A plea for justice for jailed medical workers.
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Child↗
Biomedical subjects
Peter Biberfeld
Publications and source records attributed to Peter Biberfeld.
Lymphatic and vascular origin of Kaposi's sarcoma spindle cells during tumor development.
The histogenesis of Kaposi's sarcoma (KS) tumor spindle cells (SC) remains controversial but several immunohistochemical studies favor a lymphatic origin. Twenty KS surgical biopsies were analyzed for the coexpression of LANA, CD34, LYVE-1, D2-40, VEGFR-2, VEGFR3 by using double or triple immunostaining. Most of the SC in both early and late KS expressed the lymphatic markers LYVE-1, D2-40 and VEGFR-3 and the blood vascular endothelial/endothelial precursor cell markers CD34 and endothelial stem cell marker VEGFR-2. All the LANA+ SC in early and late KS were LYVE-1+, but only 75% of these LANA+ cells were CD34(+). The CD34(+)/LANA+ cells increased from early- (68.8%) to late-stage KS (82.2%). However, approximately 18% of the LANA+ SC in early KS were CD34(-) but were LYVE-1+, suggesting that resident lymphatic endothelial cells (LEC) are targeted for primary infection by human herpesvirus-8. This LANA+/LYVE-1+/CD34(-) (resident LEC) cell population clearly decreased during the development of KS from early (18.7%) to late KS (2.9%). Thus, in late stages of KS, most SC were LANA+/CD34(+)/LYVE-1+. However, in both early- and late-stage KS, approximately 18% of the SC were CD34(+)/LANA-/LYVE-1 -- and could represent newly recruited endothelial precursor cells, which become infected in the lesion and eventually undergo a phenotype switch expressing LEC markers. Our study apparently indicates that KS represents a unique variant of tumor growth with continues recruitment of tumor precursor cells as well as proliferation and decreased apoptosis of SC.
Acquired Immunodeficiency Syndrome↗
CGH of microdissected Kaposi's sarcoma lesions reveals recurrent loss of chromosome Y in early and additional chromosomal changes in late tumour stages.
BACKGROUND: It is still unclear if Kaposi's sarcoma (KS) is a monoclonal cell proliferation or a polyclonal, hyperplastic, reactive process. Reports on KS cytogenetics are few and restricted to late stage disease and cell lines. METHOD: We analysed 27 KS, early and late, AIDS related (AKS) and endemic (EKS) by laser microdissection, global DNA amplification and comparative genomic hybridization (CGH). RESULT: Loss of Y chromosome was detected in 20/23 male KS, which was the only recurrent chromosomal aberration in all nine male early (patch) KS. Only one patch EKS showed in addition to the Y loss a loss of Xq. Late (nodular) AKS and EKS showed recurrent copy number changes in chromosomes 16, 17, 21, X and Y, as well as other random changes. The loss of chromosome 16, 17 and Y was confirmed by interphase fluorescence in situ hybridization (FISH) on paraffin sections. EKS showed a higher number of chromosomal abnormalities than AKS, indicating that rapid growth of AKS is less dependent on genetic changes than is EKS, possibly because of the immunosuppressed host environment in AKS. CONCLUSION: Clonal loss of chromosome Y was detected in all early male KS, while additional chromosomal aberrations appeared during development to late KS. This increase in chromosomal abnormalities during tumour growth indicates genetic instability and the selection of survival cell clones establishing late, aggressive sarcoma growth. Our data support the view that KS (in males) develops into a clonal tumour yet initially is a hyperplastic reactive cell proliferation.
Acquired Immunodeficiency Syndrome↗
Hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha are expressed in kaposi sarcoma and modulated by insulin-like growth factor-I.
PURPOSE: Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (alpha and beta), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF alpha subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF alpha subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line. RESULTS: Both HIF-1alpha and HIF-2alpha were expressed in KS biopsies in all tumoral stages. HIF-1alpha immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF alpha subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I-induced HIF alpha accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with alphaIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF alpha congeners. CONCLUSION: These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.
