Cellular uptake of radioiodine delivered by trastuzumab can be modified by the addition of epidermal growth factor

Purpose The purpose of this study was to analyse whether non-radiolabelled epidermal growth factor (EGF) can modify the cellular uptake of ¹²⁵I when delivered as [¹²⁵I]trastuzumab. ¹²⁵I was used as a marker for the diagnostically and therapeutically more interesting isotopes ¹²³I (SPECT), ¹²⁴I (PET) and ¹³¹I (therapy).Methods The cell-associated radioactivity was measured in squamous carcinoma A431 cells following addition of [¹²⁵I]trastuzumab. Different concentrations of [¹²⁵I]trastuzumab and unlabelled EGF were used, and the total, membrane-bound and internalised radioactivity was measured. We also analysed how EGF and trastuzumab affected the cell growth. Results It was generally found that the cellular ¹²⁵I uptake was decreased by the addition of EGF when [¹²⁵I]trastuzumab was added for short incubation times. However, if the incubation times were longer, EGF increased the ¹²⁵I uptake. This shift came earlier when higher [¹²⁵I]trastuzumab concentrations were applied. The addition of EGF also influenced cell proliferation, and concentrations above 10 ng/ml reduced cell growth by approximately 20% after 24 h of incubation.Conclusion By adding unlabelled EGF, it was possible to modify the cellular uptake of [¹²⁵I]trastuzumab. This points towards new approaches for the modification of radionuclide uptake in EGFR- and HER2-positive tumours.     

Granulocyte colony-stimulating factor affects serum levels of soluble interleukin-2 receptors after allogeneic stem cell transplantation

Soluble interleukin-2 receptor (sIL-2R) levels were analyzed in 127 stem-cell transplant recipients. Granulocyte-colony stimulating factor (G-CSF) was given to 57 patients after transplantation. We found an association between G-CSF and increased sIL-2R levels. This indicates increased T-cell activation and may be one reason for the previously found increased incidence of acute graft-versus-host disease in G-CSF-treated patients.     

Increased expression of chemokines in the skin of chronic proliferative dermatitis mutant mice

Chemokines direct the migration of leukocytes to sites of inflammation and are potential targets for anti-inflammatory therapy. Chronic proliferative dermatitis (cpdm/cpdm) mutant mice develop a persistent eosinophilic dermatitis associated with increased T(H)2 cytokines in the skin. Expression patterns of chemokines in the skin of cpdm/cpdm mice were evaluated to define the mechanisms driving cutaneous infiltration by leukocytes. RNA isolated from the skin of mutant and littermate control mice revealed a significant increase in Ccl1 (TCA-3), Ccl2 (MCP-1), Ccl11 (eotaxin), Ccl17 (TARC), Cxcl10 (IP-10), and the chemokine receptor Ccr3. The concentration of CCL11 protein was increased two- to threefold in the skin of cpdm/cpdm mice by enzyme-linked immunosorbent assay. In vitro culture of primary dermal fibroblasts from cpdm/cpdm and control mice with tumor necrosis factor, IL-4, and IL-13 stimulation did not reveal differences in their ability to secrete CCL11, suggesting that the increased chemokine expression observed in the skin of cpdm/cpdm mice is most likely caused by the increased T(H)2 cytokines in the dermis of this mouse model. Treatment of cpdm/cpdm mice with CCL11-neutralizing polyclonal antibodies did not affect the number of eosinophils in the skin or the severity of the dermatitis. Neutralizing multiple chemokines or chemokine receptors may be necessary to decrease eosinophil accumulation. The cpdm/cpdm mutant mouse is a potentially useful model to determine the role of various chemokines in eosinophil accumulation in chronic inflammation.     

Movement pattern of the Exeter femoral stem; a radiostereometric analysis of 22 primary hip arthroplasties followed for 5 years.

BACKGROUND: The design of the Exeter stem may facilitate distal migration, but radiostereometric analysis (RSA) studies have been limited to 2 years of follow-up. PATIENTS AND METHODS: We followed migration of the Exeter femoral stems in 22 primary hip arthroplasties for 5 years with RSA. RESULTS: All stems migrated distally and the median migration at 2 years was 1.34 mm, while at 5 years it was 1.77 mm. 7 stems migrated above accuracy between 3 and 5 years. (RSA) evaluation of the cement mantle could be performed in 14 cases, and in 5 slight migration was found. Most of the stems rotated towards retroversion and the median rotation at 2 years was 1.2 degrees, while at 5 years it was 1.6 degrees. We found 1 patient with impending clinical failure but no deviation in the RSA migration pattern, and 1 patient with unstable migration pattern but no clinical symptoms. INTERPRETATION: We found a greater distal migration of the Exeter stem for longer periods of time than seen with other types of cemented implants.     

Proteotypic classification of spontaneous and transgenic mammary neoplasms

Introduction  

Mammary tumors in mice are categorized by using morphologic and architectural criteria. Immunolabeling for terminal differentiation markers was compared among a variety of mouse mammary neoplasms because expression of terminal differentiation markers, and especially of keratins, provides important information on the origin of neoplastic cells and their degree of differentiation.     

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.     

Current and potential agents for the treatment of alopecia areata

Alopecia areata is considered to be a T-cell mediated autoimmune disease of the hair follicle. Current immunosuppressive approaches and immunomodulatory treatment with contact sensitizers such as diphenylcyclopropenone and squaric acid dibutylester are dealt with in this review article. The efficacy of the various modes of treatment is evaluated by a review of literature and their mode of action is discussed. In accordance with the mechanism of autoimmune pathogenesis of AA, improved future treatments may be immunosuppressive or immunomodulatory, or they should otherwise protect the hair follicle from the injurious effects of the inflammation. Such possible future therapeutic approaches include the use of liposomes as an improved vehicle, application of immunosuppressive cytokines like TGF-beta and IL-10, inhibition of apoptosis mediated by the Fas-FasL system, inhibition of the lymphocyte homing receptor CD44v10, induction of tolerance as well as principles of gene therapy.     

Human papillomavirus and skin cancer

Human papillomavirus (HPV) appears to be the most ubiquitous of the human viruses. Over 100 HPV types have been identified. A minority of HPV cause cutaneous warts and mucosal condylomata. The HPV that cause mucosal condylomata put the patient at various degrees of risk for developing cancers, particularly cervical cancer. The majority of HPV infect the skin of normal and immunocompromised individuals. In normal people, most of these HPV appear to establish a latent infection of the skin, most likely as normal flora residing in hair follicles; however, in patients with various systemic and localized depressions of cell-mediated immunity, some HPV infections appear to be involved in the development of nonmelanotic skin cancer and its precursor lesions in skin, usually in sunlight-exposed areas. Circumstantial evidence suggests that these HPV may have a role in promoting proliferative lesions of the skin, although their sites of active infection and mode of transmission to susceptible individuals remain unknown.