SARS-CoV-2 infections amongst personnel providing home care services for older persons in Stockholm, Sweden.

BACKGROUND: In Sweden, home care services is a major external contact for older persons. METHODS: Five home care service companies in Stockholm, Sweden, enrolled 405 employees to a study including serum IgG to SARS-CoV-2 and SARS-CoV-2 virus in throat swabs. RESULTS: 20.1% (81/403) of employees were seropositive, about twice as many as in a simultaneously enrolled reference population (healthcare workers entirely without patient contact, n = 3671; 9.7% seropositivity). 13/379 employees (3.4%) had a current infection (PCR positivity). Amongst these, 5 were also seropositive and 3 were positive with low amounts of virus. High amounts of virus and no antibodies (a characteristic for presymptomatic COVID-19) were present in 5 employees (1.3%). CONCLUSIONS: Personnel providing home services for older persons appear to be a risk group for SARS-CoV-2. Likely presymptomatic employees can be readily identified by screening. Increased protection of employees and of the older persons they serve is warranted.

Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab.

This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.

Incident Cardiovascular Disease Risk among Older Asian, Native Hawaiian and Pacific Islander Breast Cancer Survivors.

BACKGROUND: Cardiotoxicity among breast cancer survivors is associated with chemotherapy and radiation therapy. The risk of cardiovascular disease (CVD) among Asian, Native Hawaiian and Pacific Islander (ANHPI) breast cancer survivors in the United States is unknown. METHODS: We used the SEER-Medicare linked database to estimate the risk of CVD among older breast cancer survivors. International Classification of Disease diagnosis codes were used to identify incident CVD outcomes. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI) comparing ANHPI with Non-Hispanic White (NHW) patients with breast cancer for CVD, and among ANHPI race and ethnicity groups. RESULTS: A total of 7,122 ANHPI breast cancer survivors and 21,365 NHW breast cancer survivors were identified. The risks of incident heart failure and ischemic heart disease were lower among ANHPI compared with NHW breast cancer survivors (HRheart failure, 0.72; 95% CI, 0.61-0.84; HRheart disease, 0.74; 95% CI, 0.63-0.88). Compared with Japanese patients with breast cancer, Filipino, Asian Indian and Pakistani, and Native Hawaiian breast cancer survivors had higher risks of heart failure. ischemic heart disease and death. Among ANHPI breast cancer survivors, risk factors for heart failure included older age, higher comorbidity score, distant cancer stage and chemotherapy. CONCLUSIONS: Our results support heterogeneity in CVD outcomes among breast cancer survivors among ANHPI race and ethnicity groups. Further research is needed to elucidate the disparities experienced among ANHPI breast cancer survivors. IMPACT: Filipino, Asian Indian and Pakistani, and Native Hawaiian patients with breast cancer had higher risks of heart failure, ischemic heart disease and death among ANHPI patients with breast cancer.

Individualized therapy for metastatic colorectal cancer.

Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.

[How to optimize lymph node dissection in colorectal cancers. A technique for simple and efficacious clarification]. / Comment optimiser la dissection des ganglions lymphatiques dans les carcinomes colorectaux. Une technique de clarification simple et efficace.

Studies relating to the prognosis of colorectal carcinomas insist on the quality of mesocolic examination and on the frequency of metastases in minute lymph nodes. The aim of our study was to evaluate an easy, rapid and new clearance method recently described by Koren et al. Twenty-one surgical specimens for colorectal carcinomas have been investigated. After lymph node examination with the traditional method, the mesocolic fat was immersed in a clearing solution. After 6 hours, lymph nodes stood out as white chalky nodules, and were dissected. By the traditional method 182 lymph nodes were detected and 89 additional lymph nodes after clearing. In one case, the detection of a metastasis in lymph node after clearing allowed to upstage the tumour from Dukes B (N0) to Dukes C (N+). This easy and inexpensive method allows the detection of minute lymph nodes and helps to establish a more accurate staging.

HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer.

Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 µM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor-interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.

Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability.

