Potent antitumor activity of an auristatin-conjugated, fully human monoclonal antibody to prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.     

Induction of T helper cell type 1 response and elimination of HBeAg during treatment with IL-12 in a patient with therapy-refractory chronic hepatitis B

This study reports the increase of immunoregulatory T helper cell type 1 response and elimination of HBV-DNA during IL-12 therapy in a patient with chronic hepatitis B virus infection who had not responded to three previous interferon-alpha therapies and one treatment with Famciclovir over a period of 6 years. The patient received IL-12 at a dose of 0.5 microgram/kg bodyweight weekly. Peripheral blood mononuclear cells were isolated before and during IL-12 application and incubated for 7 days with specific type 1 (purified protein derivative) and type 2 (tetanus-toxoid) TH cell antigens as well as with a macrophage/monocyte activating antigen (Bacille Calmette-Guérin). In the supernatants cytokines were determined by a double-sandwich ELISA. After 8 weeks HBV-DNA became negative and HBeAg seroconversion to anti-HBeAg occurred. Immunologically the loss of viremia was accompanied by a strong increase of the purified protein derivative-induced production of the type 1 cytokine interferon-gamma (1219 pg/mL before, 13,138 pg/mL after IL-12 therapy). Furthermore, Bacille Calmette-Guérin-induced secretion of the macrophage/monocyte-associated cytokines IL-1, tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor was higher at the end of therapy. This case indicates that IL-12 enhances type 1 T helper cell activity which may be a predisposition for elimination of HBeAg and successful treatment of hepatitis B.     

Acute Isovolemic Anemia Does Not Impair Peripheral or Central Nerve Conduction

Background: Previous studies have found subtle slowing of responses in tests of addition and digit-symbol substitution during acute severe isovolemic anemia to a hemoglobin concentration of 5 g/dl in healthy unmedicated humans. In this study, the authors tested the hypothesis that such changes relate to the slowing of afferent neural traffic.

Methods: The median nerve was stimulated at the wrist in seven healthy unmedicated volunteers before and after induction of acute isovolemic anemia to a nadir hemoglobin concentration of 5.1 +/- 0.3 g/dl (mean +/- SD). Times for neural impulses to travel from the stimulus site to the brachial plexus, cervical spinal cord, and cerebral cortex were measured using somatosensory evoked potentials. Tests were repeated during acute anemia with the subject breathing oxygen. As a control for time and intrasubject variation, the testing was repeated on a separate day when anemia was not produced at times equivalent to those on the experimental day.

Results: Induced acute severe isovolemic anemia decreased nerve conduction latencies from the wrist to the contralateral cerebral cortex (i.e., to the N20 peak) by 2.3 +/- 1.6% compared with values at a mean hemoglobin concentration of 12.7 g/dl (P < 0.01). These decreased latencies were due solely to an increased peripheral conduction velocity, from the wrist to the brachial plexus (P < 0.05), and were not altered when subjects breathed oxygen (P > 0.05). Conduction velocity from the brachial plexus or cervical spinal cord to the cerebral cortex did not change with acute anemia (P > 0.05). Latencies did not differ on the control day among the times of testing (all P > 0.05), nor did they differ at baseline between the control and experimental days (all P > 0.05).     

New classification of recommendations for forensic assessment of patients with scoliosis

In 1977, for the first time, a recommendation for the expert evaluation of scoliosis-sufferers was given out. On the basis of this a new classification followed, which takes into consideration modern orthetics and new operative procedures. Unchanged are the classifications of incapacity to work with regard to decreasing lung capacity. The levels of vital capacity are still the main factor for determining lung capacity.     

Early human thymocyte proliferation is regulated by an externally controlled autocrine transforming growth factor-beta 1 mechanism

Early thymocytes undergo extensive proliferation after their entry into the thymus, but cellular interactions and cytokines regulating this intrathymic step remain to be determined. We analyzed the effects of various T-cell growth factors and cellular interactions on in vitro proliferation of early CD2+CD3/TCR-CD4-CD8- (triple negative [TN]) human thymocytes. Freshly isolated TN cells were then assayed for their growth capacity after incubation with CD2I+III-monoclonal antibody (MoAb), recombinant human interleukin-2 (IL-2), IL-7, and/or IL-4. These cells displayed significant proliferative responses with IL-4, IL- 7, or CD2-MoAb+IL-2. The addition of recombinant transforming growth factor beta (TGF beta) or autologous irradiated CD3+CD8+CD4- cells to TN cell cultures dramatically decreased their growth responses to IL-2 and IL-7, whereas IL-4-induced proliferation was less sensitive to growth inhibition. We thus asked whether the CD8+ cell-derived inhibitory effect was due to TGF beta. The addition of neutralizing anti-TGF beta MoAb completely abolished CD8+ cell-derived inhibition of TN cell growth. Analysis of CD8+ cell-derived supernatants indicated that these cells had low TGF beta 1 production capacity, whereas TN cells secrete significantly high levels of TGF beta 1. Cell fixation studies showed that TN cells were the source of the TGF beta. TGF beta 1 released from TN cells was in the latent form that became the active inhibitory form through interaction of TN cells with CD8+ cells. Together, these data suggest a role for TGF beta 1 as an externally controlled, autocrine inhibitory factor for human early thymocytes, with a regulatory role in thymic T-cell output.     

Zur Frage der Konstanz und Abgrenzbarkeit myeloarchitektonischer Rindenfelder

Zusammenfassung An Hand von Faserpräparaten der hinteren Zentralwindung von 11 verschiedenen Hemisphären und des Schläfenlappenpols von 10 verschiedenen Hemisphären wurde zu zeigen versucht, daß die an den genannten Rindenstellen beschriebenen Felder konstant bei allen Individuen vorkommen und sich stets scharf abgrenzen lassen. Zur raschen Orientierung an der Hirnrinde sowie zur genauen Bestimmung des Sitzes von Herden erscheint die myeloarchitektonische Methode besonders geeignet.Mit 9 Textabbildungen.Herrn Prof. Kleist in Verehrung und Dankbarkeit zum 75. Geburtstag gewidmet.     

Irritation des Plexus lumbalis durch Aneurysma der Aorta abdominalis

Case report on a 67-year-old patient presenting sensory disturbances involving the segments L1--L3 and absence of the knee jerk in the left leg. At postmortem examination an arteriosclerotic aneurysm of the aorta abdominalis was found to be the cause for the lesion of the upper lumbar roots.