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PubMed1990

A new human B-cell non-Hodgkin's lymphoma cell line (Karpas 422) exhibiting both t (14;18) and t(4;11) chromosomal translocations.

A unique B-cell non-Hodgkin's lymphoma (NHL) cell line (Karpas 422), bearing both t(14;18) and t(4;11) chromosomal translocations as well as several other chromosomal abnormalities, has been established from the pleural effusion of a patient with chemotherapy-resistant NHL. This cell line has the same karyotypic features as malignant cells from the patient. The major cell clone is characterized chromosomally by 46,XX t(2;10)(p23;q22.1), t(4;11)(q21.3; q23.1), t(14;18)(q32.1;q21.3), t(4;16)(q21.3;p13.1). Both phenotypically and genotypically, the cell line has features of a mature B-cell neoplasm with no evidence for commitment to other lineages. Rearrangements of the C-ETS-1 oncogene and N-CAM-1 and CD3 genes that map to 11q23 were not detected by conventional Southern analysis. BCL-2 was rearranged within the major breakpoint cluster. The K422 cell line has a unique karyotype; this is the first occasion that the t(4;11) translocation has been described in a t(14;18) lymphoma. The cell line will be of value in determining the molecular nature of the t(4;11) translocation.

Antigens, CD↗

PubMed1990

[Characteristics of B-cell lymphoma in Japan].

Consecutive 431 patients with B-cell lymphoma seen in Aichi Cancer Center Hospital from 1964 to 1988 were analysed. Median age was 56 yr (range 8-86). There were 76 patients (17.6%) with follicular lymphoma and 355 with diffuse lymphoma. Among the 30 patients with follicular lymphoma, 10 (33%) were found to have a bcl-2 rearrangement. The incidence was lower than those reported in the United States. This might contribute to the lower incidence of follicular lymphoma cases in Japan. There were 168 patients (39.0%) with nodal lymphoma and 263 with extranodal lymphoma. Eight-four cases arose from the stomach, 84 from Waldeyer's ring, 21 small intestine and 13 thyroid. The distributions of extranodal B-cell lymphoma differed from those of T-cell lymphoma. Patients with gastric lymphomas in stage I were treated with resection alone. In the same manner, patients with Waldeyer's ring lymphoma in stage I were treated with radiotherapy alone. More than 90% of these patients were expected to survive without relapse. On the other hand, only 55% of patients with nodal lymphoma in stage I were expected to survive for more than 10 years. These findings suggest the site of localized lymphoma is an important determinant of outcome of clinical behavior.

Adolescent↗

PubMed1989

Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype.

Chromosomes were studied in 61 patients with differentiated B-cell malignancies including 21 with non-Hodgkin's lymphoma (NHL), three with hairy cell leukemia (HCL), eight with Waldenström's macroglobulinemia (WM), and 29 with plasma cell disorder. Chromosomally abnormal clones were identified in 35 of 61 patients studied: all with NHL, all with HCL, three of eight with WM, and eight of 29 with plasma cell disorder. The most recurrent chromosomal abnormality, observed in 26 of the 35 patients whose chromosomes were abnormal, was a rearrangement involving chromosome 14, in which an additional segment was attached at band 32 in the long arm to form a 14q+ marker chromosome. This rearrangement was seen in 17 patients with NHL, three with HCL, one with WM, and five with plasma cell disorder. In NHL, the rearrangement correlates with histological subclasses: t(14;18) in all four patients with malignant lymphoma (ML)-follicular, mixed small cleaved and large cell; t(8;14) or its variant form, t(8;22), in all six with ML-small noncleaved cell; and t(11;14) in two of three with ML-diffuse, mixed small and large cell. A t(14;18) was also found in each patient with ML-diffuse, large cell, WM, and multiple myeloma, and a variant three-way translocation, t(5;18;14) (q13;q21;q32), in one with ML-diffuse, small cleaved cell. The donor sites for these 14q+ were assigned to oncogene loci: c-myc (8q24), bcl-1 (11q13), and bcl-2 (18q21). Moreover, the donor sites were also located near immunoglobulin light chain gene loci in each patient with leukemic ML-diffuse, mixed small and large cell, t(2;14) (p13;q32.3), and HCL, t(14;22)(q32.3;q11.2). These findings suggest that chimeric DNA formation, not only between an immunoglobulin gene and a certain oncogene, but also between the IgH gene and one of the IgL genes may be potentially relevant in malignant B-cell proliferation.

