Depression of natural killer cytotoxic activity in lymphocytes infiltrating human pulmonary tumors.

We assessed natural killer activity of lymphocytes present at the site of human tumors to determine the local effects of the tumor on immune function. Lymphocytes were extracted from human pulmonary tumors of varying histological types. In addition to tumor-infiltrating lymphocytes (TIL), peripheral blood lymphocytes from the same patients were prepared. Using a Michaelis-Menten kinetic model and titration of K562 targets in a 51Cr release assay, TIL exhibited a marked depression of maximal lytic capacity (Vmax) when compared to autologous peripheral blood lymphocytes. In a single cell lysis and binding assay to assess the proportion of target-binding lymphocytes and target-lysing binders, both TIL and peripheral blood lymphocytes had equivalent numbers of lymphocytes binding target cells and an equivalent number of target-binding cells that could mediate cytolysis. Analysis of lymphocyte subsets was performed using mouse monoclonal antibodies. The TIL population expressed markers found on natural killer cells, including HNK-1 and B73.1. Thus, natural killer cells are present at the tumor site, show lytic capability, but appear to be unable to recycle for multiple lytic events.

Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium.

Prostate-specific membrane antigen (PSMA), initially defined by monoclonal antibody (mAb) 7E11, is a now well-characterized type 2 integral membrane glycoprotein expressed in a highly restricted manner by prostate epithelial cells. 7E11 has been shown to bind an intracellular epitope of PSMA that, in viable cells, is not available for binding. Herein, we report the initial characterization of the first four reported IgG mAbs that bind the external domain of PSMA. Competitive binding studies indicate these antibodies define two distinct, noncompeting epitopes on the extracellular domain of PSMA. In contrast to 7E11, these mAbs bind to viable LNCaP cells in vitro. In addition, they show strong immunohistochemical reactivity to tissue sections of prostate epithelia, including prostate cancer. These mAbs were also strongly reactive with vascular endothelium within a wide variety of carcinomas (including lung, colon, breast, and others) but not with normal vascular endothelium. These antibodies should prove useful for in vivo targeting to prostate cancer, as well as to the vascular compartment of a wide variety of carcinomas.

Constitutive and antibody-induced internalization of prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed predominantly by prostate cancer cells. We have characterized four monoclonal antibodies that bind to the extracellular domain of PSMA (Liu et al., Cancer Res., 57: 3629-3634, 1997). Here we report that viable LNCaP cells internalize these antibodies. Laser scanning confocal microscopy reveals that the internalized antibodies accumulate in endosomes, and immunoelectron microscopy reveals that endocytosis of the PSMA-antibody complex occurs via clathrin-coated pits. In addition, a quantitative cell surface biotinylation assay demonstrates that PSMA is constitutively endocytosed in LNCaP cells and that anti-PSMA antibodies increase the rate of internalization of PSMA. These studies suggest that PSMA might function as a receptor mediating the internalization of a putative ligand. The availability of prostate-specific internalizing antibodies should aid the development of novel therapeutic methods to target the delivery of toxins, drugs, or short-range isotopes specifically to the interior of prostate cancer cells.

Factors affecting survival in superior sulcus tumors.

Fifty-five patients with superior sulcus syndrome were treated at the UCLA Medical Center and Wadsworth VA Hospital (Los Angeles) between 1956 and 1985. Twenty-eight underwent surgery, six of whom were found unresectable at the time of thoracotomy. Twenty-one of 22 in the resected group received preoperative irradiation. Twenty-seven patients received radiation only. Surgical morbidity was 21%, and there were two in-hospital deaths. Five-year survival for extended resection patients was 34%. The radiation only group had no 5-year survivors. Factors associated with a worse prognosis include positive margins, N2 disease, and vertebral body involvement. The best results for superior sulcus tumors are obtained by preoperative irradiation followed by en bloc resection of the tumor. In the event complete resection is impossible, radiation has a role in palliation of pain with occasional prolonged survival.

