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PubMed2001

Infectious simian/human immunodeficiency virus with human immunodeficiency virus type 1 subtype C from an African isolate: rhesus macaque model.

Human immunodeficiency virus type 1 (HIV-1) subtype C is responsible for more than 56% of all infections in the HIV and AIDS pandemic. It is the predominant subtype in the rapidly expanding epidemic in southern Africa. To develop a relevant model that would facilitate studies of transmission, pathogenesis, and vaccine development for this subtype, we generated SHIV(MJ4), a simian/human immunodeficiency virus (SHIV) chimera based on HIV-1 subtype C. SHIV(MJ4) contains the majority of env, the entire second exon of tat, and a partial sequence of the second exon of rev, all derived from a CCR5-tropic, primary isolate envelope clone from southern Africa. SHIV(MJ4) replicated efficiently in human, rhesus, and pig-tailed macaque peripheral blood mononuclear cells (PBMCs) in vitro but not in CEMx174 cells. To assess in vivo infectivity, SHIV(MJ4) was intravenously inoculated into four rhesus macaques (Macaca mulatta). All four animals became infected as determined through virus isolation, PCR analysis, and viral loads of 10(7) to 10(8) copies of viral RNA per ml of plasma during the primary infection phase. We have established a CCR5-tropic SHIV(MJ4)/rhesus macaque model that may be useful in the studies of HIV-1 subtype C immunology and biology and may also facilitate the evaluation of vaccines to control the spread of HIV-1 subtype C in southern Africa and elsewhere.

Amino Acid Sequence↗
PubMed2001

Genetic and functional diversity of human immunodeficiency virus type 1 subtype B Nef primary isolates.

We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Molecular epidemiology of human immunodeficiency virus type 1 sub-subtype A3 in Senegal from 1988 to 2001.

The global human immunodeficiency virus (HIV)epidemic is characterized by significant genetic diversity in circulating viruses. We have recently characterized a group of viruses that form a distinct sub-subtype within the subtype A radiation, which we have designated HIV type 1 (HIV-1) sub-subtype A, circulating in West Africa. A prospective study of a cohort of female sex workers (FSW) in Dakar, Senegal over an 18-year period indicated that an A3-specific sequence in the C2-V3 region of the env gene was found in 46 HIV-1-infected women. HIV-1 sub-subtype A3 appeared in the FSW population as early as 1988 and continued to be transmitted as of 2001. We also found that HIV-1 A3 is not confined to the FSW cohort in Senegal but is also circulating in the general population in Dakar. Furthermore, analyses of viral sequences from a few other West and Central African countries also demonstrated evidence of HIV-1 A3 sequence in isolates from HIV-1-infected people in Ivory Coast, Nigeria, Niger, Guinea Bissau, Benin, and Equatorial Guinea. Overall, because of the evidence of sub-subtype A3 in the general population in Senegal, as well as in a few neighboring West and Central African countries, along with the increasing incidence of infection with A3-containing viruses in the Dakar high-risk FSW population, we feel that HIV-1 sub-subtype A3 viruses are important to distinguish and monitor.

Base Sequence↗
PubMed2003

Role of peptidoglycan subtypes in the pathogenesis of bacterial cell wall arthritis.

