Attenuation of radiation- and chemoradiation-induced mucositis using gamma-D-glutamyl-L-tryptophan (SCV-07).

OBJECTIVE: To evaluate the efficacy of a novel immunomodulating peptide (SCV-07) in attenuating the course of radiation-induced mucositis in an established animal model of oral mucositis (OM). MATERIAL AND METHODS: In three separate experiments, golden Syrian hamsters received either an acute radiation challenge to the buccal mucosa of eight fractionated doses of 7.5 Gy of radiation over a 2-week-period, or a combination of acute radiation and cisplatin. In each experiment, animals were treated with varying doses or schedules of SCV-07 or placebo. OM was scored in a blinded fashion using digital images obtained during the experimental period. RESULTS: We found that SCV-07 reduced the severity and duration of both acute and fractionated radiation-induced OM. Similarly, when radiation and chemotherapy were used to induce OM, treatment with SCV-07 significantly reduced the duration of ulcerative OM. The therapeutic benefit was dependent on both dose and schedule of administration. CONCLUSION: Taken together, we found SCV-07 was able to modify the duration and severity of oral mucositis and was dependent on schedule and dose.

Immune Modulation with Thymosin Alpha 1 Treatment.

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines. Due to the immune stimulating effects of Ta1, the compound would be expected to show utility for treatment of immune suppression, whether related to aging or to diseases such as infection or cancer. Extensive studies in both the preclinical and clinical setting will be summarized in the subsequent sections. These studies have demonstrated improvements in immune system cell subsets and the potential of Ta1 for the treatment of a range of diseases.

Perinatal influences of melatonin on testicular development and photoperiodic memory in Siberian hamsters.

We assessed the influence of perinatal melatonin on reproductive development and adult responsiveness to melatonin. Testicular growth in an intermediate day length (14 : 10 h light/dark cycle) was substantially reduced in Siberian hamsters gestated by pinealectomised compared to pineal-intact females; gonadal development was normalised in offspring of pinealectomised dams that were pinealectomised at 3-4 days of age. Hamsters deprived of melatonin only during gestation, or both pre- and postnatally, underwent testicular involution during treatment with melatonin in adulthood. Photoperiodic histories acquired prenatally did not endure as long as those acquired by adult hamsters. Hamsters first exposed to melatonin in adulthood were not more proficient in acquiring photoperiodic histories than were normal males. These findings indicate that pre- versus postnatal differences in melatonin signal duration determine rates of testicular development. Exposure to melatonin perinatally does not appear to organise the neuroendocrine substrate that mediates effects of day length and melatonin on the gonads of adult hamsters.

Long-term reproductive effects of a single long day in the Siberian hamster (Phodopus sungorus).

Testicular regression was prevented or attenuated in Siberian hamsters exposed to a single 1- to 4-h extension of the 16-h photophase at 18 days of age and subsequently maintained in a short photoperiod (8L:16D) through Day 35. Testicular weights on Day 35 were not correlated with the duration of the active phase of wheel running or with the time of activity onset after transfer to the 8L:16D photoperiod. Wheel-running activity was not stably entrained to the light-dark cycle by 35 days of age. Progonadal effects of a single 33-h light pulse were greatest at 18 days of age, still evident at 30 days, but undetectable in older hamsters. In female hamsters, a single longer day at weaning was associated with increased fecundity several weeks later. Long photoperiods accelerated development of antral ovarian follicles, but exposure to males was necessary to induce ovulation before 60 days of age. The interval beginning shortly after weaning is one of heightened responsiveness to changes in day length (DL); exposure to increasing DL at this time may prolong the breeding season when DL decreases after the summer solstice. We suggest that the long-term effects of acute light treatments on reproduction are mediated by sustained changes in melatonin secretion induced by reprogramming of circadian oscillators.

Thymosinalpha1 is chemopreventive for lung adenoma formation in A/J mice.