Basic Helix-Loop-Helix Proteins↗
Peter Perlmann 1919-2005.
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Allergy and Immunology↗
Hepatitis C virus core protein transforms murine fibroblasts by promoting genomic instability.
The oncogenic potential of hepatitis C virus (HCV) core protein has been demonstrated, but the precise mechanism of cell transformation triggered by HCV core is still unclear. This study shows that constitutive expression of HCV core protein (core) in NIH 3T3 murine fibroblasts triggers malignant transformation. At the preneoplastic stage, clones that expressed HCV core constitutively demonstrated genomic instability seen as disruption of the mitotic spindle cell checkpoint leading to increased ploidy. Transformation was completed by the loss of DNA and resistance to apoptosis induced by serum starvation. Simultaneously, cells acquired a capacity for anchorage independent growth and absence of contact inhibition. Inoculation of these transformed cells into severe combined immune deficiency (SCID) mice led to formation of solid core-expressing tumors. Transformation and tumorigenicity of core-expressing cell lines coincided with a 5- to 10-fold repression of endogenous p53 transactivation. Thus, long-term HCV core expression alone is sufficient for complete transformation of immortal fibroblasts that can then induce tumors in a susceptible host. This data suggests that malignant transformation by HCV core may occur through primary stress, induction of genomic instability, and further HCV core-induced rescue of surviving mutated cells.
Animals↗
AIDS and non AIDS-related malignant lymphoma in Tanzania.
BACKGROUND: Malignant lymphoma (ML) in HIV patients, are second in frequency to Kaposi's sarcoma (AKS) as AIDS-defining tumors. In Africa the frequency of AIDS-related lymphoma (ARL) is rare and the findings are controversial. Kaposi's sarcoma (KS) lesions are now causally associated with KSHV/HHV-8 but whether African ARL shows this association is not clear. METHOD: Cancer registry data was reviewed for retrospective cases. Both retrospective and prospective lymphoma cases were classified according to the revised European-American (REAL) classification. Immunephenotyping was performed on both frozen and fixed paraffin sections. Viral DNA was assessed by polymerase chain reaction (PCR) of formalin fixed or frozen biopsies. In situ hybridization (ISH) was used to determine the presence of EBV encoded RNA (EBER). OBJECTIVES: To determine the frequency and type of AIDS and non-AIDS related malignant lymphoma in Tanzania and a possible co-association with KSHV/HHV-8 and EBV. RESULTS: An overall increasing tendency for ML in Tanzania was observed during 1991-94 and a clear increase from 1993. The tumors were classified as Burkitt's (6), diffuse large cell (10), precursor-B lymphoblastic (1) and Hodgkin's disease (5) from HIV positive and negative patients. Ten (40%) high grade ML and three Hodgkin's lymphoma from HIV patients had HHV-8 DNA. These findings were not related to age, sex or type of lymphoma. There was no association of HHV-8 with the lymphoma cells. Epstein-Barr virus (EBV) was demonstrable in most (13/18; 72%) of the tested tumors and seven (31.8%) had both HHV-8 and EBV. CONCLUSIONS: This study suggests an overall increased frequency of ML patients infected with HHV-8 in Tanzania particularly in HIV patients which may result from the well established high HHV-8 prevalence in the general population, but HHV-8 was not associated with ARL pathogenesis as reflected by lack of tumor cell infection. As opposed to EBV, measures targeting HHV-8 for control of ML may therefore not be appropriate.
Adolescent↗
Coreceptor usage of primary HIV type 1 isolates obtained from different lymph node subsets.
Biological characteristics of virus quantitatively rescued from different cell types present in lymph nodes of HIV-1-infected individuals in various stages of their disease were determined, not including patients with AIDS defining illness. Viruses were obtained by cocultivation with donor monocyte-derived macrophages and T-lymphocytes and their biological phenotype compared to viruses obtained from the peripheral blood mononuclear cells of the same patient. The biological phenotype was determined on established cell lines (U937-2, CEM, and MT-2) and on the U87.CD4 coreceptor indicator cell lines and variable region 3 (V3) of the envelope was subjected to direct sequencing. All isolates obtained from lymph node subsets used CCR5 as coreceptor. Furthermore, these viruses were also sensitive to inhibition by beta-chemokines as analyzed for viruses of one patient. All 12 V3 regions showed a unique sequence indicating compartmentalization within each patient. The biological phenotype of CCR5-dependent (R5) HIV-1 isolates obtained from PBMC resembles the phenotype of viruses isolated from different lymph node cell subsets.