Adult↗

PubMed1989

The transgenic window on lymphoid malignancy.

Transgenic mice bearing an oncogene targetted for expression in a specific tissue can reveal how that oncogene influences differentiation and help to delineate the pathways to malignancy. To explore lymphoid neoplasia, we have made strains of transgenic mice bearing different oncogenes driven by the immunoglobulin heavy chain enhancer (E mu), which promotes expression within lymphocytes and certain myeloid cells. The prototype E mu-myc mice succumb to pre-B and B cell lymphomas, following a preneoplastic phase in which cycling pre-B cells are overproduced. The similar fate of E mu-N-myc mice suggests that N-myc and myc have overlapping functions. Surprisingly, E mu-N-ras mice develop T lymphomas and macrophage tumours but no B lineage tumours; thus the ability of ras to initiate tumorigenesis may be lineage specific. Similarly, the high predisposition of E mu-v-abl mice to develop plasmacytomas may indicate that v-abl is oncogenic only at certain stages of B cell maturation. The bcl-2 gene promotes cell survival rather than proliferation, and E mu-bcl-2 mice produce copious resting B lymphocytes. The random onset and monoclonality of tumours in the transgenic strains argues for spontaneous genetic alterations that cooperate with the trans-oncogene. Indeed, most plasmacytomas of E mu-v-abl mice bear spontaneous myc rearrangements. Moreover, a minority of E mu-myc B lymphomas exhibit ras mutation, and the tumorigenesis can be reconstructed by crossing E mu-myc and E mu-ras mice, or by retroviral delivery of v-ras or v-raf, either in vitro or in vivo. To access novel cooperating oncogenes, we are using a retrovirus lacking an oncogene as an insertional mutagen. This approach should be applicable to any trans-oncogenic strain and help to delineate the genetic events that trigger malignant clones.

Animals↗

PubMed1987

Refinement of lymphoma cytogenetics by the chromosome 18q21 major breakpoint region.

A small (2.8-kilobase, kb) major breakpoint region localized to segment 18q21 rearranges in greater than 70% of t(14;18)(q32;q21) lymphomas. This rearrangement interrupts the Bcl-2 gene and introduces it into the Ig locus at 14q32. The rearrangement between the joining region (JH) of Ig on chromosome 14 and the 18q21 region creates a translocation-specific DNA rearrangement. We generated probes that distinguish the 14;18 juncture on the derivative (der) 14 and der (18) chromosomes, providing a molecular approach to t(14;18) identification. Approximately 60% of unselected follicular lymphomas, 20% of diffuse large cell lymphomas, and 50% of adult undifferentiated non-Burkitt lymphomas demonstrated 14;18 rearrangements within the major breakpoint region. Examination of DNA for 14;18 rearrangements resolved the identity of 14q+ chromosomes in two patient's cells that lacked an obvious reciprocal partner. Identification of the exact restriction fragments that mediate translocations complements routine cytogenetics. The detection of DNA rearrangements does not require dividing cells or the presence of an identifiable reciprocal partner and can detect clonal translocation rearrangements when the neoplastic cells are only a minority of all cells present.

Chromosome Banding↗

PubMed1988

[Recent progress in non-Hodgkin's lymphoma study in Japan].

Great progress has been made in clinical research on non-Hodgkin's lymphoma during the last 15 years. Surface marker and DNA analyses of immunoglobulin and T-cell receptor genes are essential for new classification of the disease according to the cellular origin of tumor cells. This approach resulted in the establishment of new disease entities such as adult T-cell leukemia/lymphoma(ATL), immunoblastic lymphoadenopathy (IBL)-like T-cell lymphoma, and the pleural B-lymphoma occurring in long-standing pyothorax. New retrovirus, HTLV-I, was found during studies on ATL. Prevention of HTLV-I infection is an important project. HTLV-I negative ATL was also found and is of particular interest in understanding leukemogenesis of ATL. An oncogen such as bcl-2 is important for characterization of follicular lymphoma. Prognostic factors of patients with T-lymphoma are completely different from those of B-lymphoma. Risk grouping by combination of major prognostic factors is useful for the selection of the best treatment modality and the accurate estimation of prognosis of patients at initial presentation. The effect of combination chemotherapy should be evaluated separately between T- and B-lymphomas because of the difference in response rate and prognostic factors.