Tat-mediated protein delivery can facilitate MHC class I presentation of antigens.

We have previously shown that the tat protein of HIV-1 can be used as a carrier to promote the intracellular delivery of heterologous proteins. Here we have tested if the tat-delivery technology can be used to direct MHC class I presentation of native protein, using ovalbumin (OVA) as a model system. We show that a tat-ovalbumin conjugate (tatOVA) can be delivered into cells and that subsequent processing and presentation occurs, resulting in effective and specific killing of these target cells by an OVA specific cytotoxic T-lymphocyte (CTL) line. Comparison with the E.G7 line that expresses the OVA gene indicates that tat-mediated delivery is as efficient as endogenous expression in this system. Tat-mediated antigenic protein delivery may be useful both as a research technique and, potentially, as a therapeutic or prophylactic vaccine.

Preliminary report of immediately loaded Altiva Natural Tooth Replacement dental implants.

BACKGROUND: Osseointegration may be described as a direct contact between living bone and an alloplastic implant. It is thought that a period of undisturbed healing is required to ensure osseointegration. The length of the healing period is dependent on a number of factors, such as implant material, surface configuration, site preparation technique, bone quality, healing capacity of the osteotomy, and implant design. Elimination of the healing period offers distinct advantages in terms of cost of therapy and convenience to patients. Recently, a new one-piece implant design was proposed that provides improved stability of the implant to allow immediate support of an interim prosthesis. PURPOSE: This article presents the initial clinical experiences when the Altiva Natural Tooth Replacement one-piece implant was used in a human clinical trial. MATERIALS AND METHODS: This was a prospective multicenter study of the placement and immediate loading of the one-piece implant. A total of 142 implants were placed in the jaws of 93 patients. Implants were placed consecutively and were followed at specified intervals in three private clinical practices. Clinical performance was recorded relative to implant survival and prosthesis support. RESULTS: The implant survival rate was 93.7%, with similar responses in the maxilla (95.0%) and the mandible (92.7%). When implant failure occurred, it was observed as mobility without infection within 3 to 5 weeks of implant insertion. CONCLUSIONS: On the basis of this trial, there is promising evidence that this implant design can succeed at rates similar to other designs that require conventional healing times.

The association between the failure of dental implants and cigarette smoking.

This paper reviews the outcome of 2,194 Brånemark implants placed in 540 patients by one of the authors over a 6-year period. The overall failure rate of 5.92% is consistent with other studies; however, when patients were subdivided into smokers and nonsmokers, it was found that a significantly greater percentage of failures occurred in smokers (11.28%) than in nonsmokers (4.76%) (P < .001). These differences were significant for all areas except the posterior mandible. While failure rates decreased with increasing implant length, failure rates for each implant length were consistently higher in smokers than in nonsmokers. The possible mechanisms of failure in smokers are discussed, and a protocol for cessation of smoking around the time of surgery is proposed.

Augmentation of the maxillary sinus floor with particulated mandible: a histologic and histomorphometric study.

This study presents the results of 10 consecutive patients treated with unilateral bone augmentation of the maxillary sinus floor using particulated mandible harvested from the symphysis. Endosseous titanium implants (Brånemark) were placed 6 months after the transplant procedure. Thirty self-tapping implants were placed with a mean follow-up period of 26 months (range 12 to 46 months). Bone biopsy specimens were obtained from the donor site and the residual alveolar process at the time of grafting. A second biopsy specimen was obtained from the grafted site after 6 months of healing (at time of implant placement), and a third biopsy specimen was obtained after 12 months of healing (at time of abutment placement). Histomorphometry was performed on microradiographs using a computerized image analysis system. The bone volume fraction at the donor site before particulation was 58% +/- 19%, and the volume fraction at the residual alveolar process was 45% +/- 15%. The mean volume fraction of bone in the grafted area increased from 40% +/- 12% after 6 months of healing to 48% +/- 10% after 12 months. Histology of the retrieved bone biopsy specimens revealed normal healing and bone maturation in all samples.