Amino Acid Sequence↗
HHV-8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry.
The human gamma-herpes virus-8 (HHV-8) was first described in AIDS-related Kaposi's sarcoma (KS) tumour samples. In this study, we report comparative studies on paraffin-embedded biopsies of AIDS-related KS (AKS) and endemic KS (EKS) with regard to HHV-8 content as evaluated using polymerase chain reaction (PCR) and immunohistochemistry. DNA was extracted either using Chelex-100 or using Qia-gene kit and was evaluated with the help of a semiquantitative PCR assay. The PCR detection of HHV-8 was more sensitive to the Chelex method than to Qia-gene. The threshold for PCR test sensitivity with the help of serial dilution of DNA was at the level of five plasmid ORF-26 regions, and DNA from 25 body cavity-based lymphoma-1 cells. The results expressed as virus load/actin unit showed progressively higher HHV-8 levels in late (nodular) cases, compared to those in early (patch/plaque) stages. Evaluation of HHV-8 DNA levels in tumour tissues, thus, indicates a correlation between virus load and KS stage. Double immunostaining of spindle cells (SC) in KS biopsies for CD34 and HHV-8/latency-associated nuclear antigen (LANA) showed an increase in double-positive SC in the lesions of nodular AKS and EKS cases, compared to that in plaque and patch stages. However, 10-15% of CD34+/LANA- SC cells were observed during the development from patch to nodular cases of AKS and EKS. Our results indicate that PCR analysis is a simple and sensitive diagnostic method for HHV-8 evaluation in KS tissues, processed for conventional histopathology.
Acquired Immunodeficiency Syndrome↗
Human herpesvirus 8/Kaposi sarcoma herpesvirus cell association during evolution of Kaposi sarcoma.
Kaposi sarcoma (KS) is associated with a herpesvirus (HHV-8/KSHV), which expresses a latency-associated nuclear antigen (LANA). The histopathology of KS is characterized by angiogenesis, inflammatory cells, and the development of CD34+ tumor spindle cells (SCs). However, the cellular basis for the recruitment and dissemination of HHV-8 during the development of KS lesions is not clear. Twenty-nine KS biopsies with AIDS (AKS, n=22) and without HIV infection (endemic KS or EKS, n=7) were immunostained by a triple antibody method to characterize HHV-8-infected and noninfected (LANA+/-) CD34+ SCs, infiltrating CD3+, CD68+, CD20+, and CD45+ leukocytes as well as proliferating (Ki67+) cells. The CD34+/LANA+ SCs were more frequent in late (nodular) as compared with early (patch/plaque) KS stages. However, in late AKS 36.0% of SCs (median of 11 cases) were CD34+/LANA- compared with 20.7% in early cases (median of 11 cases). Furthermore, both AKS and EKS showed, at all stages, a small (4.1-6.5%) population of LANA+/CD34- cells. Proliferating Ki67+ cells were seen (4.5-11.5%) at all KS stages, and were usually more frequent in early AKS, but no significant difference was observed between nodular AKS and EKS. Most of the proliferating cells in the KS lesions were LANA+/CD34+ but a small fraction was LANA+/CD34-. Lesional CD68+ and CD3+ cells varied between AKS (7.3 and 5.2%, respectively) and EKS (4.9 and 3.1%, respectively) but were not clearly stage related. No LANA+ cells were CD3+, CD20+, or CD45+ and very few (<0.5%) were CD68+. These results indicate that not all CD34+ KS SCs were LANA+, suggesting recruitment of noninfected SCs to the lesions. Cell proliferation in general was much higher in early as compared with the late AKS stages. LANA+ SCs could have a proliferative advantage as suggested by higher frequency of cycling (Ki67+) LANA+ SCs. Few macrophages but no lymphocytes are LANA+.