The effects of thymosin (THN) alpha1 were investigated using the urethane injection carcinogenesis A/J mouse model. Lung adenomas were observed 2.5, 3, and 4 months after urethane injection (400 mg/kg i.p.) into female A/J mice. Daily administration of THNalpha1 (0.4 mg/kg, s.c.) reduced lung adenoma multiplicity significantly, by approximately 45, 40, and 17%, respectively, 2.5, 3, and 4 months after urethane injection. Animals treated with THNalpha1 had a significantly greater white cell density than control A/J mice. Endogenous THNalpha1-like peptides were detected in the mouse lung. By radioimmunoassay and by Western blot, prothymosin alpha was detected in the mouse lung. By immunocytochemistry, THNalpha1-like peptides were detected in all lung compartments including the bronchus, adenoma, bronchioles, and alveoli. These results indicate that exogenous THNalpha1 prevents lung carcinogenesis in A/J mice.

High doses of thymosin alpha 1 enhance the anti-tumor efficacy of combination chemo-immunotherapy for murine B16 melanoma.

BACKGROUND: We have reported previously that combined chemo-immunotherapy with cyclophosphamide (CY), thymosin alpha 1 (T alpha 1) and low dose interferon alpha,beta (IFN alpha beta) has significant anti-tumour effects. Here, using mouse B16 melanoma as a model, we tested whether increasing the dose of T alpha 1 could increase the anti-tumour activity of triple combination chemo-immunotherapy. MATERIALS AND METHODS: C57BL/6 mice were challenged subcutaneously with B16 melanoma cells and injected intraperitoneally with saline, CY (200 mg/kg, day 7), or CY with T alpha 1 (200, 600 or 6000 micrograms/kg/day, days 10-13) and IFN alpha beta (30,000 I.U., day 13). RESULTS: Chemo-immunotherapy with high dose (HD)-T alpha 1 caused complete tumour regression for 27.5 days after tumour cell injection (3.9 times longer than untreated controls) and delayed tumour relapse compared to all other groups. Moreover, it significantly increased the median survival time of treated mice, and cured an average of 23% of animals, while none was cured in any other group. Splenocytes from HD-T alpha 1-treated mice showed markedly increased cytotoxic activities against both YAC-l and autologous B16 tumour cells. HD-T alpha 1 treatment reversed the tumour-induced reduction in percentages of CD3 and CD4-positive splenocytes to non-tumour levels, and it increased percentages of CD8, B220 and IL-2R beta-positive cells to well beyond non-tumour controls. CONCLUSIONS: High doses of T alpha 1 improve anti-tumour efficacy of tnple chemo-immunotherapy against B16 melanoma. These effects appear to be mediated by stimulation of the host immune response.

Pharmacokinetics of thymosin alpha1 after subcutaneous injection of three different formulations in healthy volunteers.

OBJECTIVE: Thymosin alpha1, an immunomodulatory endogenous peptide, has been shown to be effective in the treatment of chronic hepatitis B and C. In this study, single- and 5-day multiple-dose pharmacokinetics were characterized in nine Caucasian volunteers after subcutaneous administration of 900 microg/m2 thymosin alpha1. METHODS: Using a randomized, 3-way crossover design three available drug formulations were compared: Zadaxin (SciClone), Timosina (Sclavo), and Thymosin alpha1 (Tal-HLR; Hoffmann La Roche). AUC, Cmax, t(max), t(1/2), Cl/f, and the volume of distribution, V(Z)/f, were derived by model-independent methods. RESULTS: Endogenous serum concentrations were below the limit of quantification (0.10 microg/l) of the enzyme-linked immunosorbent assay method in most subjects. Thymosin alpha1 was well absorbed with a mean t(max) between 1-2 hours from all galenic formulations. Cmax concentrations of 30 to 80 microg/l and AUC(0-infinity) from 95 to 267 microg x h/l did not differ between single- and multiple-dose administration of all drugs. This apparent lack of accumulation was supported by the short elimination half-life of less than 3 hours. As indicated by a V(Z)/f in the range of 30-40 l, thymosin alpha1 appears to distribute within the extracellular volume. AUC and Cmax were similar for Zadaxin and T alpha1-HLR, but higher after administration of Timosina. CONCLUSION: Thymosin alpha1 kinetics from this study are comparable to those previously obtained in Japanese volunteers or cancer patients, but may be influenced by the drug formulation used.

Quantitative analysis of thymosin alpha1 in human serum by LC-MS/MS.