B-Lymphocytes↗

PubMed1987

Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region.

A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.

Alleles↗

PubMed1988

Genotypic analysis of DNA isolated from fine needle aspiration biopsies.

DNA was isolated from 20 fine needle aspiration (FNA) biopsies from lymphomas, hyperplastic lymph nodes and nonlymphoid malignant tumors. Small aliquots (0.2 microgram to 2.0 micrograms) of DNA from each sample were digested to completion with restriction endonuclease Eco RI and/or Bam HI and electrophoresed in 0.8% agarose minigels. DNA was transferred to a nylon filter after brief treatment in HCl and subsequent denaturation and neutralization. Filters were hybridized to radiolabeled JH, C kappa, TCR beta or bcl-2 probes to determine if these genes were in germline or rearranged configurations in each of the samples. It was possible to demonstrate rearrangement of at least one immunoglobulin gene in each of the samples diagnosed as lymphoma, while all samples derived from hyperplastic lymph nodes and nonlymphoid malignant tumors exhibited a germline pattern for each probe tested. Thus, FNA biopsies can provide suitable and sufficient DNA for genotypic analysis using molecular probes that detect gene rearrangement.

Adolescent↗

PubMed1988

A rearranged transforming gene, tre, is made up of human sequences derived from chromosome regions 5q, 17q and 18q.

The transfection recombinant transforming gene, tre, originated from discontinuous human genetic elements after transfection of NIH3T3 cells with genomic DNA from a Ewing's sarcoma cell line. Probes for the three normally discontinuous human elements involved in the transfection recombinant were subcloned and used in conjunction with a panel of rodent-human hybrid cells to determine their normal location in the human genome. The leftmost (5') element derives from the long arm of chromosome 5 (5q); the internal fragment derives from human chromosome 18 proximal to the bcl-2 gene; and the rightmost (3') element derives from the long arm of chromosome 17 (17q) distal to an acute leukemia breakpoint at 17q21. In situ hybridization of the same probes to human metaphase chromosomes confirmed localization of these sequences to regions 5q23----q31, 18q12, and 17q12----q22.

Animals↗

PubMed1987

The gene located at chromosome 18 band q21 is rearranged in uncultured diffuse lymphomas as well as follicular lymphomas.

The karyotypic abnormality t(14;18)(q32;q21) is reported to occur in 75% of follicular lymphomas. This translocation results in the rearrangement of a putative oncogene bcl-2, which resides at chromosome 18 band q21 (the 18q21 gene). Using two human genomic DNA fragments cloned from the chromosome 18 band q21 as probes, we analyzed 65 uncultured human lymphoma samples by the Southern blot technique. The 18q21 gene was rearranged in 18 of 26 (69%) follicular lymphomas, 3 of 5 (60%) follicular lymphomas transformed to large cell lymphomas, 8 of 20 (40%) diffuse large cell lymphomas (DLCLs), and 2 of 7 (29%) small noncleaved cell lymphomas (SNCs). Our analysis detected rearrangement of the 18q21 gene in 10 of 13 (77%) cases in which the t(14;18)(q32;q21) translocation was found by cytogenetic techniques. Our analysis also proved helpful in difficult karyotyping situations: (a) identifying the donor chromosome fragment as chromosome 18 band q21 in 4 of 9 (44%) cases that cytogenetically displayed a 14q+ chromosome of unknown origin, and (b) identifying a rearrangement of chromosome 18 band q21 in 12 of 18 (67%) cases that cytogenetically yielded no cells in metaphase. We also demonstrated three cases of submicroscopic rearrangement of the 18q21 gene. In our studies, patients with DLCLs and rearrangement of the 18q21 gene had a significantly higher incidence of extranodal involvement when compared with patients with DLCLs and no 18q21 gene rearrangement (P = 0.03).

