Remote Mesoscopic Signatures of Induced Magnetic Texture in Graphene.

Mesoscopic conductance fluctuations are a ubiquitous signature of phase-coherent transport in small conductors, exhibiting universal character independent of system details. In this Letter, however, we demonstrate a pronounced breakdown of this universality, due to the interplay of local and remote phenomena in transport. Our experiments are performed in a graphene-based interaction-detection geometry, in which an artificial magnetic texture is induced in the graphene layer by covering a portion of it with a micromagnet. When probing conduction at some distance from this region, the strong influence of remote factors is manifested through the appearance of giant conductance fluctuations, with amplitude much larger than e^{2}/h. This violation of one of the fundamental tenets of mesoscopic physics dramatically demonstrates how local considerations can be overwhelmed by remote signatures in phase-coherent conductors.

Incidentally Detected Gastric Gastrointestinal Stromal Tumor during Living Donor Liver Transplant Surgery for Hepatocellular Carcinoma: The First Two Cases.

Coexistence of hepatocellular carcinoma and gastrointestinal stromal tumor is rare. In this case series, we aimed to present an unusual coincidence of a gastrointestinal stromal tumor and hepatocellular carcinoma in patients who underwent living donor liver transplantation for hepatocellular carcinoma who had an incidental gastric gastrointestinal tumor which was detected intraoperatively.

Universal scaling of weak localization in graphene due to bias-induced dispersion decoherence.

The differential conductance of graphene is shown to exhibit a zero-bias anomaly at low temperatures, arising from a suppression of the quantum corrections due to weak localization and electron interactions. A simple rescaling of these data, free of any adjustable parameters, shows that this anomaly exhibits a universal, temperature- (T) independent form. According to this, the differential conductance is approximately constant at small voltages (V < kBT/e), while at larger voltages it increases logarithmically with the applied bias. For theoretical insight into the origins of this behaviour, which is inconsistent with electron heating, we formulate a model for weak-localization in the presence of nonequilibrium transport. According to this model, the applied voltage causes unavoidable dispersion decoherence, which arises as diffusing electron partial waves, with a spread of energies defined by the value of the applied voltage, gradually decohere with one another as they diffuse through the system. The decoherence yields a universal scaling of the conductance as a function of eV/kBT, with a logarithmic variation for eV/kBT > 1, variations in accordance with the results of experiment. Our theoretical description of nonequilibrium transport in the presence of this source of decoherence exhibits strong similarities with the results of experiment, including the aforementioned rescaling of the conductance and its logarithmic variation as a function of the applied voltage.

Interleukin-6 functions as an intracellular growth factor in hairy cell leukemia in vitro.

The role of interleukin-6 (IL-6) in the growth of B cell derived hairy cell leukemia (HCL) was characterized. Purified hairy cells (HCs) did not increase DNA synthesis in vitro in response to exogenous IL-6; however, they expressed IL-6 receptor (IL-6R) mRNA and bound directly fluorochrome labeled IL-6. IL-6 mRNA was not detectable in tumor cells by Northern blotting, but was evident using PCR amplification. Although intracytoplasmic IL-6 protein was not demonstrable, HCs did secrete low levels of IL-6. Neutralizing antibody to IL-6 did not inhibit HC DNA synthesis. Since tumor necrosis factor (TNF) is a growth factor for HCL, we determined whether the TNF effect could be IL-6-mediated. TNF markedly augmented in vitro DNA synthesis by HCs. TNF did not alter IL-6R expression or IL-6 binding; however, IL-6 mRNA and IL-6 protein were detectable after 3-d culture of HCs with TNF. In addition, IL-6 secretion by HCs was markedly augmented by TNF. Finally, although neither IL-6 nor anti-IL-6 antibody altered TNF-induced DNA synthesis by HCs, IL-6 antisense oligonucleotide inhibited TNF-induced DNA synthesis and IL-6 secretion by HCs. Therefore, IL-6 does not directly affect the growth of HCL, but rather mediates TNF-induced DNA synthesis via an intracytoplasmic mechanism.

Pregnancy After Liver Transplantation: Risks and Outcomes.