The DNA glycosylase MUTYH (mutY homolog (Escherichia coli)) counteracts the mutagenic effects of 8-oxo-7,8-dihydroguanine (8-oxodG) by removing adenine (A) misincorporated opposite the oxidized purine. Biallelic germline mutations in MUTYH cause the autosomal recessive MUTYH-associated adenomatous polyposis (MAP). Here we designed new tools to investigate the biochemical defects and biological consequences associated with different MUTYH mutations in human cells. To identify phenotype(s) associated with MUTYH mutations, lymphoblastoid cell lines (LCLs) were derived from seven MAP patients harboring missense as well as truncating mutations in MUTYH. These included homozygous p.Arg245His, p.Gly264TrpfsX7 or compound heterozygous variants (p.Gly396Asp/Arg245Cys, p.Gly396Asp/Tyr179Cys, p.Gly396Asp/Glu410GlyfsX43, p.Gly264TrpfsX7/Ala385ProfsX23 and p.Gly264TrpfsX7/Glu480del). DNA glycosylase assays of MAP LCL extracts confirmed that all these variants were defective in removing A from an 8-oxoG:A DNA substrate, but retained wild-type OGG1 activity. As a consequence of this defect, MAP LCLs accumulated DNA 8-oxodG in their genome and exhibited a fourfold increase in spontaneous mutagenesis at the PIG-A gene compared with LCLs from healthy donors. They were also hypermutable by KBrO3--a source of DNA 8-oxodG--indicating that the relatively modest spontaneous mutator phenotype associated with MUTYH loss can be significantly enhanced by conditions of oxidative stress. These observations identify accumulation of DNA 8-oxodG and a mutator phenotype as likely contributors to the pathogenesis of MUTYH variants.

Pas de deux / Pas de deux / Pas de deux / Pas de deux

Nem todo desenvolvimento psíquico alcança suas formas mais elaboradas de vigência. Por vezes, o processo só se realiza aos pedaços, marcando o sujeito de forma particular. Partindo da consideração do traumatismo precoce, o trabalho articula três conceitos, a saber: homossexualidade primária, relação alérgica de objeto e culpabilidade primária.

Not every psychic development reaches its most elaborated forms of being. Sometimes, the process is only partially implemented and it leaves a particular mark on the subject. Starting from the study of the precocious trauma, the author articulates three concepts, as follows: primary homosexuality, allergic relation of object, and primary culpability.

No todo el desarrollo psíquico alcanza su forma más elaborada de vigencia. A veces, ese proceso se realiza solamente por partes, marcando al sujeto de forma particular. Partiendo de la consideración del traumatismo precoz, este trabajo articula tres conceptos: homosexualidad primaria, relación alérgica de objeto y culpabilidad primaria.

Ce n'est pas tout le développement psychique qui atteint ses formes les plus élaborées d'usage. Parfois, le processus ne se réalise que peu à peu, en marquant le sujet de façon singulière. En partant d'une réflexion sur le traumatisme précoce, ce travail articule trois concepts, à savoir: l'homosexualité primaire, la relation allergique d'objet et la culpabilité primaire.

Dividir o indiviso, ou dialogar com Kant, Dostoiévski e Pontalis / Dividing the undivided, or dialoguing with Kant, Dostoyevsky and Pontalis / Dividir el indiviso, o dialogar con Kant, Dostoievski y Pontalis

Partindo da intensa reação provocada pela afirmação de Kant de que o sofrimento do melhor amigo não nos seria de todo desagradável, o autor se envereda pelos modos de constituição dos sujeitos, buscando considerar o lugar da fraternidade no mal-estar dos homens.

Starting from the intense reaction caused by Kant's statement that the best friend's suffering is not totally unpleasant for us, the author orientates his analysis towards the ways of constituting the subjects, in order to consider the place of brotherhood in human malaise.

Partiendo de la intensa reacción provocada por la afirmación de Kant de que el sufrimiento del mejor amigo no nos es del todo desagradable, el autor transita por los modos de constitución de los sujetos, buscando considerar el lugar de la fraternidad en el malestar de los hombres.