BACKGROUND: Bacterial cell wall (CW) arthritis develops in susceptible strains of rats after a single intraperitoneal injection of the CW from certain bacterial species, both pathogenic and non-pathogenic. For the development of chronic bacterial CW arthritis, the structure of the bacterial peptidoglycan (PG) has been found to be decisive. OBJECTIVE: To define the role of PG subtypes in the pathogenesis of chronic bacterial CW arthritis. METHOD: Arthritis was induced with CWs of Lactobacillus plantarum, L casei B, L casei C, and L fermentum. Gas chromatography-mass spectrometry was used to measure the presence of CW derived muramic acid in the liver and to determine PG subtypes. CWs were also tested for their resistance to lysozyme in vitro. RESULTS: These results and those published previously indicate that PGs of CWs which induce chronic arthritis, no matter whether they were derived from strains of Streptococcus, Bifidobacterium, Collinsella, or Lactobacillus, all have lysine as the third amino acid of the PG stem peptide, representing PG subtypes A3alpha and A4alpha. Those strains which induce only transient acute arthritis or no arthritis at all do not have lysine in this position, resulting in different PG subtypes. CONCLUSIONS: In vivo degradation of only those PGs with the subtypes A3alpha and A4alpha leads to the occurrence of large CW fragments, which persist in tissue and have good proinflammatory ability. CWs with other PG subtypes, even if they are lysozyme resistant, do not cause chronic arthritis, because the released fragments are not phlogistic. It is emphasised that a variety of microbial components not causing inflammation have been found in animal and human synovial tissue.

Animals↗
PubMed2026

Incidence patterns and genetic validation of primary glaucoma subtypes among 1 million adults in China and the UK.

BACKGROUND/AIMS: Primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) are distinct diseases, yet many glaucoma cases in population-based datasets lack subtype specification. We assessed incidence patterns of glaucoma subtypes in China and the UK and used genetic evidence to infer the likely subtype composition of cases recorded as unspecified glaucoma. METHODS: Incident primary glaucoma was identified from linked inpatient records in the prospective China Kadoorie Biobank (CKB; n=512 504) and UK Biobank (UKB; n=492 329) studies. Cohort-specific phenotyping algorithms defined POAG, PACG and unspecified glaucoma. Adjusted incidence rates were estimated by direct standardisation. To support subtype inference, polygenic risk scores (PRSs) were constructed using ancestry-specific genome-wide association studies, including a new East Asian PACG meta-analysis, and tested for association with glaucoma phenotypes using multivariable logistic regression. RESULTS: Over 12 years of follow-up, 1658 primary glaucoma cases were identified in CKB and 7643 in UKB. Most (>68%) cases lacked subtype specification. Incidence increased with age and was twofold higher among women for PACG in both cohorts and for unspecified glaucoma in CKB. In UKB, POAG incidence was fivefold higher among Black than White participants, with a similar but attenuated pattern for unspecified glaucoma. PRS analyses indicated that unspecified glaucoma closely aligned with PACG in CKB but was more heterogeneous in UKB. CONCLUSION: Healthcare-recorded incidence patterns for POAG and PACG were consistent with established demographic risk factors, whereas unspecified glaucoma showed differences in subtype composition between populations. Integrating epidemiological and genetic evidence improves interpretation of glaucoma phenotypes when detailed clinical information is unavailable.

Epidemiology↗
PubMed2006

A comprehensive strategy for the subtyping of patients with Fanconi anaemia: conclusions from the Spanish Fanconi Anemia Research Network.

BACKGROUND: Fanconi anaemia is a heterogeneous genetic disease, where 12 complementation groups have been already described. Identifying the complementation group in patients with Fanconi anaemia constitutes a direct procedure to confirm the diagnosis of the disease and is required for the recruitment of these patients in gene therapy trials. OBJECTIVE: To determine the subtype of Fanconi anaemia patients in Spain, a Mediterranean country with a relatively high population (23%) of Fanconi anaemia patients belonging to the gypsy race. METHODS: Most patients could be subtyped by retroviral complementation approaches in peripheral blood T cells, although some mosaic patients were subtyped in cultured skin fibroblasts. Other approaches, mainly based on western blot analysis and generation of nuclear RAD51 and FANCJ foci, were required for the subtyping of a minor number of patients. RESULTS AND CONCLUSIONS: From a total of 125 patients included in the Registry of Fanconi Anaemia, samples from 102 patients were available for subtyping analyses. In 89 cases the subtype could be determined and in 8 cases exclusions of common complementation groups were made. Compared with other international studies, a skewed distribution of complementation groups was observed in Spain, where 80% of the families belonged to the Fanconi anaemia group A (FA-A) complementation group. The high proportion of gypsy patients, all of them FA-A, and the absence of patients with FA-C account for this characteristic distribution of complementation groups.