OBJECTIVE: The aim of this study was to evaluate the outcomes of liver transplant recipients who became pregnant after transplantation. METHODS: The clinical data of all patients who underwent liver transplantation between January 2007 and December 2016 in our liver transplantation institute were reviewed. The following data were analyzed: indications for transplantation, recipient age at the beginning of pregnancy, the interval between transplantation and pregnancy, maternal and fetal complications, type of delivery, the health condition of neonates, and modifications in immunosuppressive therapy. RESULTS: During the study period, 1890 patients underwent liver transplantation. There were 185 women (9.8%) in childbearing age (15-45 years old), and 18 (9.7%) of them became pregnant during the study period. There were a total of 26 pregnancies. The mean age of patients at the time of operation was 25.3 ± 5.2 years, and the mean interval between operation and conception was 32.7 ± 15.3 months. Seventeen pregnancies (65.4%) ended in a live birth in the study. Six pregnancies (23%) resulted with no maternal or fetal complications. The most frequent maternal complication during pregnancy was pregnancy-induced hypertension (n = 3; 16.6%). CONCLUSIONS: Despite advances in immunosuppressive therapy and increasing experience in the management of these patients, pregnancies in liver transplant recipients are still more risky than in the general population for both the mother and the fetus. Thus, the issues related to fertility should be comprehensively discussed with the patients and their partners, preferably before transplantation, and pregnancies in liver transplant recipients should be followed up more carefully by a multidisciplinary team.

Living related donor liver transplantation with atrio-caval anastomosis of inferior vena cava graft stored in deep-freeze for budd-Chiari syndrome.

We have previously reported our experience in inferior vena cava resection and reconstruction techniques during liver transplantation for Budd-Chiari syndrome. Herein, we present on a case that demonstrates the importance of experience in complex vascular reconstruction techniques for living donor liver transplantation. A 15-year-old boy was scheduled for living donor liver transplantation for Budd-Chiari syndrome. Venous occlusion was extended up to the right atrial orifice of the supra-hepatic vena cava. Retro- and supra-hepatic segments of the vena cava was resected. Inferior vena cava graft stored in deep-freeze was available. Venous reconstruction was performed with end-to-end atrio-caval anastomosis. Surgical treatment was completed with the implantation of the right liver lobe donated by the patient's mother. Post-surgical course was uneventful.

Realizing the potential of zebrafish as a model for human disease.

The value of the zebrafish (Danio rerio) as a model for human disease has been substantiated by a number of recently published papers. Several zebrafish mutants with "human" diseases have been found, spanning a variety of human pathologies. These successful studies utilizing the zebrafish have been made possible by the development of key reagents such as YAC, PAC, and BAC libraries, as well as radiation hybrid panels. With the further establishment of new tools and access to the newly generated resources, the zebrafish is poised to serve as a novel model for human disease.

Isolation and characterization of metastatic sublines from a murine transitional cell bladder carcinoma.

Four sublines of a murine N-[4-(5-nitro-2-furyl)-2-thiazolyl]-foramide (FANFT)-induced transitional cell carcinoma (MBT-2) possessing spontaneous metastatic ability were isolated via in vivo/in vitro serial selection of metastatic lung lesions. Subcutaneous inoculation of the parent cell line (MBT-2) produced primary tumors when injected into C3H mice. These primary tumors rarely metastasize. A subline designated L3F1 was established from 1 MBT-2 pulmonary metastatic tumor. Further in vivo/in vitro selections established three additional sublines designated L3F2, L3F3 and L3F4. Serial selection resulted in MBT-2 sublines of greater metastatic potential in terms of both incidence of metastasis and the number of metastatic tumors per lung. The parent line differed from the four sublines in metastatic potential, in vitro cell morphology, and in vitro growth parameters. The L3F2 subline was examined for the time of onset of metastasis by removal of the primary tumor. Metastasis of the subcutaneously transplanted tumor occurred between 14 and 21 days after injection of the L3F2 subline. The L3F2 primary tumors and lung metastases were morphologically characterized by light and electron microscopy.

Lack of a role of interleukin 11 in the growth of multiple myeloma.

