterioses (NTM) were diagnosed in 41 patients (20 clinical/postmortem diagnoses, 11 clinical diagnoses, and 10 postmortem diagnoses), extrapulmonary tuberculosis (TB) in 19 patients (7 clinical/postmorten, 8 clinical, 4 postmortem), and pulmonary TB in 18 patients (9 clinical/postmorten, 9 clinical). Patients with a clinical diagnosis of mycobacteriosis but with no pathological evidence of disease at autopsy were considered to have recovered on the basis of negative culture findings and prolonged antimycobacterial treatment. In Italian patients with AIDS, NTM occurs less frequently and TB more frequently than in American AIDS patients. At least some of the patients reported in this study seemed to have recovered from mycobacterial disease after prolonged treatment. The lack of diagnosis during life can be attributed to aspecific symptoms, a rapidly terminal course, and the presence of concomitant opportunistic diseases.

One hundred and eleven pituitary glands of patients (93 males, 18 females; mean age 32 years, 5 months) who died of fully developed AIDS or ARC were examined under light microscopy with the aid of immunohistochemistry. On post mortem (p.m.) examination a wide series of multiorgan alterations was noticed. Microscopically various lesions in both adeno- and neurohypophysis were seen. These ranged from vessel damage to secondaries to systemic infections, neoplasms and functional derangements. Necrotic lumps due to recent infarction could appear in both parts of the gland, while old fibrous scars sustained a previously overcome necrosis. Different pathogens (mainly fungi) could be seen either within the gland or arising from its meningeal surroundings. Examples of tumour pathology were provided by microadenomas, gliosis/gliomas; the frequency of adenomas (11.7%) was similar to that typical of senility. The functional impairment was mainly connected with ACTH cell hyperplasia, which seems in keeping with corticoadrenal or ACTH-receptor damage.

Authors report a case of male pseudohermaphroditism reared as a female since birth. At abdominal exploration gonads showed the histologic pattern of immature testes, but were almost completely replaced by sex-cord mesenchymal tumors. It is remarked the opportunity of removing dysgenetic gonads earlier than usually suggested.

In 26 consecutive cases with acquired immunodeficiency syndrome (AIDS) the main cardiac findings were Kaposi's sarcoma in 2 cases, microfocal myocardial abscess in 1, subendocardial infarct necrosis in 2, contraction band necrosis in 13, lymphocytic myocarditis in 9, intramyocardial lymphocytic infiltrates without myocell necrosis in 7 and epicardial lymphocytic infiltrates in 4. No patient had congestive heart failure. However, two-dimensional echocardiography performed in eight patients demonstrated functional abnormalities in six (fractional shortening ranging from 18 to 30%, globular shape, hypokinesia, mild ventricular dilation). Four of these six patients had lymphocytic myocarditis and two had lymphocytic infiltrates in the myocardium and epicardium without myocell necrosis. No lymphocytic infiltrates were seen in the two cases with a normal echocardiogram. Quantitative analysis indicated that involvement of the heart by lymphocytic myocarditis is inadequate in itself to explain dysfunction. It remains to be established 1) whether lymphocytic myocarditis is a possible indication of a more widespread molecular disorder, and 2) what its eventual relation with dilated cardiomyopathy will be.