Acquired Immunodeficiency Syndrome↗
Dichotomy between CD1a+ and CD83+ dendritic cells in lymph nodes during SIV infection of macaques.
The prevalence and differentiation of dendritic cells (DC) in lymphoid tissue of simian immunodeficiency virus (SIV)-infected cynomolgus monkeys was studied during disease progression. Lymph node biopsies were consecutively obtained from clinical rapid and slow progressors until the development of disease consistent with simian acquired immunodeficiency syndrome (sAIDS) occurred. Quantitative evaluation of CD1a+ DC and the expression of DC antigens related to maturation (CD83, DC-LAMP and S100b) were performed at the single cell level by in situ image analysis. Despite a persistent prevalence of CD1a+ DC in lymphoid tissue during disease progression, there was a subsequent drop of mature CD83+, DC-LAMP+ and S100b+ DC, correlating with the decline of CD4+ T cells in blood. Thus, disease progression to sAIDS was associated with impaired maturation of DC, and lack of CD83, DC-LAMP and S100b expression.
Animals↗
Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma.
OBJECTIVE: Patients with rheumatoid arthritis (RA) have an increased risk of developing malignant lymphoma. It is not clear whether the increase is confined to certain subtypes of lymphomas. Immunosuppressive therapy and Epstein-Barr virus (EBV) have been linked to the development of these lymphomas. To gain information about the baseline pattern of lymphoma subtypes in RA before the current widespread use of immunosuppressive drugs, we examined the distribution of lymphoma subtypes and the presence of EBV in a cohort of RA patients with a low frequency and duration of treatment with immunosuppressive drugs. METHODS: By linking data from the Swedish Hospital Discharge Register and the Swedish Cancer Register, 42 cases of lymphoma were identified among 11683 patients with RA in the Uppsala Health Care Region between 1964 and 1984. The medical records and paraffin-embedded lymphoma tissues were collected, and the lymphomas were reclassified using the World Health Organization classification. In situ hybridization was used to detect EBV. RESULTS: Tissues from 35 patients were reviewed. Non-Hodgkin's lymphoma (NHL) was found in 33 patients and Hodgkin's lymphoma in 2 patients. There was an increased frequency of diffuse large B cell lymphoma (DLBCL) (22 of 33 NHL patients, 67%) compared with that in the general population (30-40%). EBV was detected in 5 of 30 examined lymphomas from patients (17%). Twenty of the 22 DLBCL patients had RA with medium or high inflammatory activity, and 6 had been treated with a disease-modifying antirheumatic drug for >or=1 year. CONCLUSION: The findings of this study suggest an increased incidence of one specific lymphoma subtype, DLBCL, in RA patients, as well as a possible association with RA disease activity.
Adult↗
Simian AIDS-related lymphoma growth in severe combined immunodeficiency mice is independent of karyotypic abnormalities or Bcl-6 mutations.
Simian AIDS-related lymphomas (sARL) of cynomolgus monkeys infected with a simian immunodeficiency virus (SIVsm) were studied in relation to growth in severe combined immunodeficient (SCID) mice, karyotype abnormalities, and DNA sequence of the first noncoding region of the Bcl-6 gene. The tumors were diffuse large B cell lymphomas and expressed a simian homolog to Epstein-Barr virus (HVMF-1) in 12 of 13 primary tumors and corresponding cell lines. A tested cell line was tumorigenic in SCID mice. Tumors in the SCID mice showed cell growth features similar to those in the original lymphoma, suggesting that no subpopulation with growth advantage was selected for in the mice. Spectral karyotype analysis of sARL cell lines showed normal cytogenetic features except for a trisomy of monkey chromosome 2 (corresponding to human chromosomes 7 and 21) in two of five sARL lines, which was not recovered in SCID tumors established from the same cell line. Sequence analysis of a Bcl-6 gene fragment showed sequence variations indicative of population polymorphism(s) in 10 of 13 sARLs, and no evidence of Bcl-6 mutations. Thus Bcl-6 mutations in the first noncoding region are irrelevant for sARL development in cynomolgus monkeys and for tumorigenicity of sARL cell lines. We also demonstrate that no cytogenetic alterations are needed for the development of highly aggressive lymphomas in the SIV-immunosuppressed host.