Bone Marrow Cells↗

PubMed1986

Chromosomal approaches to the molecular basis of neoplasia.

Nonrandom patterns of chromosome abnormality in tumors are providing clues to the location of oncogenes and their activation mechanisms. Studies of translocations in Burkitt's lymphoma cells have shown that the c-myc proto-oncogene is consistently juxtaposed with a rearranged and transcriptionally active immunoglobulin gene locus, with resultant myc gene deregulation. In other B cell tumors, translocations appear to bring previously unrecognized oncogenes (bcl-1, bcl-2) into similar association with the immunoglobulin heavy-chain locus. T cell receptor genes may also "activate" known and unknown oncogenes after chromosome translocation. In chronic myelogenous leukemia, the translocated c-abl oncogene forms a "hybrid" gene in its new location on the Philadelphia chromosome, with altered function. Gene amplification units, seen as cytogenetically homogeneous staining regions in chromosomes or as double-minute bodies in metaphases, can represent multiple copies of oncogenes and be important in late stages of tumor progression. Other significant alterations in gene dosage, recognized as gain or loss of all or part of a specific chromosome, also occur in human neoplasms, but their specific role in carcinogenesis is largely undefined.

Burkitt Lymphoma↗

PubMed1995

pIXY321 protects against Ara-C or taxol-induced apoptosis and loss of clonogenic survival of normal human bone marrow progenitor cells.

By suppressing apoptosis, hemopoietic growth factors (HGFs) promote the survival of CD34+, HLA-DR+ marrow cells that are enriched for hemopoietic progenitor cells (HPC). In the present studies, we have examined the effects of pIXY321, a genetically engineered fusion protein of GM-CSF and IL-3 (GM-CSF/IL-3), on high-dose Ara-C (HIDAC) and taxol-induced apoptosis and survival of a multilineage HPC, the CFU-GEMM. Exposure to 1.0 mumol/l taxol for 24 h or HIDAC > or = 10 mumol/l for 4 h induced internucleosomal DNA fragmentation and the morphologic features of apoptosis in CD34+, HLA-DR+ cells. These treatments were associated with > or = 50% inhibition of the assayable CFU-GEMM colony numbers. Incubation in serum-free medium (SFM) alone for 24 h also induced apoptosis of CD34+, HLA-DR+ cells, which was associated with reduced intracellular levels of the bcl-2 gene product p26BCL-2. Co-treatment with pIXY321 (10 ng/ml) inhibited apoptosis of CD34+, HLA-DR+ cells incubated in SFM, without significantly increasing the intracellular p26BCL-2 levels. Furthermore, co-treatment with pIXY321 significantly reduced taxol- and Ara-C-induced apoptosis and promoted the survival of CFU-GEMM (P < 0.05). Taxol and Ara-C mediated apoptosis of CD34+, HLA-DR+ cells, and its inhibition by pIXY321, was not accompanied by any significant alteration in the intracellular p26BCL-2 levels. By demonstrating that co-treatment with pIXY321 confers significant protection against apoptosis of CD34+, HLA-DR+ cells as well as promotes survival of normal HPC exposed to clinically relevant schedules and concentrations of taxol of Ara-C, these results support the design of chemotherapy regimens incorporating pIXY321 plus taxol and/or high-dose Ara-C for solid tumors and/or acute leukemias. It is hoped that the use of such a cytokine might maintain normal HPC numbers following chemotherapy, therefore avoiding prolonged suppression.

Antigens, CD34↗

PubMed1995

Apoptin, a protein encoded by chicken anemia virus, induces cell death in various human hematologic malignant cells in vitro.

Apoptin, a small protein encoded by chicken anemia virus (CAV) was expressed in various human hematologic malignant cell lines derived from leukemias and lymphoma. Three of these cell lines contain bcl-2 or BCR-ABL proteins, known to block apoptosis induced by chemotherapeutic compounds. By immunofluorescence and propidium-iodide staining apoptin was shown to induce apoptosis in all analysed cell lines. Early after expression, apoptin exhibited a fine-granular distribution in the still intact nucleus. Later, apoptin became aggregated and the nucleus segmented. The data with truncated apoptin indicate that for optimal induction of apoptosis apoptin has to be located in the nucleus.

