Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity.

The acquisition of cytotoxic effector function by CD8(+) T cells is crucial for the control of intracellular infection and tumor invasion. However, it remains unclear which signaling pathways are required for the differentiation of CD8(+) cytotoxic T lymphocytes. We show here that Notch2-deficient T cells had impaired differentiation into cytotoxic T lymphocytes. In addition, dendritic cells with lower expression of the Notch ligand Delta-like 1 induced the differentiation of cytotoxic T lymphocytes less efficiently. We found that the intracellular domain of Notch2 interacted with a phosphorylated form of the transcription factor CREB1, and together these proteins bound the transcriptional coactivator p300 to form a complex on the promoter of the gene encoding granzyme B. Our results suggest that the highly regulated, dynamic control of T cell cytotoxicity depends on the integration of Notch2 and CREB1 signals.

Functional insulin-like factor 3 (INSL3) hormone-receptor system in the testes and spermatozoa of domestic ruminants and its potential as a predictor of sire fertility.

Insulin-like factor 3 (INSL3) is essential for fetal testis descent, and has been implicated in the testicular and sperm functions in adult males; however, similar functions in domestic ruminants remain largely unknown. This study investigated the functional INSL3 hormone-receptor system in adult ruminant testes and spermatozoa, and explored its potential to diagnose the fertility of sires. Testes and spermatozoa were obtained from fertile bulls, rams and he-goats, whereas subfertile testes and spermatozoa were obtained only from bulls. As expected, INSL3 was visualized in Leydig cells, while we clearly demonstrated that the functional receptor, relaxin family peptide receptor 2 (RXFP2), enabling INSL3 to bind was identified in testicular germ cells and in the sperm equatorial segment of bulls, rams and he-goats. In comparison to fertile bulls, the percentage of INSL3- and RXFP2-expressing cells and their expression levels per cell were significantly reduced in the testes of subfertile bulls. In addition, the population of INSL3-binding spermatozoa was also significantly reduced in the semen of subfertile bulls. These results provide evidence for a functional INSL3 hormone-receptor system operating in ruminant testes and spermatozoa, and its potential to predict subfertility in sires.

Phase II study of weekly paclitaxel for relapsed and refractory small cell lung cancer.

The purpose of this study was to evaluate the efficacy and toxicity of single-agent paclitaxel given weekly to patients with relapsed and refractory small cell lung cancer (SCLC). Patients were treated with 80 mg/m2 paclitaxel administered weekly for 1 h for 6 weeks in an 8-week cycle. Twenty-two patients were enrolled, 21 of whom were eligible. The patient characteristics included: 20 males, 1 female; median age 66 years (range 48-75); performance status 0/1 in 19 and 2 in 5 patients. Grade 3/4 leukopenia and neutropenia occurred in 47.5% and 64%, respectively. Other grade 3/4 toxicities included infection, skin rash, neuropathy and pulmonary toxicity. There were 5 partial responses in 3 out of the 11 sensitive cases and 2 out of the 10 refractory cases, respectively. Paclitaxel, administered as a weekly infusion at a dose of 80 mg/m2, was effective in treating relapsed and refractory SCLC.

Regulation of acquired immune system by notch signaling.

T- and B-cells are generated from hematopoietic stem cells through lymphoid intermediates. The interplay of intrinsic and extrinsic signals determines cell fate at the branch point for T- and B-cell lineages and at the post-commitment stage of lymphogenesis. The mature lymphocytes differentiate into effector/memory cells by antigen recognition, and those differentiation steps are also governed by a series of cell fate choices and survival signals, which allows cells to acquire distinct effector functions. The identification of the molecular details that dictate lymphocyte development and differentiation will improve understanding of acquired immune responses. Recent studies have revealed that Notch molecules, evolutionarily conserved transmembrane receptors, play key roles in lymphocyte development and differentiation. In this article, we review recent knowledge regarding the roles of Notch signaling in controlling both lymphocyte development and acquisition of effector functions.

Oblique approach of computed tomography guided needle biopsy using multiplanar reconstruction image by multidetector-row CT in lung cancer.

The purpose of this study was to establish the technique of multiplanar reconstruction (MPR) with multidetector-row (MDR) computed tomography (CT) guided needle biopsy for the diagnosis to access very difficult lesions. The CT guided percutaneous biopsy are well-established methods to obtain cytological and histological material such as the peripheral tumors in lung cancer. Occasionally, the conventional CT cannot permit planning a trajectory to avoid passage through bones, avoidance of bullae, fissures or vessels. In addition, some lesions are situated in less favorable locations such as those in the costophrenic recess or close to the mediastinum. Rarely can we diagnose them. MPR with MDR-CT has recently become widely available with applications for thoracic lesions. MPR images have been used to evaluate the location of small peripheral lung nodules to the relation of bullaes, vessels, and costophrenic recess. To diagnose these lesions, the usefulness of MPR were evaluated for an planning of an oblique approach of CT guided needle biopsy. MPR images were reconstructed as a line from the needle entry point to the target lesion. The first oblique image applied as the direction of posterior-anterior and cranio-caudal axis, and the second oblique image applied as the direction of posterior-anterior and left-right. Eleven out of 151 patients were required MPR technique to allow possible access to target, because of avoidance of bone and fissures in the needle pass or located in the costophrenic recess, between April 2001 and December 2002. The 5/11 patients were at the upper site (segment 1, 2 and 6) behind the scapula and ribs, 3/11 patients were at the lower lobe (segment 10) in the costophrenic recess, and 3/11 were middle lobe or segment 3 covered by the ribs and fissures. All the lesions except one were histologically diagnosed. Five patients were adenocarcinoma, and the other five patients were benign tumors. Pneumothorax occurred in one patient before we obtained the specimens. MPR guided needle biopsy with oblique approach was thought to be useful for diagnosis of very difficult thoracic lesions and would obviate an unnecessary surgical thoracoscopy.