Electrical Detection and Nucleation of a Magnetic Skyrmion in a Magnetic Tunnel Junction Observed via Operando Magnetic Microscopy.

Magnetic skyrmions are topological spin textures which are envisioned as nanometer scale information carriers in magnetic memory and logic devices. The recent demonstrations of room temperature skyrmions and their current induced manipulation in ultrathin films were first steps toward the realization of such devices. However, important challenges remain regarding the electrical detection and the low-power nucleation of skyrmions, which are required for the read and write operations. Here, we demonstrate, using operando magnetic microscopy experiments, the electrical detection of a single magnetic skyrmion in a magnetic tunnel junction (MTJ) and its nucleation and annihilation by gate voltage via voltage control of magnetic anisotropy. The nucleated skyrmion can be manipulated by both gate voltages and external magnetic fields, leading to tunable intermediate resistance states. Our results unambiguously demonstrate the readout and voltage controlled write operations in a single MTJ device, which is a major milestone for low power skyrmion based technologies.

Pathways to Seeking Help From a Partner Abuse Intervention Program: A Qualitative Study of Voluntary and Non-Court-Mandated Latino Men's Experiences.

Involvement in treatment for intimate partner violence and abuse (IPV/A) perpetration is often limited to those who are arrested and convicted of domestic violence offenses. Consequently, the majority of research into partner abuse intervention programs (PAIPs; also known as batterer intervention programs [BIPs]) has utilized data from court-mandated participants despite the existence of voluntary programs. Therefore, little is known about the experiences of voluntary and non-court-mandated BIP/PAIP participants. Using an interpretive phenomenological analysis, this study sought to understand how participants perceived their lived experience in seeking help from a voluntary BIP/PAIP serving Latino men. Men volunteering for this study participated in semi-structured in-depth interviews (N = 16). The findings reveal that the decision to engage in a BIP/PAIP voluntarily is process laden. Participants described the process as involving a breakdown in the health of their intimate relationship, reaching tipping points at which avoiding help was no longer an option, and locating specific information on where to seek treatment. The findings also reveal that once involved, most participants anticipated and desired to engage in the program long term. This study illuminates the many factors that may contribute to decision-making when men who have acted abusively seek help. Strategies for increasing voluntary BIP/PAIP participation may involve enhancing marketing of services or information for accessing services, and personal relationship building between facilitators and potential participants.

Reversible Al Propagation in Si x Ge1-x Nanowires: Implications for Electrical Contact Formation.

While reversibility is a fundamental concept in thermodynamics, most reactions are not readily reversible, especially in solid-state physics. For example, thermal diffusion is a widely known concept, used among others to inject dopants into the substitutional positions in the matrix and improve device properties. Typically, such a diffusion process will create a concentration gradient extending over increasingly large regions, without possibility to reverse this effect. On the other hand, while the bottom-up growth of semiconducting nanowires is interesting, it can still be difficult to fabricate axial heterostructures with high control. In this paper, we report a thermally assisted partially reversible thermal diffusion process occurring in the solid-state reaction between an Al metal pad and a Si x Ge1-x alloy nanowire observed by in situ transmission electron microscopy. The thermally assisted reaction results in the creation of a Si-rich region sandwiched between the reacted Al and unreacted Si x Ge1-x part, forming an axial Al/Si/Si x Ge1-x heterostructure. Upon heating or (slow) cooling, the Al metal can repeatably move in and out of the Si x Ge1-x alloy nanowire while maintaining the rodlike geometry and crystallinity, allowing to fabricate and contact nanowire heterostructures in a reversible way in a single process step, compatible with current Si-based technology. This interesting system is promising for various applications, such as phase change memories in an all crystalline system with integrated contacts as well as Si/Si x Ge1-x /Si heterostructures for near-infrared sensing applications.

Correlated and in-situ electrical transmission electron microscopy studies and related membrane-chip fabrication.

Understanding the interplay between the structure, composition and opto-electronic properties of semiconductor nano-objects requires combining transmission electron microscopy (TEM) based techniques with electrical and optical measurements on the very same specimen. Recent developments in TEM technologies allow not only the identification and in-situ electrical characterization of a particular object, but also the direct visualization of its modification in-situ by techniques such as Joule heating. Over the past years, we have carried out a number of studies in these fields that are reviewed in this contribution. In particular, we discuss here i) correlated studies where the same unique object is characterized electro-optically and by TEM, ii) in-situ Joule heating studies where a solid-state metal-semiconductor reaction is monitored in the TEM, and iii) in-situ biasing studies to better understand the electrical properties of contacted single nanowires. In addition, we provide detailed fabrication steps for the silicon nitride membrane-chips crucial to these correlated and in-situ measurements.