Algorithms↗
PubMed2004

COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma.

BACKGROUND: Squamous cell carcinoma has a stronger association with tobacco smoking than other non-small cell lung cancers (NSCLC). A study was undertaken to determine whether chronic obstructive pulmonary disease (COPD) is a risk factor for the squamous cell carcinoma histological subtype in smokers with surgically resectable NSCLC. METHODS: Using a case-control design, subjects with a surgically confirmed diagnosis of squamous cell carcinoma were enrolled from smokers undergoing lung resection for NSCLC in the District Hospital of Ferrara, Italy. Control subjects were smokers who underwent lung resection for NSCLC in the same hospital and had a surgically confirmed diagnosis of NSCLC of any histological type other than squamous cell. RESULTS: Eighty six cases and 54 controls (mainly adenocarcinoma, n = 50) were enrolled. The presence of COPD was found to increase the risk for the squamous cell histological subtype by more than four times. Conversely, the presence of chronic bronchitis was found to decrease the risk for this histological subtype by more than four times. Among patients with chronic bronchitis (n = 77), those with COPD had a 3.5 times higher risk of having the squamous cell histological subtype. CONCLUSIONS: These data suggest that, among smokers with surgically resectable NSCLC, COPD is a risk factor for the squamous cell histological subtype and chronic bronchitis, particularly when not associated with COPD, is a risk factor for the adenocarcinoma histological subtype.

Aged↗
PubMed1991

Na(+)-H+ exchanger subtypes: a predictive review.

In recent years, many reports have appeared describing distinct heterogeneity of proteins that heretofore were considered to be a single species or type. The division of proteins into different classes or subtypes is aided by pharmacological tools such as selective ligands, functional measurements such as those examining kinetic or regulatory differences, and molecular biological approaches that have identified distinct genes coding for similar yet distinguishable gene products. Currently, much effort is directed toward understanding the significance of these sometimes subtle differences in terms of functional consequences for the cells in which they exist. Although most reports to date involve hormone and neurotransmitter receptor subtypes, it is also possible that other cell surface molecules such as ion transporters exist as multiple subtypes. In this paper we review the current evidence that Na(+)-H+ exchange activity is mediated by different Na(+)-H+ exchanger subtypes. Although subtypes have not been identified with certainty, we can predict certain distinguishing characteristics that these putative subtypes may have that may be of value in correlating predicted gene products obtained from cDNA cloning with previously characterized Na(+)-H+ exchangers.

Animals↗
PubMed1994

Muscarinic cholinergic receptor subtypes in rat sublingual glands.

Mucin glycoprotein secretion by rat sublingual glands is regulated primarily by muscarinic cholinergic receptors. Studies were conducted to identify muscarinic receptor subtypes in whole glands as well as in isolated acinar structures. In radioligand binding studies, we used subtype-selective antagonists in competition studies to initially determine receptor subtype heterogeneity. In membranes from whole glands, both pirenzepine and methoctramine displayed two affinity sites (M1 and M3) of nearly equal proportions. In contrast, acinar membranes contained a 1:2 and 2:1 ratio of M1 to M3 sites for pirenzepine and methoctramine, respectively. In all cases, p-fluoro-hexahydro-siladifenidol and 4-diphenylacetoxy-N-methylpiperidine each bound to a single class of binding sites. Northern analysis using oligonucleotide probes specific for the 5' ends of the translated regions of m1 through m5 receptors detected only m1 and m3 subtypes in poly(A)+ RNA from whole glands. We also used antisera specific for each receptor subtype to immunoprecipitate solubilized receptors from membrane preparations. Only m1 (51.7 and 64.9%) and m3 (48.3 and 34.7%) subtypes were found consistently in membranes from whole sublingual glands and isolated acini, respectively. Studies with other exocrine glands generally described the predominance of m3 receptors, and m1 receptors, if present, were presumably associated with contaminating neural structures. Our results therefore demonstrate that mucous acini from rat sublingual glands contain abundant amounts of both m1 and m3 receptors.