A high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to measure the thymosin alpha 1 (Talpha1) concentration in human serum. Tá1 in human serum was determined by solid phase extraction and reverse phase LC-MS/MS. The high-performance liquid chromatography (HPLC) system interfaced with the MS/MS system with a Turbo Ion spray interface. Positive ion detection and multiple reaction monitoring (MRM) mode were used for this human serum quantitation. Eight different concentration standards were used to establish the detection range. Six quality control (QC) and 2 matrix blanks were checked by calibration curves performed on the same day. The lower quantitation limit was 0.5 ng/mL Talpha1 in human serum. Calibration curves were established between 0.5 to 100 ng/mL by weighted linear regression. The correlation coefficients for different days were 0.9955 or greater. Quantitation of Talpha1 by the LC-MS/MS method is fast, accurate, and precise.

[THYMOSIN ALFA 1,A NEW BIOLOGIC RESPONSE MODIFIER FOR THE TREATMENT OF VIRAL HEPATITIS AND HEPATOCELLULAR CARCINOMA] / Thymosin alfa 1,a new biologic response modifier for the treatment of viral hepatitis and hepatocellular carcinoma.

Thymosin alpha-1 is a new biologic response modifier that has been investigated in humans for treatment of chronic hepatitis B, chronic hepatitis C, and some types of cancer, particularly hepatocellular carcinoma. All these particular aspects are here reviewed.

A PDMS-based integrated stretchable microelectrode array (isMEA) for neural and muscular surface interfacing.

Numerous applications in neuroscience research and neural prosthetics, such as electrocorticogram (ECoG) recording and retinal prosthesis, involve electrical interactions with soft excitable tissues using a surface recording and/or stimulation approach. These applications require an interface that is capable of setting up high-throughput communications between the electrical circuit and the excitable tissue and that can dynamically conform to the shape of the soft tissue. Being a compliant material with mechanical impedance close to that of soft tissues, polydimethylsiloxane (PDMS) offers excellent potential as a substrate material for such neural interfaces. This paper describes an integrated technology for fabrication of PDMS-based stretchable microelectrode arrays (MEAs). Specifically, as an integral part of the fabrication process, a stretchable MEA is directly fabricated with a rigid substrate, such as a thin printed circuit board (PCB), through an innovative bonding technology-via-bonding-for integrated packaging. This integrated strategy overcomes the conventional challenge of high-density packaging for this type of stretchable electronics. Combined with a high-density interconnect technology developed previously, this stretchable MEA technology facilitates a high-resolution, high-density integrated system solution for neural and muscular surface interfacing. In this paper, this PDMS-based integrated stretchable MEA (isMEA) technology is demonstrated by an example design that packages a stretchable MEA with a small PCB. The resulting isMEA is assessed for its biocompatibility, surface conformability, electrode impedance spectrum, and capability to record muscle fiber activity when applied epimysially.

Maternal melatonin treatment influences rates of neonatal development of meadow vole pups.

Meadow vole dams, housed in a 14L:10D photoperiod were injected daily 3 h before onset of darkness with 10 micrograms melatonin. Treatment during gestation or lactation produced offspring that exhibited altered somatic, testicular, and pelage growth. Gestational melatonin treatment decreased preweaning weight gain, delayed testicular development, and increased pelage growth in offspring, whereas melatonin treatment during lactation increased pelage depth at weaning and increased post-weaning somatic growth. These results suggest that pre- and postnatal maternal melatonin secretory patterns influence postnatal development of photosensitive traits in offspring.

Retrospective monitoring: A review.

The development of chronological reference points to which present levels of inorganic pollutants can be compared is increasingly needed. This review is directed toward biological samples which are datable and have been characterized for one or more elements.

Sustained reproductive responses in Djungarian hamsters (Phodopus sungorus) exposed to a single long day.

Male and female Djungarian hamsters maintained from birth in a short photoperiod (8 h light per day; 8L:16D) showed substantial testicular and uterine growth in response to a single long photoperiod or a 15-min light pulse that interrupted the 16-h dark period at 18 days of age. These light regimens resulted in heavier testes and uteri at 30 and 35 days of age when compared with those of control animals. Similar results were obtained in hamsters maintained from birth to Day 18 in a long photoperiod (16L:8D), given a single longer day (20L:4D) or constant light on Day 18 and then transferred to a short photoperiod (8L:16D) on Day 19. At 35 days of age animals that received extended light treatment on Day 18 had significantly more developed reproductive structures than did control hamsters. The marked effects of brief light treatment in producing long-term changes in the reproductive axis provide a convenient mammalian model system in which to study neuroendocrine events that underlie photoperiodism.