The Men's Group at St. Pius V: A Case Study of a Parish-Based Voluntary Partner Abuse Intervention Program.

Literature on Latino men and intervention for intimate partner violence/abuse (IPV/A) is slim. Over 100 men have voluntarily sought help for IPV/A perpetration from "The Men's Group" (TMG) at St. Pius V parish in Chicago, IL (US) and remained engaged for extended periods. Given the rarity of prolonged non-court mandated engagement in batterer intervention programs (BIPs), a case study was conducted to explore how TMG functions. Drawing on multiple data sources, this study examined development and implementation of TMG, while also investigating contextual factors, motivators and facilitators of participants' involvement. Data revealed that TMG functions within a supportive community context by using a mixture of traditional techniques and innovative practices, creating a unique treatment modality. The program was found to be culturally-sensitive and spirituality-based. Reasons for initial attendance varied but included: (1) fear of losing or actual loss of their partner/family; (2) acknowledging a problem and desiring to change for self or others; and (3) a desire to reach inner peace. Three themes shed light on why men remain engaged in TMG, including: (1) being met with respect by facilitators; (2) experiencing TMG as "family"; and (3) gaining benefits. Reliance upon the criminal justice system is not enough to address IPV/A perpetration. This program shows promise as an alternative or supplement to traditional BIPs, which typically rely on clients being court-mandated to attend treatment. Given the widespread nature of IPV/A, understanding the operation of potential community-based alternatives or supplements to BIPs is critical in widening access to treatment.

BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale.

BRAF V600 mutations have been found in 1-2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.

Profile of alectinib for the treatment of ALK-positive non-small cell lung cancer (NSCLC): patient selection and perspectives.

Discovered in 2007, anaplastic lymphoma kinase (ALK) gene rearrangements positive (ALK+) lung cancers compose a small subset of non-small cell lung cancer (NSCLC), with rapidly expanded treatments. There are currently several ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib which have been licensed by the US Food and Drug Administration or the European Medicines Agency for the treatment of ALK+ NSCLC patients. Along with the multiple therapies, the survival of this subtype of NSCLC has been significantly expanded, even for patients whose disease has spread in the brain. Alectinib (Alecensa), a specific ALK and rearranged during transfection tyrosine kinase inhibitor is approved as first-line therapy for metastatic ALK+ NSCLC patients. It is additionally approved for ALK+ NSCLC previously treated with crizotinib. The main aim of this review is to assemble on the efficacy of alectinib for the treatment of ALK+ NSCLC, to elaborate the activity of the drug in the central nervous system, and to debate on which is the position of this compound in the treatment course of ALK+ lung cancer patients.

EGFR first- and second-generation TKIs-there is still place for them in EGFR-mutant NSCLC patients.

Identification of epidermal growth factor receptor (EGFR) as a molecular target has radically changed the treatment of metastatic non-small cell lung cancer (NSCLC) from standard chemotherapy to personalized, targeted therapy. First-, second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) are now available for the treatment of EGFR-mutant NSCLC patients. This review will focus on the clinical development of first- and second-generation EGFR TKIs. We will emphasize on essential points like the head-to-head comparison among EGFR TKIs, their activity on brain metastases, mechanisms of resistance, as well as their combination with anti-angiogenic compounds, other targeted therapies, or immunotherapy. The efficacy of first- and second-generation EGFR TKIs in early-stage EGFR-mutant NSCLC will be also finally reviewed.

Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC).

BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. METHODS: We analyzed tumor ILK, ß-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. RESULTS: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. INTERPRETATION: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Sklodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)-receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656). METHODS: The study was a prespecified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes (RNF8, RIF1, ATM and 53BP1) as biomarkers in tissue from 177 patients with cisplatin-docetaxel-treated NSCLC. We examined the relationship of gene expression levels with progression-free survival, overall survival, and response. RESULTS: In 177 patients with NSCLC (who had a median age of 62 years and included 140 men and 91 patients with adenocarcinoma), only high PALB2 mRNA expression was predictive in the progression-free survival Cox regression analysis (hazard ratio = 0.63, 95% confidence interval: 0.42-0.83, p = 0.0080). PALB2 was also predictive of overall survival (hazard ratio = 0.68, 95% confidence interval: 0.42-0.90, p = 0.0266). Among the 158 patients evaluable for response, high PALB2 mRNA expression was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared with a rate of only 23 % for those with low PALB2 mRNA expression (p = 0.0448). CONCLUSIONS: High PALB2 mRNA expression identified patients with NSCLC who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy will become the standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making.

Challenges and unanswered questions for the next decade of immune-oncology research in NSCLC.

Over the last 20 years there have been great advances in the treatment of lung cancer. Immune checkpoint blockade together with targeted therapies have provided oncologists with the means to improve survival of non-small cell lung cancer (NSCLC) and patients with a better quality of life and therapies with manageable toxicity. Maybe in a short period of time the possibility of a cure in metastatic NSCLC will be raised. Therefore, continued research into new drugs, biomarkers and especially combination therapies is necessary in order to expand the clinical benefit of the current treatments to a broader population of NSCLC patients. The purpose of our review is to highlight our thoughts about potential mechanisms of resistance to immunotherapy that, if better explored, can provide us with both biomarkers to predict response to these therapies and partners to combine with and prolong the benefit of immune checkpoint blockade. We are presenting our own experience of immunotherapy with a case report from our institution.

[Historic evolution of psychiatric care paradigms]. / La evolución histórica de los paradigmas de atención en psiquiatría.

The rehabilitation of severely mentally-ill patients and their return to the community are related to historical progress. Their potential of achieving these goals is higher or lower depending on the presence of more or less stigma attached to their condition. Watts and Bennett have divided psychiatric rehabilitation into three phases: Phase 1: Very little was done because there was not much to be done. Patients were rejected and received mistreatment. Phase 2: Their vulnerability was admitted and protection was given to the disabled; services were provided by charity and voluntary religious institutions; there was no clear distinction between illness and poverty. Phase 3: Modern psychiatric rehabilitation began after the two World Wars in the 20th century, with attempts to modify and to oppose disability with the development of other skills. Psychiatric rehabilitation programs help these patients to resume life in the community and prevent their social isolation. By ensuring continuity of their treatment, rehabilitation programs reduce relapses and hospitalizations, thereby contributing to preserve family life and social inclusion. This reduces treatment costs to both families and communities, while promoting patients' reinsertion and recovery in the community according to their individual needs.

Quimioterapia neoadyuvante en el cáncer de mama localmente avanzado / Neoadjuvant chemotherapy in locally advanced breast cancer

La quimioterapia neoadyuvante (QTN) es el tratamiento de elección en las pacientes con cáncer de mama localmente avanzado e inflamatorio. Los objetivos de este tratamiento son mejorar las opciones quirúrgicas (convertir tumores inoperables en operables, así como obtener mejores resultados estéticos), determinar la respuesta a la quimioterapia (respuesta patológica completa [pCR, en sus siglas en inglés]) y aumentar la supervivencia libre de enfermedad. La QTN es una situación clínica ideal para investigar predictores moleculares de respuesta, predecir los pacientes que conseguirán una pCR y los pacientes con un pronóstico favorable, aunque no alcancen una pCR. Los estudios actuales definirán mejor el esquema óptimo de quimioterapia (nuevos fármacos) y los pacientes que más se beneficiarán de este tratamiento(AU)

Neoadjuvant systemic therapy (NST) has become widely accepted as the treatment of choice for patients with locally advanced and inflammatory breast cancer. In general, NST is used to improve the surgical options (induction of tumour shrinkage that may render inoperable tumours amenable to surgery and may allow smaller resection and better cosmetic outcome for patients with operable tumours), to determine the response to NST (pCR: pathologic complete response), and to obtain long-term disease-free survival. NST is an ideal clinical setting to discover molecular predictors of response to therapy, to predict patients who will achieve a pCR, and patients who will have a favourable prognosis despite not achieving a pCR. Current trials will better define the optimal NST (new drugs) and those patients who might best benefit from this therapy(AU)

Biosimilars: company strategies to capture value from the biologics market.

Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming to enter the biosimilars market: research and development, manufacturing, supporting activities, marketing, and lobbying. Understanding the importance of each of these capabilities will be key to maximising the value generated from the biologics patent cliff.

Rehabilitación psiquiátrica: claves para la recuperación / Psychiatric rehabilitation: recover keys

Contenido: Los síntomas negativos de la esquizofrenia. Sexualidad y esquizofrenia: breve revisión del tema y resultados de una encuesta a pacientes en rehabilitación. Psiquiatría metropolitana: la ascención de la psiquiatría aguda hospitalaria como una nueva especialidad. La búsqueda del tratamiento farmacológico de la esquizofrenia: desde los neurolépticos convencionales a los antipsicóticos atípicos y más allá. Tratamiento psicofarmacológico de las psicosis esquizofrénicas durante la rehabilitación. Remediación cognitiva para la enfermedad mental grave. Tratamiento integrado de la enfermedad mental grave con uso de sustancias concomitante. Recuperación de la enfermedad mental grave. Alternativas residenciales a la hospitalización crónica. La historia del Programa Second Chance. Abordaje de terapia ocupacional con enfoque psicosocial en el trastorno mental severo. Terapia ocupacional en una casa de medio camino. Internación y reponsabilidad profesional: bases médico-legales de la intervención en dispositivos previos y posteriores a la internación.

[Alternatives to chronic hospitalization in mental health]. / Alternativas a la hospitalización crónica.

It is not possible to work on alternatives to chronic institutionalization without taking into account a reform of the mental health care system. A great deal of experience has been accumulated and a lot of unsolved problems have arisen since the beginning of the deinstitutionalization in USA and Europe in the 60s. The aim was the closing of psychiatric hospitals, and so the accent was put on the physical place of treatment instead on the quality of the treatment or on the actual needs of the people involved. A review of the experiences is made and some clues are given to avoid the major problems and errors that have presented. Political decisions, experienced professionals, a stable and sufficient budget, modification of some laws, the creation of community institutions that fulfill the patient's needs before moving them, postgraduate training in rehabilitation, flexibility and creativity with empirical and scientific grounds are needed for a successful reform of the mental health care system.

[Foster Home for children with mild and moderate behavioral problems]. / Hogar infantil de tratamiento para niños con trastornos de conducta leves a moderados.

A methodology for working with children and adolescents with disruptive behavior is presented. This program has been in use since 1998 in a boarding home for boys in Buenos Aires. A common issue in this sample is the presence of non-functional families with high levels of violence between their members.

Alternativas a la hospitalización crónica / Alternatives to chronic hospitalization in mental health

No es posible ocuparse de alternativas a la hospitalización crónica sin tomar en cuenta una reforma del sistema de atención en salud mental. Desde el inicio del proceso de deshospitalización en la década de 1960, en los EE.UU. y en los países europeos, se ha acumulado mucha experiencia y se han hallado muchos problemas que aún no se han resuelto. Buscando el cierre de los hospitales psiquiátricos monovalentes se puso el énfasis en el sitio físico de tratamiento y no siempre en la calidad de la atención brindada ni en las necesidades reales de los individuos afectados. Se hace un repaso de la experiencia acumulada y se señalan pautas para evitar algunos de los principales errores y problemas que se presentaron. Para una reforma de la atención psiquiátrica exitosa son fundamentales la decisión política, la consulta a profesionales con experiencia, "un presupuesto adecuado y estable, la modificación de las leyes, la creación de las instituciones necesarias acordes con las necesidades de los pacientes antes de mudados, la formación de postgrado en rehabilitación, flexibilidad y creatividad con bases empíricas y científicas sólidas.(AU)

It is not possible to work on alternatives to chronic institutionalization without taking into account a reform of the mental health care system. A great deal of experience has been accumulated and a lot of unsolved problems have arisen since the beginning of the deinstitutionalization in USA and Europe in the 60s. The aim was the closing of psychiatric hospitals, and so the accent was put on the physical place of treatment instead on the quality of the treatment or on the actual needs of the people involved. A review of the experiences is made and some clues are given to avoid the major problems and errors that have presented. Political decisions, experienced professionals, a stable and sufficient budget, modification of some laws, the creation of community institutions that fulfill the patients needs before moving them, postgraduate training in rehabilitation, flexibility and creativity with empirical and scientific grounds are needed for a successful reform of the mental health care system.(AU)