Interleukin (IL) 11 is a recently described lymphokine which, like IL-6, stimulates normal hematopoietic murine and human hematopoietic progenitor cells and therefore has potential value for either enhancing hematopoiesis in disease states or augmenting hematopoietic recovery after myeloablative therapies. Since IL-6 is known to promote the growth of human myeloma, either in an autocrine or paracrine fashion, we examined the effect of IL-11 on the growth of a murine plasmacytoma cell line, human myeloma-derived cell lines, and freshly isolated human myeloma cells. Interleukin 11 does increase DNA synthesis by the murine plasmacytoma line T10 in the presence of neutralizing antibody to IL-6. However, neither human myeloma cells nor derived cell lines express IL-11 mRNA; secrete IL-11; express IL-11 cell surface receptors; or augment either DNA synthesis or Ig secretion in response to exogenous IL-11. These findings strongly suggest that IL-11 does support the growth of a murine plasmacytoma cell line but does not play a role in the growth of either freshly isolated human myeloma cells or derived cell lines.

Role of interleukin 6 in the growth of myeloma-derived cell lines.

The role of interleukin 6 (IL-6) in the growth of five multiple myeloma-derived cell lines was characterized. The U266 and RPMI 8226 cell lines demonstrated increased DNA synthesis when cultured with exogenous IL-6, expressed IL-6 cell surface receptors (IL-6Rs) and expressed mRNA for IL-6R. However, these cells did not secrete detectable IL-6 protein, and a neutralizing antibody to IL-6 did not inhibit their growth. Three other myeloma-derived cell lines ARH-77, IM-9 and HS-Sultan did not respond to exogenous IL-6, secrete IL-6 or express cell surface IL-6Rs. The IL-6 responsive cell lines bore late B-cell surface antigens (Ags), CD38 and PCA-1, whereas those lines which were non-IL-6 responsive strongly expressed B1 (CD20) and B4 (CD19) Ags, representing earlier stages in B-cell differentiation. Finally, the two IL-6 responsive cell lines did not express Epstein-Barr virus (EBV) proteins; in contrast, EBV encoded proteins typically expressed during latency could be detected in the three non-IL-6 responsive lines, confirming infection with virus. These studies clarify the heterogeneity observed in the myeloma cell line phenotype and biology and suggest that the U266 and RPMI 8226 cell lines, which express IL-6 cell surface receptors and are IL-6 responsive, may be useful for further study of IL-6 signal transduction in and related IL-6 mediated growth of myeloma in vivo. In contrast, those cell lines which are IL-6-independent provide a model for further study of EBV transformation and IL-6-dependent growth mechanisms in malignancy.

The efficacy of chemotherapeutic agents against murine bladder metastasis.

Three chemotherapeutic agents, methotrexate, cyclophosphamide and cis-diamminedichloro-platinum (cis-platinum), were examined for their effectiveness against metastases in a murine transitional cell carcinoma model. Systemic treatment of the drugs was applied against a MBT-2 derived subline which generates 100% incidence of lung metastases in C3H mice by five weeks. The drugs were examined for their effect against the number of metastases, incidence of metastasis and size of the subcutaneously implanted primary tumor. All three compounds significantly reduced both the number of lung metastases and the incidence when compared to untreated animals. None of the agents proved 100% effective against metastatic tumors. These results suggest the existence of a chemotherapeutic resistant population of metastatic cells. Administration of methotrexate and cis-platinum effectively reduced the size of the primary tumor as compared to untreated animals. Cyclophosphamide did not significantly affect primary tumor size. The response of the antineoplastic agents against the metastatic tumor cells indicates that the L3F2 metastatic cell line is an effective model to study agents against metastatic bladder cancer.

Influence of transplantation site on metastatic ability of mouse bladder carcinoma sublines.

The influence of the primary implantation site on the metastatic behavior of a murine transitional cell carcinoma line (MBT-2) and three metastatic sublines (L3F1, L3F2, and L3F3) was studied. The parent MBT-2 cell line produced a low incidence of lung metastasis after intravenous injection and no metastases from the primary tumor when injected either subcutaneously in the right hind flank or in the footpad. Intramuscular implantation of the MBT-2 cells in the right hind flank resulted in a significant increase over the subcutaneous, footpad, and intravenous sites in the incidence and number of lung metastases. Three in vivo/in vitro selected metastatic sublines (L3F1, L3F2, and L3F3) were highly metastatic when injected subcutaneously, intramuscularly, and intravenously. A low number of pulmonary metastases was observed after footpad implantation of the three sublines. This study demonstrated a definite implantation site-influence on the metastatic ability of the parent MBT-2 line and the three selected sublines. Intramuscular implantation was the most permissive implantation site for the development of spontaneous metastasis for the MBT-2 line and the L3F1, L3F2, and L3F3 sublines.

