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PubMed1979

Functional differentiation of mouse T lymphocytes. GVHR-precursors: tissue origin and specificity of activity inducer.

For theoretical and practical reasons, it is important to find out whether the differentiation of T cell precursors to the functional lymphocytes can be induced under in vitro conditions. Using the local GVHR assay (based on the enlargement of the popliteal lymph node), the inducibility of the precursors of reactive cells was studied with bone marrow, thymus, spleen, and lymph node cell suspensions submitted to short-term incubation with cell-free extracts from calf thymus, spleen or brain. GVHR-precursors from bone marrow were inducible not only specifically (i.e., with thymus extract) but also--and even to a higher degree--with spleen or brain extract. Thymus and spleen cell suspensions (the latter also depleted of the reactive subpopulation by treatment with anti-Thy 1.2 serum and complement) were, on the other hand, inducible mainly specifically, whereas lymph node cells were refractory to induction. The inductive action of tissue extracts obviously depends on the tissue origin of T cell precursors; their effects on pre- and postthymic differentiation of T lymphocytes are discussed.

Animals↗

PubMed1976

Appearance of antibody-forming cells in lymphocytes from the lower respiratory tract of the dog after intrapulmonary or intravenous immunization with sheep erythrocytes.

To investigate the mechanisms of expression of humoral immunity in the lower respiratory tract, dogs were immunized either locally (intrapulmonary) or systemically (intravenous) with low doses of sheep erythrocytes. Bronchoalveolar cells obtained by pulmonary lavage and hilar lymph nodes were assayed during the primary immune response for their concentrations of antibody-forming cells with the Jerne plaque technique. Antibody-forming cells consistently appeared among bronchoalveolar cells after intravenous immunization but failed to accumulate in this cell population after local administration of the identical dose of sheep erythrocytes. By contrast, after local immunization, antibody-forming cells appeared in the hilar lymph nodes in generally greater concentrations than after intravenous immunization. The results demonstrated that the anatomic site of presentation of this particulate antigen to the lung (intravascular versus intra-alveolar) as well as the dose of antigen are important determinants of the distribution of antibody-forming cells in these 2 pulmonary lymphoid tissues. The data suggested that bronchoalveolar lymphocytes and hilar lymph node cells function independently in the expression of humoral immunity in the lower respiratory tract.

Animals↗

PubMed2000

The fungal cell wall component beta-1,3-glucan has an adjuvant effect on the allergic response to ovalbumin in mice.

The polyglucose beta-1,3-D-glucan is a major structural component of the cell wall of yeasts and fungi. In the present study, the adjuvant activity of beta-1,3-glucan from the fungus Sclerotinia sclerotiorum (SSG) on the response to the model allergen ovalbumin (OA) was studied, using the popliteal lymph node assay (PLNA) in BALB/c mice. The adjuvant activity on the local cellular response was determined by measuring the weight, cell number, and proliferation of the extracted PLNs. The levels of OA-specific immunoglobulin (Ig)E, IgG1, and IgG2a in serum were measured by enzyme-linked immunosorbent assay (ELISA). Groups of 8 mice were given either SSG + OA, SSG alone, or OA alone on d 0. Thereafter they were exsanguinated on d 20, or reinjected with OA on d 21, before exsanguination on d 26 or 33. Only on d 26 was SSG + OA found to significantly increase the PLN weight and cell numbers, but not cell proliferation (thymidine incorporation), compared with OA or SSG alone. SSG + OA was also found to significantly increase both the anti-OA IgE and IgG1 levels on d 20, 26, and 33 compared to OA alone. Compared to SSG alone, SSG + OA increased the OA-specific IgE and IgG 1 levels significantly on d 26 and 33, but not on d 20. A similar increase was not found for IgG2a. Our results show that beta-1,3-D-glucan provides a clear Th2-dependent (allergic) immune response to OA, indicated by elevated levels of IgE and IgG1 and not IgG2a, in the mouse model used.

Adjuvants, Immunologic↗

PubMed1998

Measurement of serum monocyte chemoattractant protein-1 and its clinical application for estimating the activity of granuloma formation in sarcoidosis.