Kinetic Analysis: Benzo(a) pyrene in Southeastern Ohio.

Kinetic Analysis has been successful for metallic elements in relatively isolated areas. In this study it is applied to a complex organic compound in a geographical area with a large urban component. Ten media compartments are included, with man as the ultimate receptor. Field data were collected for only 6 of the media and were not used in the analysis but were compared to the calculated steady state concentrations. The greatest differences between calculated and observed values were 4.8-fold for soil and 5.4-fold for sediment. The field sampling regime for soils was biased towards areas of industrialization and probably explains the higher observed value. The lower observed value for sediment is likely due to unknown variables necessary for the estimation of the compartment size and/or the associated transfer rate constants. This study indicated that the Kinetic Analysis technique can be applied successfully to the pre-sampling estimation of the distribution of organic pollutants in environmental systems.

Efficacy of repeated cycles of chemo-immunotherapy with thymosin alpha1 and interleukin-2 after intraperitoneal 5-fluorouracil delivery.

We have used chemo-immunotherapy with 5-fluorouracil (5-FU), thymosin alpha1 (T alpha1) and interleukin-2 (IL-2) to treat multiple liver metastases from colorectal cancer induced by DHD/K12 cells in syngeneic BDIX rats, comparing one and two cycles of treatment, and different treatment combinations. 5-FU was delivered loco-regionally as a continuous infusion via an intraperitoneal (i.p.) catheter from a subcutaneously implanted mini-pump, a method we developed for this study. We show here that two cycles of a triple chemo-immunotherapy regimen significantly increased the average survival time compared to one cycle, and compared to untreated controls or those treated with two cycles of 5-FU alone. At 150 days, two rats treated with two cycles of triple therapy were cured, showing no signs of cancer at autopsy; all the other rats died before this time. Triple chemo-immunotherapy resulted in significantly fewer extra-hepatic metastases than in the controls and in those treated with 5-FU only. Further, we found that two cycles of triple treatment significantly increased the absolute number of peripheral T cells expressing IL-2 receptor, CD4 and CD8 compared to controls. We conclude that two cycles of chemo-immunotherapy with 5-FU, T alpha1 and IL-2 were superior to one cycle of treatment and to other treatments tested. Our results suggest that the triple therapy acts by increasing numbers of effector T cells. This method shows promise for the use of multi-cycle chemo-immunotherapy in the treatment of unresectable metastases of colorectal cancer in humans.

In vitro effect of thymosin-alpha1 and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C.

Current evidence suggests that increased expression of Th1-associated cytokines is important for immune-mediated eradication of hepatitis C infection, while an increase in Th2-associated cytokines is associated with persistence of infection. In this study we evaluated the effects of thymosin-alpha1 (TA1), a naturally occurring thymic peptide, and interferon-alpha (IFN-alpha) on cytokine production in peripheral blood mononuclear cells from untreated patients with chronic hepatitis C. We examined the effect of incubation with TA1, IFN-alpha, or both, on production of Th1-associated cytokines (IL-2, IFN-gamma), Th2-associated cytokines (IL-4, IL-10), and synthesis of the antiviral protein 2',5'-oligoadenylate synthetase. TA1 treatment induced a significant increase in production of IL-2 and 2',5'-oligoadenylate synthetase. Smaller increases were also seen after treatment with IFN-alpha, while incubation with TA1 and IFN-alpha together led to an additive or synergistic effect. Incubation with TA1 resulted in a decrease in IL-4 and IL-10, whereas IFN-alpha increased these cytokines. The addition of TA1 to IFN-alpha significantly reversed this IFN-alpha-induced increase. Hence, TA1 treatment could benefit patients with hepatitis C infection by increasing the Th1-type response, fundamental for sustained clearance of hepatitis C; and by decreasing the Th2-type response, associated with persistence of viraemia.