Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies.

Cytolytic CD8 T cells play a crucial role in the control and elimination of virus-infected cells and are a major focus of HIV cure efforts. However, it has been shown that HIV-specific CD8 T cells are infrequently found within germinal centers (GCs), a predominant site of active and latent HIV infection. We demonstrate that HIV infection induces marked changes in the phenotype, frequency, and localization of CD8 T cells within the lymph node (LN). Significantly increased frequencies of CD8 T cells in the B cell follicles and GCs were found in LNs from treated and untreated HIV-infected individuals. This profile was associated with persistent local immune activation but did not appear to be directly related to local viral replication. Follicular CD8 (fCD8) T cells, despite compromised cytokine polyfunctionality, showed good cytolytic potential characterized by high ex vivo expression of granzyme B and perforin. We used an anti-HIV/anti-CD3 bispecific antibody in a redirected killing assay and found that fCD8 T cells had better killing activity than did non-fCD8 T cells. Our results indicate that CD8 T cells with potent cytolytic activity are recruited to GCs during HIV infection and, if appropriately redirected to kill HIV-infected cells, could be an effective component of an HIV cure strategy.

Targeting tyrosine kinase receptors in hepatocellular carcinoma.

The recent discoveries of genomic and molecular markers in hepatocellular carcinoma (HCC) have improved the understanding about the complexity of the signal transduction pathways as well as their relevance in normal and liver cancer cells. The identification of the functional repercussions of punctual mutations and crosstalk among cell signaling will promote the identification of specific combinatorial targeted molecular therapies to specific subsets of patients which will allow the development of personalized-based therapy and increase the survival of patients. Numerous molecular targets are in the cross-road between oncogenic and anti-apoptotic programs, genetic or epigenetic alterations, which overall may have a similar cellular phenotype. The standard antineoplastic chemotherapeutic regimes based on cytotoxic agents leads to significant side effect and modest response rates, marginal changes in natural history, and toxicities that may impact the quality of life of patients. Different strategies involving gene therapy, targeted antibodies or small molecules have been used to regulate cell death/proliferation signals, as well as angiogenesis in liver tumors. In this sense, Sorafenib recently approved for renal cell carcinoma, represents the first tyrosine kinase inhibitor (TKI) licensed for the treatment of patients with advanced HCC. This review summarizes the current status of molecular receptor TKI-based targeted therapy in HCC driving different pathways involved in cell survival, proliferation, migration, angiogenesis and metastasis, which include the regulation of Raf/MEK/ERK, PI3K/Akt/mTOR, and Jak/STAT cell signaling. The study also provides information about cell signaling crosstalk relevant in tyrosine kinase receptors (TKR)-based systemic therapy in HCC.

Genotypic diversity of imipenem resistant isolates of Acinetobacter baumannii in Spain.

OBJECTIVES: To investigate relevant clinical and microbiological features of Acinetobacter baumannii in Spanish hospitals and to establish the genotypic diversity of imipenem resistant isolates. MATERIAL AND METHODS: Seven Spanish hospitals collected 354 consecutive isolates that were subjected to antimicrobial susceptibility testing by standard methods. Further genetic analysis was determined by PFGE in a subset of 135 isolates from three hospitals selected because each of them presented high-, medium-, and low imipenem resistance rates. RESULTS: Most isolates were from males (61.9%), age >65 years (52.3%), admitted to ICU (35.6%), and isolated from the respiratory tract (31.1%). Rates of carbapenem- and sulbactam resistance were 44.9% and 39.9%, respectively. Colistin was active against multiresistant isolates. Rates of imipenem resistance varied according to individual hospital (average: 43.8%; range: 13.5%-85.0%), medical department (more prevalent in ICU), and clinical sample (higher in isolates from the respiratory tract). Of the 135 isolates studied by PFGE (64 of them imipenem-resistant), 115 (85.1%) were distributed among 14 clusters and 20 were unrelated. Of the imipenem-resistant isolates, 45 (70.3%) belonged to six clusters that also had imipenem- susceptible isolates; 14 constituted four exclusive clusters, and five were unrelated. CONCLUSIONS: Acquisition of imipenem resistance in A. baumannii is likely due to both clonal and non-clonal dissemination; resistance rates strongly vary between different hospitals and even between different hospital departments.

Etiología y diagnóstico del hematoma retroperitoneal complicado, actitud e indicación quirúrgica / Etiology and diagnosis of severe retroperitoneal hematoma: therapeutic options and surgical indication

El hematoma retroperitoneal es una entidad poco frecuente cuya repercusión clínica varía en función de la velocidad y la cuantía de la hemorragia: desde asintomático, que suele diagnosticarse casualmente en pruebas de imágenes, hasta complicado, cuyo síntomas característicos son el dolor y el shock hipovolémico. Presentamos 3 casos clínicos de hematoma retroperitoneal complicado. Si bien la bibliografía describe múltiples causas, en nuestros pacientes el origen fue siempre tumoral: 1 mielolipoma suprarrenal, 1 adenocarcinoma renal y 1 metástasis suprarrenal de adenocarcinoma broncogénico. La tomografía computarizada fue la prueba de imagen utilizada, no sólo para definir la naturaleza del proceso (hematoma, absceso, tumor), sino también para valorar la compresión de estructuras adyacentes y la existencia de hemorragia activa. Aunque se intentó el tratamiento conservador mediante reposición de la volemia y corrección de la coagulación, en todos los casos fue necesaria intervención quirúrgica urgente, 2 por inestabilidad hemodinámica y 1 por compresión de la vena cava (AU)

Retroperitoneal hematoma is a rare entity with clinical consequences that vary according to the speed and amount of bleeding. Thus, it may be asymptomatic, in which case it is usually diagnosed incidentally through imaging tests, or severe, in which case the most common symptoms are pain and hypovolemic shock. We report three cases of severe retroperitoneal hematoma. Although the literature on the subject describes a wide variety of causes, in all three patients the etiology was tumoral, consisting of one suprarenal myelolipoma, one renal adenocarcinoma and one suprarenal metastasis from bronchogenic adenocarcinoma. Computed tomography was the imaging test employed not only to determine the nature of the process (hematoma, abscess, tumor) but also to assess compression of adjacent structures and the occurrence of active bleeding. Conservative treatment consisting of volemic replacement and correction of coagulation was initially attempted. However, all three patients required emergency surgery due to hemodynamic instability in two patients and compression of the vena cava in the other (AU)

[Etiology and diagnosis of severe retroperitoneal hematoma: therapeutic options and surgical indication]. / Etiología y diagnóstico del hematoma retroperitoneal complicado, actitud e indicación quirúrgica.

Retroperitoneal hematoma is a rare entity with clinical consequences that vary according to the speed and amount of bleeding. Thus, it may be asymptomatic, in which case it is usually diagnosed incidentally through imaging tests, or severe, in which case the most common symptoms are pain and hypovolemic shock. We report three cases of severe retroperitoneal hematoma. Although the literature on the subject describes a wide variety of causes, in all three patients the etiology was tumoral, consisting of one suprarenal myelolipoma, one renal adenocarcinoma and one suprarenal metastasis from bronchogenic adenocarcinoma. Computed tomography was the imaging test employed not only to determine the nature of the process (hematoma, abscess, tumor) but also to assess compression of adjacent structures and the occurrence of active bleeding. Conservative treatment consisting of volemic replacement and correction of coagulation was initially attempted. However, all three patients required emergency surgery due to hemodynamic instability in two patients and compression of the vena cava in the other.