Apoptosis↗

PubMed1995

Bcl-XL protects cancer cells from p53-mediated apoptosis.

Oncogenesis is a process resulting from genetic events which cause loss of growth control or inhibition of appropriate cell death. The Bcl-XL protein is a recently discovered member of the bcl-2 family which has been shown to protect cells from some forms of programmed cell death, but has not yet been implicated in the genesis of human carcinomas. In this report we explore the role of Bcl-XL overexpression in protecting cancer cells from p53-mediated apoptosis. Increased levels of Bcl-XL were found in a subset of primary human breast carcinomas, as well as in the breast cancer line, T47D. T47D cells were then transfected with a temperature-sensitive mutant of the tumor suppressor p53 (p53ts). Although many tumor cell lines undergo apoptosis when p53 is expressed, the T47D transfectants remained viable at temperatures permitting wild-type p53 phenotype. This suggested that endogenous Bcl-XL could protect cancer cells from p53-mediated apoptosis. To test this hypothesis, murine erythroleukemia cells were transfected with bcl-XL and p53ts. While cell lines expressing p53 alone rapidly died, those cells co-expressing Bcl-XL survived. These results demonstrate that Bcl-XL is capable of protecting cells from p53-mediated apoptosis, and suggest a possible mechanism by which tumors expressing Bcl-XL are able to partly overcome the tumor suppressor functions of p53.

Animals↗

PubMed1995

Characterization of transforming growth factor-beta 1 induced apoptosis in normal human B cells and lymphoma B cell lines.

Transforming growth factor beta 1 (TGF beta 1) has been shown to inhibit growth stimulation in normal human B cells as well as in Epstein Barr virus (EBV)-negative Burkitt's lymphoma (BL) cell lines. The mechanisms for this potent growth inhibition are not completely defined. Here we show that a number of EBV-negative lymphoma B cell lines (BL-41, Ramos and CAPA-2), when exposed in vitro to TGF beta 1, undergo apoptosis. Maximum apoptosis was observed at 48 h following TGF beta 1 treatment, with no apparent effect on the expression of c-myc and bcl-2 proteins. Similar induction of apoptosis was observed when these lymphoma cell lines were treated with aphidicolin, a DNA synthesis inhibitor. In contrast, various preparations (14 out of 17) of normal human tonsilar B cells showed no significant apoptosis, although both TGF beta 1 and aphidicolin inhibited anti-mu/IL-4 induced DNA synthesis in all preparations. Furthermore, another TGF beta 1 sensitive EBV-negative BL cell line, CA46, exhibited no apoptosis in response to TGF beta 1 and aphidicolin, corroborating the findings in normal human B cells. Taken together, these data support the hypothesis that exposure to TGF beta 1, which results in cell cycle arrest and DNA synthesis inhibition, may not be obligatory or sufficient for the induction of apoptosis. Rather, induction of apoptosis or lack of it may be intrinsically determined by an interplay between extracellular and intracellular regulators of cellular growth.

Aphidicolin↗

PubMed2026

Suppression of HIV-1 replication in CEM-A cell cultures by trans-splicing group I introns targeting PAS/PBS sequences and conditionally expressing ΔN-Bax.

