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C Franks

Publications and source records attributed to C Franks.

At least 19 recordsLinked to original sources
PubMed2001

Hypoxia induces the expression of the pro-apoptotic gene BNIP3.

It has been shown that oxygen deprivation results in apoptotic cell death, and that hypoxia inducible factor 1 (HIF1) and the tumor suppressor p53 play key roles in this process. However, the molecular mechanism through which hypoxia and HIF1 induce apoptosis is not clear. Here we show that the expression of pro-apoptotic gene BNIP3 is dramatically induced by hypoxia in various cell types, including primary rat neonatal cardiomyocytes. Overexpression of HIF1alpha, but not p53, induces the expression of BNIP3. Overexpression of BNIP3 leads to a rather unusual type of apoptosis, as no cytochrome c leakage from mitochondria was detected and inhibitors of caspases were unable to prevent cell death. Taken together, these data suggest that HIF1-dependent induction of BNIP3 may play a significant role during hypoxia-induced cell death.

Animals↗
PubMed2000

Possible community immunity to small round structured virus gastroenteritis in a rural aboriginal community.

In April 1998 an outbreak of gastroenteritis affected visitors, but none of the Aboriginal residents, at a Territory Health Services luncheon in a rural Aboriginal community in Central Australia. The epidemiological features and identification of Small Round Structured Virus (SRSV) from two participants suggest that this was an outbreak caused by a SRSV. The attack rate in the visitors who ate or drank food at the luncheon was 73% (11 of 15). Seventeen Aboriginal residents were interviewed, none had gastroenteritis. The community potable water supply was contaminated with faecal bacteria around the time of the outbreak. No particular food could be implicated and laboratory examination of foods was not possible. It is proposed that past exposure to SRSVs may have resulted in the Aboriginal residents developing clinical immunity to infection. The process and consequences of the investigation in this community are also discussed.

Adult↗
PubMed1998

Transforming growth factor-beta-mediated apoptosis in the Ramos B-lymphoma cell line is accompanied by caspase activation and Bcl-XL downregulation.

Upon transforming growth factor-beta (TGF-beta) treatment, Ramos cells, a B-cell lymphoma cell line, undergo apoptosis, as measured by annexin V labeling, DNA fragmentation, and propidium iodide staining. Apoptosis could be observed by 24 h after TGF-beta exposure and occurred before the development of a significant blockage of cell cycle progression. TGF-beta-mediated apoptosis was also accompanied by a strong induction of caspase-3 subfamily activity. Incubation of cells with the caspase inhibitor Z-VAD.FMK at 20 microM, but not at 10 microM, prevented TGF-beta-induced apoptosis from occurring. By comparison, caspase-3 subfamily activity was 87% inhibited at 10 microM Z-VAD.FMK and completely inhibited at 20 microM. Because of TGF-beta's well-established role of regulating gene transcription, the mRNA levels for proteins associated with apoptosis (Fas- and Fas-associated proteins, Bcl-2 family members, IAP proteins, and I kappa B) were also studied. After 24 h of TGF-beta treatment, the most significant mRNA changes occurred with Bcl-XL (two-fold decrease) and Bik (twofold increase). TGF-beta treatment also resulted after 48 h in a fivefold decrease in Bcl-XL protein levels, based on immunoblotting analysis. Therefore, TGF-beta-mediated apoptosis involves the activation of caspases. In addition, TGF-beta transcriptionally regulates Bcl-2 family members, Bcl-XL and Bik, to further influence the apoptosis process.

Amino Acid Chloromethyl Ketones↗
PubMed1998

Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue.

We report on the cloning and sequence analysis of the mRNA coding for full-length human Janus kinase 2 (Jak2). The human form of Jak2 is 1132 amino acids in length with a M(r) of 131 KDa. It has 95% sequence similarity to pig and rat Jak2. The highest level of mRNA expression was found in the spleen, peripheral blood leukocytes, and testis. Also a significantly high level of Jak2 mRNA was found in heart and skeletal muscle. Northern blot analysis showed three mRNA species in all tissues tested, except heart and skeletal muscle, of 7.6, 5.9, and 4.8 Kb. In skeletal muscle and heart, three mRNA species of 7.6, 4.8, and 3.9 Kb were identified. The catalytic domain of the human Jak2 was expressed and its specificity for phosphorylating peptide substrates derived from the gp130, STAT, and Jak3 molecules was determined and compared to that for human Jak1 and Jak3.