BACKGROUND AND AIM OF THE WORK: The role of monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluids from sarcoidosis patients was previously reported. To study the role of MCP-1, we evaluated the serum MCP-1 and its clinical significance in sarcoidosis. METHODS: The serum MCP-1 level was measured in 47 patients with sarcoidosis and 10 normal healthy controls with the use of an enzyme-linked immunosorbent assay. The localization and mRNA expression of MCP-1 in sarcoid lymph nodes were evaluated by an immunohistochemical method using an anti-MCP-1 monoclonal antibody and an in situ hybridization technique to determine the cellular source(s) of MCP-1. RESULTS: Serum MCP-1 levels were significantly elevated in the sarcoidosis patients compared with the healthy controls (698.3 +/- 101.9 vs. less than 39 pg/ml, p < 0.001). A comparison of the patients' serum MCP-1 levels among standard radiographic stages revealed that the serum MCP-1 was significantly higher in early stages: stage 0 vs. III, and stage I vs. II. In addition, the serum MCP-1 levels were significantly correlated with the serum angiotensin converting enzyme levels (r = 0.539, p = 0.0006). MCP-1 expression was detected in macrophages peripheral to the epithelioid granuloma in sarcoid lymph nodes, by both immunohistochemistry and in situ hybridization. CONCLUSIONS: These data suggest that MCP-1 may be expressed by the macrophages in the granuloma throughout the body, and that the measurement of serum MCP-1 levels may have clinical value as an indicator in estimating the activity of granuloma formation throughout the body in sarcoidosis.

Adult↗

PubMed1980

Comparison of three assays measuring the local graft-versus-host (GVH) reaction in mice.

Three assays estimating the local graft-versus-host (GVH) reaction were compared in normal and immunosuppressed mice. The GVH reaction was evoked by administration of spleen cells from normal or specifically immunized donors: a) under the kidney capsule by the Elkins technique, b) subcutaneously in the foot pad, for the popliteal lymph node weight gain (PLN) assay, and c) intradermally, for lymphocyte-induced angiogenesis (LIA) assay. In the Elkins model, the intensity of the GVH reaction was estimated by the weight ratio of the injected to the non-injected kidney and by the microscopic evaluation of infiltrative and destructive changes in renal parenchyma. In PLN assay, the draining to the contralateral popliteal lymph node weight ratio was measured, and in the LIA assay, the number of newly formed blood vessels directed the injection site was counted. The sensitivity of Elkins local GVH model was shown to be the lowest as compared with PLN or LIA assay, the latter being the most sensitive and rapid.

Angiogenesis Inducing Agents↗

PubMed1990

Local immune reaction in syngeneic mice against tumorigenic and nontumorigenic BPV-transformed mouse cell lines.

The role of cytotoxic T cells in immune response to Bovine Papillomavirus type 1 (BPV1)-transformed mouse cell lines was assessed. The chromium release assay was used to follow the induction of cytotoxicity in local lymph nodes of syngeneic C57BL/6J (B6) mice after injection of BPV1-transformed cell lines tumorigenic in nude mice but tumorigenic or nontumorigenic in B6 mice. The nontumorigenic cell line B6B31.C-NuT.A induced cell line-specific cytotoxicity with a maximal activity on day 7 after subcutaneous inoculation of one million B6B31.C-NuT.A cells. After injection of nontumorigenic B6B31.J or tumorigenic B6B31.J-NuT.A or B6B31.A cell lines, only low levels of nonspecific cytotoxicity were observed. These results suggest a role for cytotoxic T cells only in rejection of B6B31.C-NuT.A cells. One reason for the poor immunogenicity could be the lack of transformation-induced/virus-specific antigens on most of the present BPV1-transformed cell lines. However, in a transplantation rejection experiment, protection was induced in B6 mice against a challenge of the highly tumorigenic B6B31.A-B6T.1 line by repeated injections of BPV1-transformed cells. These results suggest the expression of common transplantation rejection antigens on the three BPV1-transformed cell lines used in the immunization experiments.

Animals↗

PubMed1990

Reduction in popliteal lymph node graft-versus-host reactivity by homologous and heterologous pregnancy serum.