Animals↗
Cross-protection against mucosal simian immunodeficiency virus (SIVsm) challenge in human immunodeficiency virus type 2-vaccinated cynomolgus monkeys.
In this study we compared the efficacy of live attenuated human immunodeficiency virus type 2 (HIV-2) vaccine alone versus boosting with live non-pathogenic HIV-2 following priming with ALVAC HIV-2 (recombinant canarypox virus expressing HIV-2 env, gag and pol). Six monkeys were first inoculated intravenously with live HIV-2(SBL-6669) and 7 to 10 months later were challenged intrarectally with 10 MID(50) of cell-free simian immunodeficiency virus (SIV) strain SIVsm. One monkey was completely protected against SIV infection and all five monkeys that became SIV-infected showed a lower virus replication and an initial lower virus load as compared with a parallel group of six control animals. In another experiment five monkeys were immunized either three times with ALVAC HIV-2 alone or twice with ALVAC HIV-2 and once with purified native HIV-2 gp125. The monkeys were then challenged with HIV-2 given intravenously and finally with pathogenic SIVsm given intrarectally. After challenge with SIVsm, three of five monkeys were completely protected against SIVsm infection whereas the remaining two macaques became SIV-infected but with limited virus replication. In conclusion, vaccination with an ALVAC HIV-2 vaccine followed by exposure to live HIV-2 could induce cross-protection against mucosal infection with SIVsm and seemed to be more efficient than immunization with a live HIV-2 vaccine only.
AIDS Vaccines↗
Cross-talk between human herpesvirus 8 and the transactivator protein in the pathogenesis of Kaposi's sarcoma in HIV-infected patients.
AIDS-associated Kaposi's sarcoma (AKS) is particularly aggressive and it is one of the principal neoplasms in regions of Africa affected by both high endemic HHV8 and epidemic HIV infection. In this study, serum samples from 18 patients with Kaposi's sarcoma from Tanzania, mostly males (n = 15 vs 3), were subjected to analysis with respect to HHV8-DNA load and antibody spectrum against the HIV-1 tat protein. Of the 18 patients, 14 were HIV-1-positive. The median HHV8 virus load in the HIV-1-positive group was 2075 DNA copies/ml, compared to 450 copies/ml in the HIV-1-negative group. In the HIV-1-positive group, the males had a higher HHV8-DNA virus load as compared to females (median: 4600 vs 1400 genome copies per ml). Since tat can promote AKS development (4-6) by intercellular signalling pathways, and these signals can be abolished by anti-tat IgG (7-9), we have examined the anti-tat IgG spectrum in this study. It would be expected that the levels of serum HHV8-DNA are higher in KS patients who have low anti-tat IgG titer, or who are anti-tat IgG-negative. In the present study, seven out of fifteen AKS patients were positive for anti-tat IgG. Although, we have not seen a strict quantitative relationship between serum anti-tat IgG and HHV8-DNA levels, our data appear to suggest a correlation between the two parameters. In view of these observations and the published data, we suggest that cross-signalling pathways between the tat protein and HHV8-DNA are involved in the complexity of pathogenesis of Kaposi's sarcoma.
Adult↗
Serum HHV8 DNA and Tat antibodies in Kaposi's sarcoma patients with and without HIV-1 infection.