Amino Acid Sequence↗
PubMed1998

hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity.

hUBC9, an E2 ubiquitin conjugating enzyme, was identified by yeast two-hybrid screening and coprecipitation studies to interact with MEKK1 and the type I TNF-alpha receptor, respectively. Because both of these proteins regulate NFkappaB activity, the role of hUBC9 in modulating NFkappaB activity was investigated. Overexpression of hUBC9 in HeLa cells stimulated the activity of NFkappaB as determined by NFkappaB reporter and IL-6 secretion assays. hUBC9 also synergized with MEKK1 to activate NFkappaB reporter activity. Thus, hUBC9 modulates NFkappaB activity which, at least in part, can be attributed to its interaction with MEKK1 and the type I TNF-alpha receptor.

Antigens, CD↗
PubMed1995

A phase II study of tamoxifen combined with cisplatin-interleukin 2 and alpha-interferon in metastatic melanoma.

Tamoxifen (TAM) has been reported to enhance cisplatin (CDDP) cytotoxicity in experimental and clinical melanoma studies. Based on our previous experience with sequential cisplatin-interleukin-2 (IL2)-interferon (IFN), we performed a phase II study of TAM combined with our original CDDP-IL2-IFN regimen in 22 pretreated metastatic melanoma patients. With a 41% response rate (95% CI, 21-61) we confirmed the interesting antitumor activity of CDDP-IL2-IFN combination; however, TAM enhanced neither the response rate nor the duration of response, but appeared to induce significantly more myelotoxicity, as compared to our previous results with CDDP-IL2-IFN alone. Whereas mechanisms by which TAM may modulate CDDP cytotoxicity in melanoma tumors remain unknown, the exact place of TAM, if any, and its safety in chemotherapeutic or chemoimmunotherapeutic combinations require further investigations.

Adult↗
PubMed1995

Adult respiratory distress syndrome and artificial surfactant replacement in the pediatric patient.

Adult respiratory distress syndrome (ARDS) frequently develops after near-drowning, smoke inhalation, burns, blunt trauma to chest, and overwhelming sepsis. Surfactant depletion, inactivation or destruction by the accumulation of proteinaceous material in the alveoli, and changes in the relative composition of phospholipids or protein component have been associated with ARDS. Artificial surfactant reverses these changes in experimental animals. Seven cases of ARDS have been treated on an experimental basis with artificial surfactant after approval and in accordance with ethical standards of the institution's committee on human experimentation. Informed consent was obtained from parents prior to administering artificial surfactant. We identified five cases of ARDS in retrospective analysis and used them as historical controls. Mortality between these two groups was analyzed with Fisher's exact test. One of seven (14.2%) children treated with surfactant died of overwhelming infection, and 2/5 (40%) of the historical controls died of pulmonary causes (P = 0.523). Statistically, surfactant therapy did not improve survival in patients with ARDS; however, ARDS patients receiving surfactant improved in their pulmonary dynamic compliance and had a tendency to stabilize earlier in gas exchange, allowing us to decrease ventilatory support.

Child↗
PubMed1994

In vivo cytokine production and recombinant interleukin 2 immunotherapy: an insight into the possible mechanisms underlying clinical responses.

Recombinant interleukin 2 (rIL-2), when given to patients with advanced malignant disease, induces a limited beneficial effect, with only 20-30% of patients with solid tumours responding. This present study has identified those patients with advanced colorectal cancer most likely to respond to rIL-2 therapy, by analysis of serum cytokine levels, prior to and during rIL-2 treatment, documented in responders and non-responders. Responders were found to have significantly lower pretreatment serum IL-6 and soluble IL-2 receptor levels (sIL-2R) than non-responders (P < 0.01 and P < 0.05 respectively). During rIL-2 infusion, responders developed high circulating levels of IL-6 and had low constant levels of prostaglandin E2 (PGE2). Non-responders failed to produce IL-6 and demonstrated elevated serum concentrations of PGE2, during infusions of rIL-2. Thus, an enhanced ongoing IL-6 and sIL-2R response, prior to therapy, was detrimental to subsequent treatment with rIL-2. Differential production and/or release of cytokines and prostaglandins, during therapy, further determined the likelihood of response to rIL-2.

Biomarkers↗
PubMed1993

Chemoimmunotherapy of metastatic malignant melanoma. The Salpétrière Hospital (SOMPS) experience.

Optimistic results were obtained in the treatment of 39 patients with surgically incurable metastatic malignant melanoma using a regimen including 2 to 3 monthly induction cycles of cis-diamminedichloroplatinum (CDDP), recombinant interleukin-2 (rIL-2) and interferon alpha-2a (IFN alpha-2a). 33 of 39 patients were pretreated with chemotherapy (dacarbazine and/or fotemustine:31, CDDP:6) and 17 of 39 with IFN alpha-2a. Overall response rate was 54% with 13% achieving a complete response for up to 59+ weeks. Moderate to severe side-effects were reversible on rIL-2 cessation and toxicity was manageable in a routine inpatient setting. These results are especially encouraging as they were seen in previously treated patients, classically low responders, including 3 who were resistant to cisplatin or other platinum complexes. The question remains if this regimen bypasses traditional mechanisms of drug resistance.