Anti-HIV group I introns containing antisense guide sequences directed against the HIV-1 primer activation signal and primer-binding site (PAS/PBS) were designed and evaluated. Because PAS/PBS sequences are present in the viral RNA species examined, these RNAs can serve as trans-splicing substrates. The introns were active against both artificial target RNAs and viral RNA generated during infection. Cleavage and degradation of targeted viral RNA may have contributed to suppression, whereas inclusion of a 3' exon encoding the proapoptotic protein ΔN-Bax was associated with increased programmed cell death and may have augmented suppression of viral replication. In cultured CEM-A cells, transgene expression of these introns markedly suppressed HIV-1 replication, with p24 levels falling below the assay detection limit in selected clones. RESULTS: RT-PCR and sequence analysis detected splice products containing the expected PAS/PBS junctions. In the dual-luciferase assay, intron expression reduced normalized Gaussia luciferase signal by approximately 70% relative to the negative control. Qualitative Annexin V imaging and caspase-3 assays were consistent with infection-dependent apoptosis after ΔN-Bax splice-product formation. Transient expression of each intron in HEK293T cells followed by infection with VSV-G-pseudotyped HIV-1NL4-3 at an MOI of 2 reduced p24 levels by approximately 50% at 4 days post-infection. Construct 128L produced the strongest RT-PCR band under the tested conditions and was selected for subsequent experiments. A canonical splice product and a low-abundance noncanonical splice product were detected; both involved the intended HIV-derived target RNA, although transcriptome-wide off-target splicing was not assessed. Heterogeneous transformed HEK293T populations showed an approximately 2-log10 reduction in p24. In selected clonal HEK293T and CEM-A lines, p24 was below the assay detection limit at the measured endpoints, including up to 90 days after infection in some CEM-A clones. CONCLUSIONS: PAS/PBS-targeting group I introns suppressed HIV-1-associated p24 production in the tested cell-culture models. Linking the introns to a ΔN-Bax 3' exon was associated with infection-dependent apoptosis and may further limit viral replication and spread. The use of highly conserved, functionally constrained target sequences may reduce the likelihood of escape, but viral evolution and transcriptome-wide off-target effects were not assessed. This conditional death-upon-infection strategy warrants further evaluation in primary-cell and in vivo models.

Humans↗

PubMed2026

Overlapping genetic etiology of pediatric and adult germ cell tumors.

BACKGROUND: Germ cell tumors are heterogeneous neoplasms arising from primordial germ cells. Although genome-wide association studies have identified numerous susceptibility loci for adult testicular germ cell tumors, the heritable basis of pediatric testicular germ cell tumors and germ cell tumors that arise outside the testes remain poorly understood. METHODS: We conducted a multi-ancestry genome-wide association study of pediatric germ cell tumors, including 1927 cases from the Germ Cell Tumor Epidemiology Study and 10 601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) germ cell tumor between the ages of 0 and 19 years. RESULTS: We identified 4 loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chromosome [chr] 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide statistically significant associations were identified in subgroup analyses, including 6 loci for intracranial germ cell tumors (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), 1 locus for testicular germ cell tumor (rs1907702 [KITLG]), and 1 locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported testicular germ cell tumor loci were significantly associated with germ cell tumor overall or in at least 1 subgroup with a particularly strong correlation between testicular germ cell tumor and intracranial germ cell tumor effect estimates (rho = 0.63, P = 5.5 × 10-10). Expression quantitative trait locus (QTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). CONCLUSIONS: Our data support a role for germline genetic variation in the development of germ cell tumors in locations outside the testes and highlight shared genetic architecture across age group and tumor location.

Humans↗

PubMed2024

Proteomic serum profiles before and after lipoprotein apheresis in patients with peripheral artery disease with ulceration.

INTRODUCTION: The efficacy of lipoprotein apheresis (LA) in peripheral arterial disease (PAD) has been primarily attributed to its anti-atherosclerotic effects through the adsorption of lipoproteins. However, the other potential effects of LA remain unknown. We evaluated changes in serum profiles before and after LA using a comprehensive analysis to explore the underlying mechanism. METHODS: Ten patients with leg ulcers were included from the LETS-PAD study, in which patients with lipoprotein-controlled PAD underwent LA. Serum samples collected at baseline and 1 month after LA were analyzed for proteomic changes. RESULTS: Six patients exhibited ulcer epithelialization and skin perfusion pressure improvement. Proteomic analysis identified 2033 proteins. Fifty-five proteins showed significant differences. B-cell lymphoma protein-2 associated X (BAX) and C-X-C motif chemokine 10 (CXCL10) were downregulated. CONCLUSION: Serum BAX and CXCL10 levels significantly decreased after LA, which may be involved in the ulcer epithelialization mechanism of LA, which potentially acts through angiogenesis promotion.

Humans↗