The popliteal lymph node assay was used to investigate the effect of pregnancy on graft-versus-host reactivity (GvHR) of mouse spleen cells. After local injection of splenocytes from primiparous syngeneically pregnant (by BALB/cJ males) or allogeneically pregnant (by CBA/Ca males) mice no differences in lymph node weight gain were observed in F1 recipients (CBA/Ca x BALB/cJ) when compared to injections of cells from age-matched non-pregnant BALB/cJ mice. However, lymphocytes of pregnant BALB/cJ females which had previously been pregnant between 4 and 6 times by CBA/Ca males induced a significantly lower GvHR compared to cells of matched non-pregnant multiparous mice. These results suggested an inhibitory effect of gestation on cells possibly primed towards paternal antigens by multiple pregnancies. To test this hypothesis, virgin BALB/cJ mice were actively immunized with lymphocytes of male CBA/Ca mice. Before injection into F1 recipients, spleen cells of immunized animals were incubated for 1 h at 37 degrees C in heat-inactivated serum of primiparous pregnant or virgin non-pregnant mice. Pre-incubation in pregnancy serum had no effect on unprimed cells, but GvHR of cells derived from immunized donors was significantly depressed in female recipients. In male animals this effect was only irregularly observed. Inhibition of GvHR was also observed with serum from pregnant but not non-pregnant pigs. Depression of cellular immune response was observed as early as days 4-9 post-coitum (p.c.) with mouse serum and days 16-19 p.c. with pig serum. These results indicate that pregnancy serum contains factor(s) which modulates the GvHR of primed lymphocytes in both a species- and an antigen-non-specific manner while reactivity of naive spleen cells is not changed.

Animals↗

PubMed1983

Mechanisms of the potentiation of specific antitumor immunity by intratumor injection of Corynebacterium parvum.

Meth A fibrosarcoma-bearing BALB/c mice given intratumoral injections of 0.5 mg of Corynebacterium parvum showed a highly and tumor-specific transplantation antigen specifically potentiated concomitant immunity to a subsequent tumor challenge. This potentiated antitumor immunity could be locally transferred in the Winn assay to normal recipients with whole draining lymph node cells from the tumor-bearing mice, but the potentiated effect disappeared when adherent cells were removed from these cells. Moreover, the potentiated cytostatic effect on tumor cells was detected in the peritoneal macrophages but not in the nonadherent draining lymph node cells in in vitro tests. On the other hand, nonadherent draining lymph node cells from the tumor-bearing mice, when mixed with C. parvum-induced macrophages, exhibited a specifically potentiated antitumor effect. In addition, this effect was completely abolished by treatment of the draining lymph node cells with anti-Thy-1 and complement. Thus, the potentiated antitumor effect following intratumor injection of C. parvum may be ascribed to the collaboration of specifically sensitized T-lymphocytes with C. parvum-activated macrophages.

Animals↗

PubMed2001

Neoadjuvant chemotherapy in inoperable, locally advanced, and inflammatory breast carcinoma: a pilot study of MTT assay in vitro and outcome analysis of 10 patients.

Patients with inoperable, locally advanced, and inflammatory breast carcinoma (LAIBC), whether with supraclavicular lymph nodes (SLN) or not (stage IIIB and IV), usually carry an overall poor prognosis. The current treatment for these patients is by means of combined modality, including preoperative chemotherapy. This strategy has led to a substantial improvement in clinical response, making some patients operable, and even making breast conservative surgery possible. However, the long-term results still are not promising. The aim of this pilot study was to determine the efficacy of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in vitro in directing chemotherapy (including preoperative adjuvant chemotherapy and postoperative adjuvant chemotherapy) for these patients. Between June 1994 and March 1997, 10 patients with inoperable LAIBC, whether with SLN or not, were enrolled. During the period of the combined therapy modalities, the neoadjuvant chemotherapy was adopted for three cycles according to the results of chemosensitivity in vitro by MTT assay. Then a modified radical or radical mastectomy was performed, which was followed by radiotherapy and further postoperative adjuvant chemotherapy with the same regimen as that of neoadjuvant chemotherapy. All patients had been followed up from the beginning of neoadjuvant chemotherapy to the end of October 1999. Two patients had clinical complete response (CRs), with one having pathologic CR in both breast tumor and axillary lymph node, and the other having pathologic CR in axillary lymph node. The other eight patients had partial response. By the time of analysis, six patients had been dead of relapse or progression. Among the four patients who were still alive, one had local relapse, one had distant metastatic disease, and the other two had no evident disease. By retrieving from MEDLINE before 1999, the authors learned that this is the first pilot study of neoadjuvant chemotherapy for inoperable LAIBC using MTT assay to predict the chemosensitivity in vitro. Compared with conventional chemotherapy, the clinical response and long-term results seem to be more encouraging.