Adult↗
PubMed1991

Interleukin-2 therapy for refractory and relapsing lymphomas.

Recombinant interleukin-2 (rIL-2) has been reported to be active in metastatic renal cell carcinoma and malignant melanoma. The purpose of this trial was to determine the efficacy and toxicity of rIL-2 administered in continuous infusion in patients with Hodgkin's disease (HD) and non-Hodgkin lymphoma (NHL). 21 patients with HD (4 patients), diffuse large-cell NHL (7) or low-grade NHL (10) in failure or relapse after multiple-conventional treatments were included in this trial. rIL-2 therapy consisted of an induction period of two cycles separated by 3 weeks of rest, and, in the absence of progressive disease or undue toxicity, a maintenance period of 4 monthly cycles. Each induction cycle comprised the continuous infusion of rIL-2: 18 x 10(6) IU/m2 per day on days 1-5 and days 12-16. Each maintenance cycle comprised the continuous infusion of rIL-2: 18 x 10(6) IU/m2 per day on days 1-5. Among the 21 treated patients, 5 (all of those with low-grade NHL) responded to the induction phase (1 complete response, 4 partial responses) and 2 patients had a mixed response. Conversely, no response was observed in patients with HD or large-cell NHL. The median duration of response was 4 months. rIL-2 administered as a continuous infusion was well tolerated and most patients received the full dosage, and management did not require intensive care. During the induction period, 2 patients experienced grade III cardiovascular or renal toxicity. During the maintenance period, rIL-2 had to be interrupted in 1 patient because of a myocardial infarction. This trial confirms the inefficacy of rIL-2 for the treatment of large-cell NHL and HD. Conversely, in low-grade NHL, rIL-2 activity needs to be explored by further studies. rIL-2 may have a place in the early phase of the disease, when the immune system is not compromised, as an adjuvant treatment in residual disease in order to improve the duration of response.

Adult↗
PubMed1990

Effect of phospholipase C-gamma overexpression on PDGF-induced second messengers and mitogenesis.

Platelet-derived growth factor (PDGF) stimulates phospholipase C (PLC) activity and the phosphorylation of the gamma isozyme of PLC (PLC-gamma) in vitro and in living cells. The role of PLC-gamma in the phosphoinositide signaling pathway was addressed by examining the effect of overexpression of PLC-gamma on cellular responses to PDGF. Overexpression of PLC-gamma correlated with PDGF-induced tyrosine phosphorylation of PLC-gamma and with PDGF-induced breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2). However, neither bradykinin- nor lysophosphatidic acid-induced phosphoinositide metabolism was enhanced in the transfected cells, suggesting that the G protein-coupled phosphoinositide responses to these ligands are mediated by other PLC isozymes. The enhanced PDGF-induced generation of inositol trisphosphate (IP3) did not enhance intracellular calcium signaling or influence PDGF-induced DNA synthesis. Thus, enzymes other than PLC-gamma may limit PDGF-induced calcium signaling and DNA synthesis. Alternatively, PDGF-induced calcium signaling and DNA synthesis may use biochemical pathways other than phosphoinositide metabolism for signal transduction.

Animals↗
PubMed1990

Lymphokine-activated killer cell expansion for clinical trials of adoptive immunotherapy with interleukin-2: optimization of the culture technique.

On leukopheresis products obtained from patients included in a protocol interleukin-2/lymphokine-activated killer (IL-2/LAK) cell therapy, we analyzed, in parallel with the standard culture and on large volumes of these products, different parameters which could either improve LAK cell enhancement or simplify the procedure. We demonstrated first that purification of the mononuclear cells from the leukopheresis product before its culture is not required. An excess of red blood cells and granulocytes (up to 50%) in nonpurified samples improved both the mononuclear cell recovery in short-term culture (4 days) and the activation of LAK cells when the total nuclear cell concentration did not exceed 3 X 10(6)/ml. Different factors can contribute to this enhancing effect: the presence of red blood cells, the liberation of cytokines by granulocytes, or the loss of a population of activated lymphocytes, with liberation of cytokines by granulocytes, or the loss of a population of activated lymphocytes, with larger size and density than resting lymphocytes, during the separation. Supplementation of the medium with 2% heat-inactivated autologous plasma obtained before any treatment rather than with 2% pooled human AB serum does not modify the mononuclear cell recovery in 4-day culture, but it does enhance LAK activity. The inhibitory effect of heat-inactivated autologous plasma on proliferation and activation of LAK cells was never observed, suggesting the absence of suppressive factors in the plasma of the 23 analyzed patients. Similarly, autologous plasma did not modify natural killer and LAK cell functions when added during the cytotoxic assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Interleukin-2 after autologous bone marrow transplantation as consolidative immunotherapy against minimal residual disease.