Animals↗
PubMed1994

Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts.

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.

Angiotensin II↗
PubMed1997

Localization of adenosine-receptor subtype mRNA in rat outer medullary descending vasa recta by RT-PCR.

Adenosine has a multitude of functions in the kidney, including vasoregulation of the renal vasculature. The actions of adenosine are mediated by its binding to specific receptors. Four adenosine-receptor subtypes have been cloned and sequenced, the A1, A2a, A2b, and the A3. In this study, the expression of individual adenosine-receptor subtype RNAs in outer medullary descending vasa recta (OMDVR) was investigated. Total RNA isolated from the outer medulla and microdissected, permeabilized OMDVR were subjected to reverse transcription-polymerase chain reaction (RT-PCR) with primers specific for each of the adenosine-receptor subtypes. Subtype-specific probes were used to verify the PCR products by Southern hybridization. Our studies, performed in triplicate on five different rats, indicate the presence of A1, A2a, and A2b adenosine-receptor subtype mRNAs. These products were not attributable to extraneous RNA contamination from other tissue sources, nor did they result from genomic DNA amplification. These data are consistent with pharmacological evaluations, favor A1, A2a, and A2b adenosine-receptor subtype expression in OMDVR, and support a role for adenosine in the regulation of medullary blood flow.

Animals↗
PubMed1994

Distinct cellular localization of mRNAs for three subtypes of prostaglandin E receptor in kidney.

Distribution of the mRNAs for three subtypes of prostaglandin E (PGE) receptors in the mouse kidney was investigated by in situ hybridization. The mRNA for EP1 subtype, which is coupled to Ca2+ mobilization, was specifically localized to the collecting ducts from the cortex to the papilla. The mRNA for EP2 subtype, which is linked to stimulation of adenylate cyclase, was localized to the glomeruli. The mRNA for EP3 subtype, which is coupled to inhibition of adenylate cyclase, was located densely in the tubules in the outer medulla and in the distal tubules in the cortex. These results exhibit distinct cellular localization of three subtypes of PGE receptor in the kidney and suggest that PGE2 exerts multiple functions via these subtypes expressed in different segments of the nephron.

Adenylyl Cyclases↗
PubMed2005

[Helicobacter pylori and gastric cancer: relationship with histological subtype and tumor location].

INTRODUCTION: Helicobacter pylori (HP) has been implicated in the pathogenesis of gastric adenocarcinoma. Published data on HP infection and its association with both histological subtype and tumor localization are contradictory and few data are available on this topic in Spain. The aim of the present study was to evaluate the association of HP infection with histological subtype and tumor localization in a series of patients with gastric adenocarcinoma. MATERIAL AND METHOD: We retrospectively reviewed all the patients diagnosed with gastric neoplasms in Hospital del Mar in Barcelona between 1995 and 2001. The histological subtype was established using Lauren's classification. Tissue samples were obtained from the surgical specimen or from endoscopic biopsies. HP infection was histologically determined through hematoxylin-eosin, Masson's trichromic, and Giemsa staining. RESULTS: During the study period, 304 gastric neoplasms, 275 (90.4%) adenocarcinomas, 22 (7.2%) lymphomas, 3 (1.0%) leiomyosarcomas, 2 (0.7%) degenerated gastrointestinal stromal tumors (GIST) and 2 (0.7%) Kaposi's sarcomas were diagnosed. In patients with adenocarcinoma, the mean age at diagnosis was 69 years and most patients were male (62%). A total of 48.1% of the neoplasms were located in the gastric antrum, 23.7% in the body and 19.1% in the fundus (13.6% in the period 1994-1997 and 25.4% in the period 1998-2001, p = 0.018). Intestinal-type gastric carcinoma was observed in 56% of the patients, diffuse-type in 28% and indeterminate-type in 16%. HP infection was confirmed in 69% of the patients (68% in intestinal subtype, 69% in diffuse subtype, and 69% in indeterminate subtype, p = 0.84), and was significantly associated with distal adenocarcinomas vs. proximal adenocarcinomas (73.6% vs 48.6%, p < 0.05). CONCLUSIONS: No differences were observed between the histological type of adenocarcinoma and HP infection. In the last few years, the incidence of fundic adenocarcinomas has increased. These tumors show a lower association with HP infection.

