Biomedical subjects

Peng Li

Publications and source records attributed to Peng Li.

At least 145 records · Page 8Linked to original sources

PubMed2003

Concise and enantioselective synthesis of Fmoc-Pmp(But)2-OH and design of potent Pmp-containing Grb2-SH2 domain antagonists.

[reaction: see text] L-Phosphonomethylphenylalanine (L-Pmp) is an important phosphatase-resistant pTyr analogue. A most concise and stereoselective approach to the synthesis of the suitably protected Fmoc-Pmp(Bu(t))(2)-OH was developed in order to incorporate the functionally significant L-Pmp residue into peptides and peptidomimetics efficiently using standard Fmoc protocol. With this key building block, we are able to efficiently synthesize a series of potent Pmp-containing Grb2-SH2 domain antagonists, which can be used as chemotherapeutic leads for the treatment of erbB2-overexpressed breast cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Cidea-deficient mice have lean phenotype and are resistant to obesity.

The thermogenic activity of brown adipose tissue (BAT), important for adaptive thermogenesis and energy expenditure, is mediated by the mitochondrial uncoupling protein1 (Ucp1) that uncouples ATP generation and dissipates the energy as heat. We show here that Cidea, a protein of unknown function sharing sequence similarity with the N-terminal region of DNA fragmentation factors Dffb and Dffa, is expressed at high levels in BAT. Cidea-null mice had higher metabolic rate, lipolysis in BAT and core body temperature when subjected to cold treatment. Notably, Cidea-null mice are lean and resistant to diet-induced obesity and diabetes. Furthermore, we provide evidence that the role of Cidea in regulating thermogenesis, lipolysis and obesity may be mediated in part through its direct suppression of Ucp1 activity. Our data thus indicate a role for Cidea in regulating energy balance and adiposity.

Adipose Tissue, Brown↗

PubMed2003

Structural basis for a non-phosphorus-containing cyclic peptide binding to Grb2-SH2 domain with high affinity.

Blocking the interaction between phosphotyrosine (pTyr)-containing activated receptors and the Src homology 2 (SH2) domain of the growth factor receptor bound protein 2 (Grb2) is considered to be an effective and non-cytotoxic strategy to develop new anti-proliferative agents due to its potential to shut down the Ras activation pathway. Generally, the pTyr-X-Asn minimal binding motif is required for a high-affinity ligand binding to the Grb2-SH2 domain. Using phage-display techniques, we discovered a non-pTyr-containing cyclic peptide G1 with moderate binding affinity from 10(7) different sequences. To understand the structural basis for the high-affinity binding of these novel non-phosphorus-containing inhibitors to the Grb2-SH2 domain, we extensively studied herein the unique functional requirements of the acidic side chain in Tyr-2 position due to the absence of the phosphate group in these non-phosphorylated peptides. A comprehensive SAR study was also carried out to develop potent Grb2-SH2 domain antagonists based upon this novel template. With both the peptidomimetic optimization of the amino acid side-chains and the constraint of the backbone conformation guided by molecular modeling, we developed several potent antagonists with low nanomolar range binding affinity, such as cyclic peptide 20 with an IC(50)=0.026 microM, which is one of the most potent non-phosphorus-containing Grb2-SH2 antagonists reported to date. Whole cell assays indicate that peptide 20 can penetrate the cell membranes and inhibit the association of Grb2 with p185(erbB2) in erbB2-overexpressing MDA-MA-453 cancer cells at low micromolar concentrations.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Prolonged inhibition of rostral ventral lateral medullary premotor sympathetic neurons by electroacupuncture in cats.

We have shown that electroacupuncture (EA) at the Neiguan-Jianshi (N-J) acupoints over the median nerve reduces myocardial ischemia by modulating the pressor response induced by application of bradykinin on the gallbladder. The present study was designed to investigate the neural substrate underlying the prolonged modulatory effect of EA on visceral afferent input into the rostral ventral lateral medulla (rVLM). Experiments were performed on ventilated anesthetized cats. Neuronal activity was recorded while either stimulating the splanchnic nerve or applying EA at the N-J acupoints. Thirty-three cells responsive to splanchnic nerve and median nerve stimulation were antidromically driven from the intermediolateral columns, T(2)-T(4), indicating their function as premotor sympathetic neurons. These neurons also received baroreceptor input demonstrating that they were cardiovascular sympathoexcitatory cells. Arterial pulse-triggered averaging and coherence analysis demonstrated a correlation between cardiac-related discharge activity with 2.8+/-0.3 Hz rhythms and arterial blood pressure. Stimulation (2 Hz, 1-4 mA, 0.5 ms) of the splanchnic nerve for 30 s evoked excitatory responses. These neuronal responses were reduced during and after 30-min stimulation of EA at the Neiguan-Jianshi acupoints. These splanchnic nerve-induced excitatory responses in neurons subjected to 30 min of EA were reduced by 68%. Iontophoresis of naloxone promptly reversed the EA-induced inhibitory effect by 52%. Neuronal activity in the rVLM induced by splanchnic nerve stimulation was reduced for 50 (or more) min after termination of EA in 7 of 12 rVLM neurons. Our results indicate that rVLM premotor sympathetic cardiovascular neurons receive convergent input from the gallbladder through the splanchnic nerve and N-J acupoints through the median nerves. Through an opioid mechanism, EA inhibits splanchnic nerve-induced excitatory responses of these rVLM neurons. Many of these neurons receiving convergent visceral and somatic input exhibit long-lasting inhibition by EA.