Adenocarcinoma↗

PubMed1998

Adenocarcinoma of the pancreas: detection of occult metastases in regional lymph nodes by a polymerase chain reaction-based assay.

BACKGROUND: Stage I (T1-2NOM0) adenocarcinoma of the pancreas is associated with a 5-year survival rate of 15-25%. Despite apparently curative resection and pathologic staging indicating localized disease, these cancers recur. The authors hypothesized that there exists microscopic regional disease that is not detected by surgical exploration or routine histopathology. METHODS: Because 90-95% of pancreatic cancers exhibit codon 12 K-ras mutations, the authors examined regional lymph nodes for mutated K-ras as a marker of metastasis. DNA was extracted from paraffin embedded archival specimens (primary tumors and histologically negative lymph nodes) of patients with Stage I pancreatic adenocarcinoma. The target region of K-ras was amplified by polymerase chain reaction (PCR) and tested for codon 12 mutation by BstN1 restriction digestion (restriction fragment length polymorphism [RFLP]) that recognized normal but not mutated sequences. Cell lines that harbored normal or mutated K-ras and resected jejunum or gallbladder were used as controls. The regional lymph nodes of 22 patients whose tumors harbored mutated K-ras were tested. RESULTS: Dilution experiments with normal and mutant control cell line DNA demonstrated an assay sensitivity for mutated K-ras of 0.1%. Mutated K-ras was found in at least 1 regional lymph node in 16 (73%) of 22 patients with pathologic Stage I pancreatic adenocarcinoma, which suggested metastases not detected by routine histopathology. DNA sequence analysis was performed in four patients and confirmed identical point mutations in the primary tumor and accompanying PCR/RFLP positive lymph nodes. CONCLUSIONS: Pathologic examination of regional lymph nodes in pancreatic adenocarcinoma specimens fails to detect metastases in many patients. Lymph node micrometastasis is one reason for the poor survival rates observed among patients with Stage I cancers. PCR/RFLP may have a role in staging early pancreatic cancers.

Adenocarcinoma↗

PubMed1983

The effect of vitamin A depletion on antigen-stimulated trapping of peripheral lymphocytes in local lymph nodes of rats.

The effect of vitamin A depletion on antigen-stimulated trapping of peripheral lymphocytes in lymphatic organs was studied in rats. Distribution of [3H]-uridine-labelled syngenic peripheral lymphocytes was quantified by assaying radioactive content of brachial and axillary lymph nodes, spleen and liver of normal and vitamin A-depleted F344/Ducrj rats immunized with sheep red blood cells. Localization of labelled cells in the ipsilateral brachial lymph nodes of the normal rats was stimulated by three times upon immunization with sheep erythrocytes as compared with the contralateral nodes. Recruitment of cells in axillary lymph nodes, spleen and liver was not significantly different from non-immunized values. The vitamin A-depleted rats exhibited marked deterioration in antigen-stimulated trapping of labelled cells in the draining brachial lymph nodes. These results suggest that this effect of vitamin A depletion is due to derangement of integrity of lymphocyte-trapping mechanism in the draining lymph nodes and not to any change in nature of lymphocytes per se.

Animals↗

PubMed1993

Localization of LAK cells and IL-2-stimulated regional lymph node lymphocytes by regional arterial infusion in renal tumor-bearing rats.

We describe the results of a traffic assay of the regional arterial administration of either lymphokine-activated killer cells or recombinant interleukin-2-activated regional lymph node lymphocytes in tumor-bearing rats in comparison with the results of systemic or intracardiac administration. The lymphocytes were labeled with 51Cr before infusion. The distribution and localization of these cells were serially evaluated by counting the radioactivity of the removed tissues. Concerning arterial administration, the labeled cells were directly infused into the abdominal aorta just proximal to the left renal artery. In the systemic or intracardiac route, the labeled cells preferentially localized to the lung, spleen and liver 2 h after injection. Radioactivity of the lung decreased thereafter and that of the spleen increased. In contrast, regional arterial administration yielded a remarkable accumulation of radioactivity in the left renal parenchyma 2 and 6 h after injection, similar to other distal organs tested. In the renal tumor model, the percentage radioactivity of the tumor tissue (% injectate recovered/g tissue) obtained at 6 h after injection in the arterial administration group ranged from 0.40 to 1.33, which was significantly higher (p < 0.05) than that in the systemic administration group. However, the radioactivity rapidly decreased from the tumor tissue 18 h after the injection. This study raises the essential issue on the mechanism of tumor destruction by lymphokine-activated killer lymphocytes in adoptive immunotherapy.