Role of the implantation site on metastatic ability of the murine MBT-2 transitional cell carcinoma.

The influence of implantation site on the metastatic behavior of a murine transitional cell carcinoma line (MBT-2) was examined. MBT-2 cells were injected into one of four anatomic sites; subcutaneously, intramuscularly, intravenously or into the footpad, to evaluate the influence of implantation site on the formation and number of metastases. The MBT-2 cell line produced a low incidence of lung metastases after intravenous injection with a mean of 1.1 lung tumors per mouse. Injection of MBT-2 cells into the footpad or subcutaneously did not produce metastases from the primary tumor. Intramuscular implantation, however, resulted in a sixty percent incidence of metastasis with a mean of 8.2 lung nodules per mouse. This study demonstrated a definite implantation site influence on the metastatic ability of the MBT-2 line.

Phenotypic and functional characterization of normal and malignant terminal B (plasma) cells.

A number of antigens (Ags) are expressed on normal and malignant terminal B (plasma) cells, including plasma-cell, earlier B-cell, and non-B cell-Ags. These Ags, coupled with indirect and dual fluorochrome labelling techniques, permit characterization of normal and malignant in vitro and in vivo terminal B-cell differentiation. The majority (90%) of B cells within spleen bear Bl and lack PCA-1 Ags. As B cells differentiate to pokeweed mitogen in vitro, immunoglobulin (Ig) secretion precedes the appearance of cell surface PCA-1 and plasmacytoid morphology. Dual fluorescence cell sorting permits characterization of in vivo B-cell differentiation: Bl + PCA-1 + cells are more "differentiated" since they are more prevalent in lymph node than spleen, exhibit plasmacytoid morphology and maximal Ig secretion, and no longer respond to triggers of B-cell proliferation; in contrast, Bl + PCA-1-cells are lymphoid in morphology and may respond to triggers of B-cell proliferation as "resting" B cells. Similar studies of myeloma cells demonstrated that they may also include cells expressing plasma-cell, earlier B, and non-B cell Ags. Although they neither proliferated nor secreted Ig in vitro to G/M-CSF, G-CSF, M-CSF, IL-1, IL-1B, IL-2, or IL-4, proliferation without Ig secretion (Stimulation Index greater than or equal to 3.0) was induced to IL-6 in 6 of 10 patients (pts); to IL-3 (2 pts) and to IL-5 (2 pts).(ABSTRACT TRUNCATED AT 250 WORDS)

Preliminary studies on the usefulness of medaka, Oryzias latipes, embryos in carcinogenicity testing.

Medaka (Oryzias latipes) embryos were exposed continuously for 10 days to diethylnitrosamine (DENA) at concentrations of 25, 50, or 100 ppm. Following exposure and after hatching, the embryos were placed in clean, carcinogen-free water. Fish were sampled for pathological examination after 1 month, 3, and 6 months. Grossly visible liver tumors were evident after 3 months in 10 and 30% of the fish treated with 50 and 100 ppm DENA, respectively. Following 6 months exposure, 4% of the fish treated with 25 ppm, 15% of those given 50 ppm, and 43% of those treated with 100 ppm DENA contained liver tumors. Focal areas consisting of 10 to 40 highly basophilic cells in the liver were noted at all the exposure concentrations. The incidence of the focal areas increased proportionately with the concentration of DENA and the age of the fish. Liver tumors were examined by light and electron microscopy. Most of the hepatic tumors were moderate to well-differentiated trabecular hepatomas, although 2 cholangiomas and 2 poorly differentiated hepatomas were noted. No liver lesions or tumors were observed in controls.

Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion.