Histomorphometry of bone apposition around three types of endosseous dental implants.

Three different types of commercially available dental implants (Nobelpharma, IMZ, and Integral) were implanted in the edentulous mandibles of seven adult mongrel dogs. Twenty-one implants were harvested with block sections after 12 weeks and embedded in polymethyl methacrylate resin. Undecalcified sections were prepared with the sectioning-grinding technique. The percentage of bone contacting the implant surface was measured with a self-designed histomorphometry method using a millimeter grid in a stereomicroscope. The results demonstrated a significantly higher percentage of bone along the hydroxyapatite-coated implant than that seen with the titanium-surfaced implant types.

Surgical considerations for endosseous implants in the craniofacial region: a 3-year report.

From 1987 to 1990, 28 patients were treated with titanium implants (Brånemark flange fixtures) in the craniofacial area for the support of craniofacial prosthesis or anchorage of bone-conduction hearing aids in the Orofacial Implant Center at the University of California, Los Angeles (UCLA). A total of 88 implants were placed, of which 22 were placed in previously irradiated areas. Twenty-three of the implants were placed in the orbital area, 37 in the mastoid area, 20 in the nasal area, and eight in various other craniofacial regions. Seven implants were lost in four different patients. The proper location and positioning of implants in specific areas of the craniofacial regions, as well as soft-tissue complications and management, are discussed.

Subfailure injury affects the relaxation behavior of rabbit ACL.

OBJECTIVE: To study changes in viscoelasticity of a ligament due to an incomplete or a subfailure injury. DESIGN: An in vitro study of anterior cruciate ligament preparations. BACKGROUND: The viscoelastic properties are an inherent part of the physical characteristics of a ligament. An injury to a ligament alters both its elastic and viscous properties. Although the effects of several parameters on the mechanical properties of a ligament have been studied, there is no information in the literature concerning the effect of an incomplete or subfailure injury on its viscoelastic behavior. METHODS: Ten pairs of rabbit femur-anterior cruciate ligament-tibia specimens were used. A standardized relaxation (Relax) test was adopted to quantify the viscoelastic behavior, before and after a subfailure injury. One member of the pair was subjected to three sequential tests: Relax 1; Relax 2; and stretch to failure. The other member of the pair was subjected to other three tests: Relax 3; 80% subfailure injury, i.e. stretch of 80% of failure deformation; and Relax 4. RESULTS: We found that the relaxation test by itself (Relax 1 vs Relax 2), did not affect the viscoelasticity of the ligament. On the other hand, the 80% subfailure injury (Relax 3 vs Relax 4) affected the ligament viscoelastic behavior. The force was decreased by about 50% at time zero (10.46 vs 4.79 N, p = 0.014), and at 180 s (8.14 vs 4.11 N, p = 0.018). Fitting a three-element linear viscoelastic solid model to our data, we found the serial spring stiffness to decrease by about 50% (p = 0.01), the parallel spring remained unchanged, and there was a tendency for the dashpot coefficient to decrease (by 57%, p = 0.09). CONCLUSIONS: The 80% subfailure injury decreased the initial stiffness of the ligament, and tended to decrease its viscoelastic property. RELEVANCE: Subfailure or incomplete injuries of ligaments are more common than the complete injuries. The present study describes the effects, on both the elastic and viscous properties, of a ligament subjected to a subfailure injury.

Soft-tissue modifications of surgical techniques for placement and uncovering of osseointegrated implants.

The recommended modifications of soft-tissue management for two-stage implant surgeries have resulted in improved access for implant placement, accommodation of surgical stents, less formation of cicatrix in the vestibules, better control of flap extensions resulting in improved esthetics, and improved tissue quality for long-term peri-implant maintenance and success. The implication of periodontal guidelines to the uncovering procedure of dental implants result in decreased thickness of peri-implant tissues and less pocket formation around the transmucosal sleeves. These modifications contribute significantly to the long-term periodontal maintenance of peri-implant tissues.