Animals↗

PubMed1999

[The current status of molecular detection of micrometastatic prostate cancer cells].

We summarized and reviewed published reports, including our studies, on the reverse transcription-polymerase chain reaction (RT-PCR) detection of micrometastatic prostate cancer cells in lymph nodes, bone marrow and peripheral blood. Some published data preliminarily suggest that the RT-PCR assay of micrometastatic prostate cancer cells may allow a more accurate assessment of lymph node and bone metastases of prostate cancer, and offer a presurgical prediction of the pathological stage of clinically localized disease. In addition, the RT-PCR assay may have a unique prognostic value in prostate cancer. However, controversy remains over the clinical significance of the RT-PCR assay. This assay could potentially develop into a diagnostic procedure for the clinical decision making in patients with prostate cancer. To establish the clinical significance of the RT-PCR assay, further optimized and standardized RT-PCR assay studies are needed, investigating large populations and involving long-term follow-up for the determination of any association between the results of the RT-PCR assay and specific clinical outcome.

Humans↗

PubMed1975

Modification of hybrid responsiveness in the local graft-versus-host reaction by injection of parental lymphocytes.

The local graft-versus-host reaction in F1 hybrid rats, assayed by popliteal lymph node enlargement, is specifically depressed by pretreating the host with parental lymphocytes. The conditions for demonstrating specific depression are injection of a small dose of parental lymphocytes and assay 7 days later. Pretreatment with cells from thymus and bone marrow is ineffective, as is pretreatment with purified B lymphocytes. The structures which stimulate the suppressed response of F1 hybrids are not present on parental B lymphocytes.

Animals↗

PubMed1986

Sex-dependent local cellular immunity to alloantigens.

A local component of cellular immunity was detected in mice that had been immunized against histocompatibility antigens. The status of this local immunity was determined using a node-onto-kidney (NOK) assay in which lymph nodes draining the site of immunization as well as distant (nondraining) lymph nodes of the immunized mice were grafted onto the kidneys of mice of the immunizing strain. In this assay, the weight gained by each node piece was taken as a measure of its immunological responsiveness. The responsiveness of a draining lymph node was directly compared with that of a distant node after both had been grafted onto the same host kidney. We consistently found that the draining lymph nodes of immunized male mice were more responsive than their distant nodes, whereas the draining lymph nodes of immunized female mice were less responsive than their distant nodes. Male mice were converted to the female pattern of hyporesponsiveness in the draining nodes by performing bilateral orchidectomy, suggesting that the male pattern depends upon the presence of testicular hormones. Additional studies showed there was a significant reduction in the reactivity of uterine draining lymph nodes during both syngeneic and allogeneic pregnancy, raising the possibility that the female pattern of hyporesponsiveness facilitates fetal survival by reducing the maternal immune response to fetal antigens and alloantigens during pregnancy.

Animals↗

PubMed1997

Effect of sublethal X-irradiation on follicular trapping of immune complexes in the mouse lymph node.

In one set of experiments, the effect of sublethal X-irradiation on the 24 h localization of subcutaneously injected immune complexes in the lymph node follicles was studied in mice which were given HRP-anti-HRP complexes into the rear footpad at 1-3 weeks after irradiation and killed 1 day later. The 24 h follicular localization of injected immune complexes in draining popliteal nodes was severely impaired at 7 days after irradiation, at which time residual follicles were markedly depleted of B lymphocytes. In following weeks, residual follicles began to be repopulated, and the 24 h follicular localization of immune complexes became restored. Follicular dendritic cells (FDC), as was detected by the in vitro trapping assay and/or by the immunostaining for complement receptors CR1, were present in lymph nodes at any time after irradiation. Another group of mice were given HRP-anti-HRP complexes at 6 days of X-irradiation and killed from 15 min to 24 h later. Following the injection, complexes localized in residual follicles in draining nodes within 15 min but soon diminished in density and finally disappeared by 24 h after injection. It is obvious that sublethal irradiation affect neither transport of immune complexes to lymph node follicles nor their localization in these follicles. Rather rapid disappearance after temporal localization of immune complexes in residual follicles irradiated mice indicates that persisting FDC were unable effectively to trap immune complexes which were transported and localized in residual follicles. Ineffective trapping by FDC of immune complexes temporally localized in residual follicles is discussed in relation to the depletion of follicular B lymphocytes due to X-irradiation.