Estranho eu / Strange self / Extraño yo

Intrusão e estrangeiridade se articulam na vivência de estranhamento do eu. A partir da reflexão de Jean Luc Nancy no texto O intruso, em que examina e metaforiza sua vivência de estranhamento a partir de sua experiência como transplantado de coração, o autor propõe alguns desdobramentos e consequências sobre o preconceito.

Intrusion and foreignness intertwine in the experience of estrangement from the self. From the considerations of Jean Luc Nancy, in his text “The Intruder “, in which Nancy examines and reflects on his experience of estrangement by creating a metaphor concerning his being the subject of a heart transplant, the author proposes a few developments on prejudice and its consequences.

La intrusión y la extrañeza se articulan en la experiencia del distanciamiento de sí mismo. De la reflexión de Jean Luc Nancy, en su texto “El Intruso”, en la cual examina y metaforiza su vivencia de distanciamiento a partir de su experiencia como trasplantado de corazón, el autor propone una serie de implicaciones y consecuencias sobre el prejuicio.

A new inducible adenoviral expression system that responds to inflammatory stimuli in vivo.

BACKGROUND: Gene transfer using inducible promoters, which control expression of transgenic proteins in response to physiological conditions, may have significant advantages. In this study, we tried to achieve an inducible adenoviral expression system for physiologically responsive gene therapy of autoimmune or inflammatory diseases. METHODS: A luciferase reporter vector with a hybrid promoter containing the human IL-1beta enhancer region (-3690 to - 2720) and the human CIITA promoter IV (-399 to + 2) was constructed. A replication-deficient adenovirus was engineered with luciferase controlled by the IL1beta/CIITApIV promoter (Ad-IL1beta/CIITApIV-Luc). The reporter vector or adenovirus was transfected to C57Bl/6 myeloid dendritic cells (DCs), RAW264.7, and Hep G2 to study the in vitro characteristics of this hybrid promoter. An inflammation model was prepared by injecting lipopolysaccharide (LPS) into Balb/c mice intraperitoneally (i.p.), and infected with Ad-IL1beta/CIITApIV-Luc or Ad-CMV-Luc to study the in vivo characteristics of the IL1beta/CIITApIV promoter. RESULTS: The IL1beta/CIITApIV hybrid promoter has pronounced promoter activity, broad-range responsiveness to cytokines or LPS, and can be rechallenged after first induction. In the inflammation model, IL1beta/CIITApIV could drive hepatic luciferase expression increasedly rapidly after LPS challenge and in a LPS dose-dependent manner. CONCLUSIONS: Using the IL1beta/CIITApIV hybrid promoter in gene transfer vectors may make it possible to produce transgenic proteins in vivo in direct relationship with the intensity and duration of an individual's status. By providing endogenously controlled production of transgenic proteins, this approach might limit the severity of autoimmune or inflammatory response without interfering with the beneficial components of host defense and immunity.

Para clinicar, clinico (parafraseando Pablo Neruda em "Para nascer, nasci" ) / Para clinicar, clinico / In my Practice, I practice

Um relato subjetivo da experiência vivida pelo autor no Grupo de Trabalho "Especificidades", mediado por Leopoldo Bleger e Ruggero Levy no congresso da Fepal em Bogotá. O autor traça paralelos entre a clínica contemporânea e a experiência do grupo, em especial no corpo a corpo a partir do qual as representações se dão.

Este texto es el relato subjetivo de la experiencia vivida por el autor en el Grupo de Trabajo "Especificidades", mediado por Leopoldo Bleger y Ruggero Levy, en el XXVIII Congreso de Fepal, en Bogotá. El autor traza paralelos entre la clínica contemporánea y la experiencia del grupo, especialmente en el cuerpo a cuerpo a partir del cual tienen origen las representaciones.

This paper is a subjective report of the author's experience in one of the Working Parties held during the Fepal Congress in Bogota, Colombia, namely the one entitled "Specificities", mediated by Leopoldo Bleger and Ruggero Levy. In this paper the author describes the parallels between contemporary clinical practice and group experience, mainly in the direct, hand-to-hand experience from which the representations are originated.