Recipients of autologous BMT demonstrate clinically significant immune deficiency, particularly involving the T lymphocytes. While quantitatively the immune system generally returns to normal during the first 3 months, there is a prolonged delay in the recovery of qualitative immune functions. T cell proliferation is impaired immediately after transplantation and slowly recovers over a period of more than 1 year. In addition, a defect has been documented in IL-2 producing cells and may be of major importance in the pathophysiology of this immunodeficiency. However, post-ABMT, PHA-stimulated T cells are TAC+ and are able to respond to exogenous IL-2 in vitro. Very early after ABMT, NK and LAK activities of PBMC normalize but are significantly increased in vitro by IL-2. On this basis, a clinical assessment of rIL-2 administration on the immunological reconstitution of ABMT patients and as consolidation immunotherapy against minimal disease has been initiated in a phase I/II study.

Bone Marrow Transplantation↗
PubMed1989

Chemical carcinogen Epstein-Barr virus (EBV) synergism: EBV genome amplification and site-specific mutation during transformation.

When treated with chemical carcinogens, peripheral blood lymphocytes (PBLs) from normal adults or patients with acquired immunodeficiency syndrome (AIDS) were more readily transformed than non-treated PBLs into immortalized lymphoblastoid cell lines (LCLs) by the Epstein-Barr virus (EBV, FF41-1). Chemical carcinogens also enhanced spontaneous transformation in both PBL populations. Co-cultivation of lethally ultraviolet (UV)-irradiated uninfected PBLs with EBV-infected PBLs resulted in a dose-related enhancement of transformation, providing evidence that enhancement is in part mediated by carcinogen-induced diffusible trans-acting factors. Analysis of the EcoRI J region of resident EBV genomes showed that LCLs established from carcinogen-treated PBLs frequently had EBV genome amplification higher than that seen in controls. Carcinogen-induced EBV genome amplification was shown to be dose-related. The organization of the terminal region of the EBV genome was analyzed in LCLs derived from carcinogen-treated PBLs and compared to that of FF41-1 and B95-8. LCLs established from N-methyl-N'-nitroso-nitrosoguanidine (MNNG)- and aflatoxin B1-treated PBLs frequently had 2 circular forms of the EBV genome and several linear forms varying by numbers of terminal repeats (TRs) at the 3' and 5' end. This is in contrast to the single episomal circular and linear form of the EBV genome found in the parent FF41-1 and single episomal circular form in control FF41-1-carrying LCLs. Linear forms of the EBV genome were only found in FF41-1-transformed LCLs derived from carcinogen-treated PBLs and were associated with the production of unusually large amounts of infectious EBV. These results demonstrate that chemical carcinogen-mediated enhancement of transformation is accompanied by quantitative and qualitative alterations in the physical structure, organization and expression of the EBV genome which may in turn be the result of a carcinogen-induced cellular SOS response.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Immune reconstitution after bone-marrow transplantation.

Recipients of both allogeneic and autologous BMT demonstrate clinically significant immune deficiency involving T and B lymphocytes. While quantitative aspects of the immune system generally return to normal in the first 3 to 4 months, there is a prolonged delay in the recovery of qualitative immune functions. T-cell proliferation is impaired immediately after transplantation and recovers after more than 1 year. There is a documented defect in IL-2 producing cells post-BMT, but PHA-stimulated T cells are TAC+. Therefore, addition of IL-2 in vitro may normalize the T-cell proliferation defect. NK and LAK activities normalize very early post-BMT. In the light of these data, the clinical assessment of rIL-2 administration on the immunological reconstitution of ABMT patients and as consolidative immunotherapy is being investigated.

Antibody Formation↗
PubMed1987

Clinical status of carboplatin.

Carboplatin, a cisplatin derivative, shows promise of being an effective weapon against ovarian, cervical, and small-cell lung cancer, as well as epidermoid cancer of the head and neck, with fewer toxic effects than cisplatin. It has successfully completed phase III investigation and clinical trials continue.

Animals↗
PubMed1976

Stimulation of healing of varicose ulcers by ultrasound.

The local application of theraputic ultrasound has been shown, in a controlled trial, to stimulate the healing of chronic varicose ulcers. The change in ulcer size by the end of the period of treatment was noted. It was found that healing of insonated ulcers was significantly more marked than that exhibited by the controls.

Female↗