Animals↗

PubMed1998

Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury.

Failure of GI tract mucosa to act as a barrier against bacterial translocation (BT) has been proposed as a potential source of sepsis and subsequent multiple organ failure post thermal injury. Nitric oxide (NO) is an inorganic radical produced by NO synthase (NOS) from L-arginine. Gut mucosal constitutive NOS (cNOS) provides protection for itself. In contrast to cNOS, inducible NOS (iNOS) releases far greater amounts of NO, promotes oxidative reactions and is responsible for tissue injury. Peroxynitrite formed by the rapid reaction between superoxide and NO, is a toxic substance that contributes to tissue injury in a number of biological systems. This study was designed to investigate the effect of iNOS specific inhibitor S-methylisothiourea (SMT) on the postburn intestinal mucosal barrier function and the possible mechanism of SMT's action. Female SPF Sprague Dawley rats underwent 35% total body surface area (TBSA) or sham burn. Either SMT or the same volume of saline was given (5 mg/kg, i.p. q 12 h) for 2 days to assess the effect of iNOS inhibition. On postburn day 2, the intestinal mucosal cNOS and iNOS activity were assayed by using Griess' reagent, the mesenteric lymph node (MLN), spleen and liver were collected and cultured for BT assay and the cellular localization of nitrotyrosine, a marker for peroxynitrite activity, was examined by immunostaining. After thermal injury in rats, administration of SMT for 2 days decreased the intestinal mucosal iNOS activity/ tNOS activity ratio and the BT incidence. Nitrotyrosine immunostaining of the intestinal mucosa showed a decrease in the SMT-treated group. These findings suggest that SMT, a specific inhibitor for iNOS improves the barrier function after burn by suppression of the intestinal mucosal iNOS activity. The decrease in NO production resulted in decreased formation of peroxynitrite and subsequently decreased damage of mucosal tissue.

Animals↗

PubMed1999

Expression of p16 and CDK4 in oral premalignant lesions and oral squamous cell carcinomas: a semi-quantitative immunohistochemical study.

The protein, p16, the product of cyclin-dependent kinase number 2 (CDKN2) gene, is one of the negative regulators of the cell cycle. CDK4, encoded by CDK4 gene, is the substrate of p16. We investigated the expression of p16 and CDK4 and their role in the progression of oral premalignant lesions (OPLs) and oral squamous cell carcinomas (OSCCs) in a Chinese cohort. A total of 74 samples were obtained from patients with hyperkeratosis (10), OPLs [30; mild (10), moderate (10) and severe (10) dysplastic lesions], OSCCs (15; 8 non-metastatic, 7 metastatic), and normal oral tissues (10), together with local lymph nodes (9) of patients with metastatic OSCCs. A labelled streptavidin biotin (LSAB) immunohistochemistry assay was performed and a semi-quantitative method was used to evaluate the staining intensity. The staining patterns of p16 and CDK4 were similar in all tissues and were located in both the nuclei and the cytoplasm. However, the antigen distribution characteristics and the degree of expression of both p16 and CDK4 varied at different developmental stages of the lesions. Hyperkeratotic and dysplastic lesions tended to display a progressively increasing degree of p16- and CDK4-positive nuclei as compared with normal tissues. Also, positive staining cytoplasm was highly evident in OSCCs with a very low nuclear staining (P<0.05). Forty-six of 56-, p16-positive cases were CDK4-positive, while only 6 were CDK4-positive but p16-negative, implying a high correlation between these parameters (r=0.813, P<0.001). This study indicates that the expression of p16 and CDK4 is intimately involved in the development of OPLs and OSCCs and the likely existence of a positive feedback loop between p16 and CDK4.

Adult↗