A follow-up study of 300 ex-clients of a drug-free narcotic treatment program in New York City.

This article deals with an attempt at evaluating the success of a drug-free narcotic treatment program in New York City through a follow-up study of 300 ex-clients of the program. Two hundred ex-clients out of the 300 target population were actually interviewed. The number of months the clients had remained in the treatment program was found to be a key factor in the outcome of the program. The length of time in the program was itself highly dependent upon the client's background: the higher the pretreatment pathology the lower the chance of treatment success.

A compulsão nossa de cada dia / Nuestra compulsión diaria / Our daily compulsion

O autor parte de suas experiências pessoais as mais mínimas para tentar estabelecer os pontos onde as compulsões se apoiam: pequenas marcas identificatórias, pequenas experiências que vão modelando os modos de ser e existir de cada um de nós. N esta direção, enfatiza o papel e a função do meio ambiente nos processos que resultam na capacidade de representar psiquicamente.

El autor parte de sus experiencias personales las más mínimas para tratar de establecer los puntos donde las compulsiones se apoyan: pequeñas marcas identificadoras, pequeñas experiencias que van modelando las formas de ser y existir de cada uno de nosotros. En este sentido, enfatiza el papel y la función del medio ambiente en los procesos que resultan en la capacidad de representar psíquicamente.

The author bases himself on his most minimal personal experiences to attempt to establish the points where our compulsions seek support: small identifying marks, small experiences that shape the being and existence of each one of us. Towards this, he emphasizes the role and function of the environment in the processes that result in the ability of psychic representation.

O fascínio do poder na sociedade contemporânea / The fascination of power on the contemporary society

As relações entre as coisas e as palavras estão esgarçadas. E no vale-tudo de sentidos, os laços sociais se afrouxam. Este hiper-sentido da contemporaneidade provoca mudanças importantes nos modos de constituição das relações sociais e afetivas.

E então? Com ou sem dor? / And so? With or without pain?

O autor discute as resistências à psicanálise. No primeiro momento as resistências oriundas da contemporaneidade e, mais tarde, o modo com que a psicanálise resiste à própria psicanálise. Não reconhece na exigência de novos conceitos uma marca distintiva dos tempos atuais e discute os riscos do imediatismo e eficácia para a aplicação do método psicanlítico; estuda a concepção de dor como desvio; e conclui com uma pequena reflexão sobre a clínica psicanlítica, tomando o paradoxo como o mais próprio desse discurso

E então? Com ou sem dor? / Now what? With or without pain?

O autor discute as resistências à psicanálise. No primeiro momento, as resistências oriundas da contemporaneidade e, mais tarde, o modo com que a psicanálise resiste à própria psicanálise. Não reconhece na exigência de novos conceitos uma marca distintiva dos tempos atuais e discute os riscos do imediatismo e eficácia para a aplicação do método psicanalítico; estuda a concepção de dor como desvio; e conclui com uma pequena reflexão sobre a clínica psicanalítica, tomando o paradoxo como o mais próprio desse discurso

Sobre as bases freudianas da psicossomática psicanalítica: um estudo sobre as neuroses atuais / On the Freudian basis of psychoanalytical psychosomatics: a study about current neuroses

Partindo da necessidade de aprender a escutar os estados-limite, os autores buscam na leitura das neuroses atuais as bases freudianas para os esforços de teorização destes novos modos de adoecer, onde o banal ganha destaque todo especial. Trata-se de uma clínica marcada por ritmos, intensidades e pequenos movimentos, que obrigam o analista a colocar entre parênteses, mesmo que temporária e parcialmente, o modelo de aparelho psíquico tal como concebido em A interpretação dos sonhos. Dentre estes esforços de estabelecimento de uma metapsicologia dos estados-limite, destacam a Escola de Psicossomática de Paris e apresentam seus conceitos fundamentais: regressão somática e desligamento psicossomático.