Adenocarcinoma↗
PubMed2006

[Prognostic influence of immunological subtypes of T-cell acute lymphoblastic leukemia. Study of 81 patients].

BACKGROUND AND OBJECTIVE: T-cell acute lymphoblastic leukemia (ALL) includes 4 immunological subtypes: pro-T, pre-T, thymic or cortical and mature. In some studies, pro-T and mature subtypes have a poor prognosis. The objective of this study was to describe the clinical characteristics, the result of treatment and the prognosis of the immunological subtypes of T-cell ALL in 81 adult patients included in 2 protocols of the Spanish PETHEMA group (ALL-96 and ALL-93). PATIENTS AND METHOD: Between 1993 and 2003, 81 adult patients from 22 Spanish hospitals were included in two PETHEMA protocols: ALL-96 for standard-risk patients, and ALL-93 for high- risk patients. The main clinical and biological parameters as well as the rate of response to treatment, the frequency of complete remission , disease free survival and overall survival were compared in each T-cell ALL subtype. RESULTS: Of the 64 evaluable patients the distribution of the immunological subtypes was: 3 pro-T, 17 pre-T, 22 thymic or cortical and 22 mature. Patients with mature T-ALL had higher frequency of central nervous system involvement and myeloid antigen expression than those of the remaining subgroups. Patients with mature T-cell ALL had a slow rate of response to treatment in comparison with patients wit pre-T and mature T-cell ALL but this did not translate to significant differences in frequency of complete remission (77% vs 94%), disease free survival (42% vs 46%) and overall survival (29% vs 47%). CONCLUSIONS: Although patients with mature T-cell ALL had a slow rate of response to treatment and their survival tended to be shorter, in the present study there were no statistically significant differences in the prognosis of the different subtypes of T-cell ALL.

Adolescent↗
PubMed2005

Gene expression profiling identifies molecular subtypes of inflammatory breast cancer.

Breast cancer is a heterogeneous disease. Comprehensive gene expression profiles obtained using DNA microarrays have revealed previously indistinguishable subtypes of noninflammatory breast cancer (NIBC) related to different features of mammary epithelial biology and significantly associated with survival. Inflammatory breast cancer (IBC) is a rare, particular, and aggressive form of disease. Here we have investigated whether the five molecular subtypes described for NIBC (luminal A and B, basal, ERBB2 overexpressing, and normal breast-like) were also present in IBC. We monitored the RNA expression of approximately 8,000 genes in 83 breast tissue samples including 37 IBC, 44 NIBC, and 2 normal breast samples. Hierarchical clustering identified the five subtypes of breast cancer in both NIBC and IBC samples. These subtypes were highly similar to those defined in previous studies and associated with similar histoclinical features. The robustness of this classification was confirmed by the use of both alternative gene set and analysis method, and the results were corroborated at the protein level. Furthermore, we show that the differences in gene expression between NIBC and IBC and between IBC with and without pathologic complete response that we have recently reported persist in each subtype. Our results show that the expression signatures defining molecular subtypes of NIBC are also present in IBC. Obtained using different patient series and different microarray platforms, they reinforce confidence in the expression-based molecular taxonomy but also give evidence for its universality in breast cancer, independently of a specific clinical form.