Human herpesvirus 8 or Kaposi's sarcoma-associated herpesvirus (HHV8/KSHV) is believed to be the most important etiopathological factor of Kaposi's sarcoma (KS) and some specific types of malignant lymphomas. The diagnostic and prognostic significance of serum viral load in endemic (African) areas is poorly understood. In AIDS-related KS (AKS) it has been shown that HIV-Tat may be of pathogenic importance and that immunoreactivity to Tat may have prognostic significance. Here we report on the quantitative analysis of HHV8 DNA in serum from Tanzanian patients with KS (n = 19), either AIDS-related (AKS) (n = 14) or endemic KS (EKS) (n = 5) and non-KS control individuals (n = 4). Fourteen AKS sera were also tested for HIV-tat antibodies by a direct ELISA assay. In AKS patients detectable (12 out of 14) serum HHV8 DNA levels showed a median of 1400 copies/ml as compared to a median of 200 copies/ml for EKS, but for one AKS case with an exceptionally high level (25,500 copies/ml). The serum HHV8 DNA levels were usually higher in males (n = 17; median 580 DNA copies/ml) as compared to females (n = 6; median 120 DNA copies/ml) and in early, patch stages (n = 8; median 2,750 copies/ml) as compared to late, nodular stages (n = 11; median 200 DNA copies/ml). Of fourteen sera from AKS patients, seven were positive for antibody against HIV-1 tat. Epitope analysis of the anti-tat antibody spectrum showed reactivity to various non-functional sites, but not towards the functional epitopes 46-60 (TAR-binding region).
Adult↗
A synthetic peptide derived from the human eosinophil-derived neurotoxin induces apoptosis in Kaposi's sarcoma cells.
Several commercial preparations of human chorionic gonadotropin (hCG) have been tested as therapy for Kaposi's sarcoma (KS) in clinical trials, but with discordant outcomes. We also have found dramatic differences in the cytotoxic effects of four different commercial hCG preparations on an established KS cell line, KSIMM. A co-purified moiety (ies) present in these preparations may explain these differences. The eosinophil-derived neurotoxin ribonuclease, extended with four extra residues ((-4)EDN), has been suggested to be the putative anti-KS compound in the hCG preparations, being specifically recognized by the cells through its N terminal extension. We therefore synthesized a 16-residue peptide (MSLHV-NT12 EDN), made to resemble the active recognition sequence of (-4)EDN. MSLHV-NT12 EDN displays a dose-dependent cytotoxic effect on KSIMM (killing 50% of the cells at 9 microg/ml). The cytotoxic effect is specific for KS cells, MSLHV-NT12 EDN being harmless even at 100 microg/ml for a melanoma cell line (SK-MEL-28) or for normal human fibroblasts. We also demonstrated that MSLHV-NT12 EDN induces apoptosis in KSIMM cells. In conclusion, MSLHV-NT12 EDN is a specific proapoptotic substance for KS cells, which warrants further investigation into its in vivo effects.
Apoptosis↗
Epstein-Barr virus LMP1 status in relation to apoptosis, p53 expression and leucocyte infiltration in nasopharyngeal carcinoma.
BACKGROUND: Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection. EBV-encoded LMP1, expressed in most of NPC, has been suggested to have an important role in the pathogenesis and development of NPC and its expression correlates with poor prognosis. MATERIALS AND METHODS: Eighty-seven NPC biopsies were analyzed by immunohistochemistry for expression of markers of cell proliferation, apoptosis, infiltrating T lymphocytes and macrophages in relation to the LMP1 status. RESULTS: Our findings indicate that the p53 accumulation in NPC was significantly correlated to LMP1 and MMP9 overexpression in NPC cells. The frequency of apoptotic cells in NPC, as analyzed by TUNEL labeling, correlated to Fas-L and caspase-3 expression, and inversely to LMP1, p53 and MMP 9 expression. CD8+ T cell infiltration was predominately seen in nests of cancer cells with a high level of EBV-LMP1 expression, but these CD8+ T cells showed low expression of CD25 and TIA-1, indicating that they were not activated. CONCLUSION: Our observation suggests that the heavy infiltration by lymphocytes in LMP1-positive NPC tumors does not appear to counteract tumor growth by cytoxicity as indicated by the low apoptotic index. Thus, LMP1 seems to enhance survival- and proliferation-related signals in NPC. In analogy with other tumors, both the infiltrating T cells and the accumulated p53 may be inactive.
Adolescent↗