Previous studies show that human myeloma-derived cell lines specifically adhere to fibronectin (FN) through very late antigen-4 (VLA-4; alpha 4 beta 1 integrin complex) and RGD-peptide mechanisms, which may contribute to the localization of tumor cells in bone marrow (BM). In these studies, we characterized the adhesion of myeloma-derived cell lines to both normal and myeloma BM stromal cells (BMSCs) and the effect of adhesion on DNA synthesis. Because interleukin-6 (IL-6) plays an important role in the pathogenesis of multiple myeloma, we also examined the effects of tumor cell adhesion on IL-6 secretion by BMSCs. In 51chromium binding assays, the U266, ARH-77, and IM-9 cell lines showed 52% +/- 12%, 55% +/- 6%, and 47% +/- 7% specific adherence, respectively, to normal BMSCs and 74% +/- 4%, 60% +/- 3%, and 61% +/- 6% specific adherence, respectively, to myeloma BMSCs. In contrast, only 12% to 13% specific binding of HS-Sultan cells to BMSCs was noted. The binding of myeloma cells to BMSCs was partially blocked with anti-beta 1 monoclonal antibody (MoAb), anti-beta 2 integrin MoAb, and excess RGD peptide, suggesting multiple mechanisms for the adhesion of myeloma cell lines to BMSCs. Binding of cell lines to FN or myeloma BMSCs did not affect cell line proliferation; however, adhesion of myeloma cell lines to normal BMSCs decreased DNA synthesis, ie, stimulation indices are 0.1 +/- 0.04, 0.2 +/- 0.1, 0.2 +/- 0.07, and 0.1 +/- 0.06 for the adherent non-IL-6-dependent U266, ARH-77, HS-Sultan, and IM-9 cells, respectively (n = 5, P < .01). In contrast, adherence of IL-6-dependent B9 cells increased their proliferation (stimulation index, 3.2 +/- 0.7). Significant (twofold to eightfold) increases in IL-6 secretion were evident in cell line-adherent (> or = 12 hours) normal and myeloma BMSC cultures. Paraformaldehyde fixation of BMSCs before adhesion completely abrogated IL-6 secretion, suggesting that IL-6 secretion was triggered in BMSCs rather than in cell lines. Partial blocking of cell line adhesion to BMSCs, using anti-beta 1 integrin and anti-beta 2 integrin MoAbs and RGD peptide, also partially blocked the triggering of IL-6 secretion by BMSCs. When cell lines were placed in Transwell inserts and then cultured with either normal or myeloma BMSCs, permitting juxtaposition without cell to cell contact between myeloma cell lines and BMSCs, no increase in IL-6 secretion was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization of adhesion molecules on human myeloma cell lines.

In multiple myeloma, malignant plasma cells are localized in marrow and rarely circulate in peripheral blood. To investigate the role of adhesion proteins in this process, we determined the expression and function of adhesion molecules on cell lines derived from patients with myeloma. The U266, ARH-77, IM-9, and HS-Sultan cell lines strongly expressed beta 1 and alpha 4 integrins (89% to 98% positive), confirming that VLA-4 is the principal integrin on these cell lines. The U266 and IM-9 cell lines also expressed alpha 3 integrin on 15% to 20% cells. In contrast, all lines lacked cell surface alpha 2, alpha 5, and alpha 6 integrin expression (< 5% positive). These cell lines adhered to fibronectin (20% to 40% specific binding), without significant binding to either collagen or laminin. Adhesion of these cell lines to fibronectin was partially blocked with either anti-beta 1 integrin monoclonal antibody (MoAb) (75% inhibition), anti-alpha 4 integrin MoAb (75% inhibition), or RGD peptide (50% inhibition), but was unaffected by anti-alpha v beta 3 or anti-alpha IIb beta 3 MoAbs. Moreover, the combination of anti-beta 1 plus RGD peptide or anti-alpha 4 plus RGD peptide inhibited binding to fibronectin by 80% and 95%, respectively. Finally, pretreatment and coculture of the IM-9 cell line with interleukin-6 (IL-6) resulted in a 52% decrease in specific binding to fibronectin (30% +/- 6% to 15% +/- 6%; P = .001), associated with a decrease in the number of cells expressing VLA-4 and a decrease in intensity of VLA-4 expression. These data suggest that myeloma cells adhere to fibronectin through VLA-4 as well as through RGD-dependent mechanisms, and that this binding can be downregulated by IL-6. Future studies of binding of both myeloma cell lines and freshly isolated tumor cells to extracellular matrix proteins and to marrow stroma may enhance our understanding of localization and trafficking of cells within the bone marrow microenvironment.