Adenocarcinoma↗
PubMed2004

Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung.

PURPOSE: Gefitinib (IRESSA; AstraZeneca, Osaka, Japan) shows excellent antitumor activity against advanced non-small-cell lung cancer, especially for the treatment of adenocarcinoma. However, the predictive factors for the response to gefitinib are still controversial. The aim of this study was to identify the clinicopathological and immunohistochemical features that are favorable to the use of gefitinib in adenocarcinoma patients. EXPERIMENTAL DESIGN: Between June 2002 and October 2003, 36 adenocarcinoma patients who experienced a relapse after surgical resection were treated with gefitinib at our hospital. The histologic patterns of the tumors were divided into four distinctive subtypes according to the revised World Health Organization histologic classification, and the dominant histologic subtype for the maximum cut surface of each resected specimen was documented. Association between the response to gefitinib and the clinicopathological features or immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, or c-erbB-2 were then investigated. RESULTS: A significant association between the response to gefitinib and dominant papillary subtype findings was observed (P = 0.0021); the survival time of papillary subtype patients was also significantly prolonged compared with that of non-papillary subtype patients (P = 0.03). No other clinicopathological features or the expression of EGFR, phosphorylated EGFR, or c-erbB-2 were associated with the response to gefitinib. CONCLUSIONS: The results of the present study indicate that dominant papillary subtype findings of lung adenocarcinomas can be an important predictor of the response to gefitinib. Thus, this type of adenocarcinoma might be susceptible to postoperative adjuvant treatment with gefitinib.

Adenocarcinoma↗
PubMed2005

Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer.

PURPOSE: The presence of similar histologic subtypes of epithelial ovarian and endometrial cancers has long been noted, although the relevance of this finding to pathogenesis and clinical management is unclear. Despite similar clinical characteristics, histologic subtypes of cancers of the ovary and endometrium are treated according to organ of origin. This study compares the gene expression profiles of analogous histologic subtypes of cancers of the ovary and endometrium using the same genomic platform to determine the similarities and differences between these tumors. EXPERIMENTAL DESIGN: Gene expression profiles of 75 cancers (endometrioid, serous, and clear cell) of the ovary and endometrium, five renal clear cell cancers, and seven normal epithelial brushings were determined using a 11,000-element cDNA array. All images were analyzed using BRB ArrayTools. Validation was done using real-time PCR on select genes and immunohistochemical staining. RESULTS: Comparison across endometrial and ovarian cancers and serous and endometrioid tumors showed expression patterns reflecting their organ of origin. Clear cell tumors, however, showed remarkably similar expression patterns regardless of their origin, even when compared with renal clear cell samples. A set of 43 genes was common to comparisons of each of the three histologic subtypes of ovarian cancer with normal ovarian surface epithelium. CONCLUSIONS: The comparison of the gene expression profiles of endometrioid and serous subtypes of ovarian and endometrial cancer are largely unique to the combination of a particular subtype in a specific organ. In contrast, clear cell cancers show a remarkable similarity in gene expression profiles across organs (including kidney) and could not be statistically distinguished.

Adenocarcinoma, Clear Cell↗
PubMed2006

Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma.

PURPOSE: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1(+) (VEGFR-1(+)) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68(+) hemangiogenic cells and alpha-smooth muscle actin(+) (alpha-SMA(+)) stromal cells correlates with neoangiogenesis and progression in human non-Hodgkin's lymphoma subtypes. EXPERIMENTAL DESIGN: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, alpha-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia. RESULTS: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68(+) cells and VEGFR-1(+) neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68(+) cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68(+) cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in alpha-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34(+) microvessel density and lymphoma histologic subtype. CONCLUSIONS: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1(+)CD68(+)VEGF-A(+) cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas alpha-SMA(+) stromal vascular network may be differentially targeted in CLL/SLL.

Actins↗