Response patterns of purified myeloma cells to hematopoietic growth factors.

Tumor cells were isolated from the bone marrow of seven patients with multiple myeloma and from the peripheral blood of three patients with plasma cell leukemia using Ficoll-Hypaque (FH) density sedimentation followed by immune rosette depletion of T, myeloid, monocytoid, and natural killer (NK) cells. Enrichment to greater than or equal to 93% plasma cells was confirmed with Wright's-Giemsa staining, with intracytoplasmic immunoglobulin staining, and with staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, monocytoid, and myeloma antigens in indirect immunofluorescence assays. Myeloma cells neither proliferated nor secreted Ig in response to G/M-CSF, G-CSF, M-CSF, interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), or interleukin-4 (IL-4). Significant proliferation (SI greater than or equal to 3.0) was induced by interleukin-6 (IL-6) in six of ten patients (SI of 31 and 43 in two cases); and to interleukin-3 (IL-3) and interleukin-5 (IL-5), independently, in two patients each. Peak proliferation to IL-5 or IL-6 and to IL-3 occurred in cells pulsed with 3[H] thymidine at 24 and 48 hours, respectively; and proliferation to combinations of factors did not exceed that noted to IL-6 alone; Ig secretion was not documented under any culture conditions. Three myeloma-derived cell lines similarly studied demonstrated variable responses. The heterogeneity in the in vitro responses of myeloma cells and derived cell lines to exogenous growth factors enhances our understanding of abnormal plasma cell growth and may yield insight into the pathophysiology of plasma cell dyscrasias.

Response patterns of hairy cell leukemia to B-cell mitogens and growth factors.

The effect of mitogens and/or recombinant B-cell growth factors (M/GFs) on the in vitro growth of hairy cells was examined. Tumor cells were isolated from the spleens of four patients with hairy cell leukemia (HCL) by Ficoll-Hypaque sedimentation and E-rosetting. Enrichment for tumor cells was confirmed with intracytoplasmic immunoglobulin (Ig) staining, tartrate resistant acid phosphatase (TRAP) staining, and staining using monoclonal antibodies (MoAbs) directed at B, T, myeloid, and monocytoid antigens (Ags) in indirect immunofluorescence assays. Tumor cells were B1(CD20)+ B2(CD21)- B4(CD19)+ IL-2R(CD25)+ PCA-1 +/- TRAP+. HCLs neither synthesized DNA nor secreted Ig in response to culture with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, or IL-6. However, a proliferative response (stimulation index greater than or equal to 3.0) without Ig secretion was triggered in HCLs by mitogens or combinations of GFs. Specifically, DNA synthesis was induced at 3 days in three of four HCL samples cultured with Staphylococcus aureus Cowan A (SAC) or the combination of phorbol ester (TPA) and the calcium ionophore A 23187 (Ca2+); DNA synthesis was triggered later (day 7) by tumor necrosis factor (TNF) or by IL-4 and IL-5. In contrast, the fourth patient, a nonresponder to SAC or TPA/Ca2+, demonstrated increased DNA synthesis at day 3 when cocultured with IL-4 and IL-5. Both autoradiography and staining with antibromodeoxyuridine (BrdU) MoAb conjugated to fluorescein confirmed DNA synthesis by only a minority (5% to 23%) of tumor cells within each patient. Dual staining confirmed that responsive cells were both BrdU+ and TRAP+. DNA synthesis induced by TPA/Ca2+ was blocked specifically by anti-IL-6 Ab; in contrast, the HCL proliferative response to SAC, TNF, or IL-4 and IL-5 was not inhibited by anti-IL-6 Ab. alpha-Interferon inhibited the response to TPA/Ca2+, TNF, or IL-4 and IL-5 without any effect on response to SAC. Finally, peroxidase-antiperoxidase staining demonstrated that HCLs are induced by TPA/Ca2+, but not by SAC, to produce intracytoplasmic IL-6. These data demonstrate IL-4, IL-5, and IL-6 mediated DNA synthesis by HCLs in vitro and suggest a possible in vivo role for these growth factors in the pathophysiology of HCL.