Action Potentials↗

PubMed2003

Potent Grb2-SH2 domain antagonists not relying on phosphotyrosine mimics.

Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC(50) of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse.

This study tested the hypothesis that atrial natriuretic peptide has direct antihypertrophic actions on the heart by modulating expression of genes involved in cardiac hypertrophy and extracellular matrix production. Hearts of male, atrial natriuretic peptide-null and control wild-type mice that had been subjected to pressure overload after transverse aortic constriction and control unoperated hearts were weighed and subjected to microarray, Northern blot, and immunohistochemical analyses. Microarray and Northern blot analyses were used to identify genes that are regulated differentially in response to stress in the presence and absence of atrial natriuretic peptide. Immunohistochemical analysis was used to identify and localize expression of the protein products of these genes. Atrial natriuretic peptide-null mice demonstrated cardiac hypertrophy at baseline and an exaggerated hypertrophic response to transverse aortic constriction associated with increased expression of the extracellular matrix molecules periostin, osteopontin, collagen I and III, and thrombospondin, as well as the extracellular matrix regulatory proteins, matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3, and the novel growth factor pleiotrophin compared with wild-type controls. These results support the hypothesis that atrial natriuretic peptide protects against pressure overload-induced cardiac hypertrophy and remodeling by negative modulation of genes involved in extracellular matrix deposition.

Animals↗

PubMed2003

[Construction of eukaryote expression vector carrying human soluble interleukin-1 receptor gene].

OBJECTIVE: The purpose of this study was to construct a eukaryote expression vector carrying human sIL-1R gene. METHODS: Both sIL-1R gene and plasmid pcDNA 3.1(+) DNA were digested with KpnI and XhoI. After purification, the two fragments obtained were ligated by using TakaRa DNA Ligation Kit. This recombinant DNA was then transformed into E. coli Competent Cells JM109 and positive clones were selected on the LB agarose plate containing Ampicillin (80 micrograms/ml). RESULTS: Six single clones were identified by double digestion with KpnI and XhoI, and two fragments with the size of 5.4 kb and 1.0 kb were produced as expected. CONCLUSION: The sIL-1R gene was successfully inserted into the eukaryote expression vector plasmid pcDNA 3.1(+) by the recombination technique in vitro.

Cloning, Molecular↗

PubMed2003

Structure-based design of thioether-bridged cyclic phosphopeptides binding to Grb2-SH2 domain.

A series of phosphotyrosine containing cyclic peptides was designed and synthesized based upon the phage library derived cyclopeptide, G1TE. Considering the type-I beta-turn feature of peptidic ligand binding to Grb2 SH2 domain, we introduce alpha,alpha-disubstituted cyclic amino acid, Ach, into the 4th position of the cyclic peptide to induce a local right handed 3(10) helical conformation. In order to stabilize the favorable binding conformation, the bulky and hydrophobic amino acids, neopentylglycine (NPG) and phenylalanine, were introduced into the 8th and 2nd positions of the peptide ligand, respectively. To facilitate the sidechain of pTyr3 reaching into the phosphotyrosine binding pocket, a less bulky alanine was preferred in position 1. Based upon these global modifications, a highly potent peptide ligand 12 was discovered with an IC(50)=1.68 nM, evaluated by ELISA binding essay. Ligand 12 is at least 10(5) more potent than the lead peptide, termed G1TE.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Supernatants from dengue virus type-2 infected macrophages induce permeability changes in endothelial cell monolayers.

The ability of dengue virus-infected human monocyte-derived macrophages to induce permeability changes in primary human umbilical vein endothelial cells was investigated. Supernatants from dengue virus type 2-infected monocyte-derived macrophages increased permeability in human umbilical vein endothelial cell monolayers without inducing endothelial cell infection. Production of permeabilising activity from monocyte-derived macrophages occurred after the peak of progeny virus release. TNF-alpha, a known inducer of endothelial cell permeability, was released from dengue virus infected monocyte-derived macrophages but its release did not coincide with release of endothelial cell permeabilising activity. Permeability induction was enhanced by pre-incubation with supernatants from infected monocyte-derived macrophages harvested at the time of peak release of TNF-alpha and infectious virus. Thus, supernatants from dengue virus-infected monocyte-derived macrophages contain factors that increase human umbilical vein endothelial cell permeability, but this is not accompanied by endothelial cell infection or directly correlated with release of dengue virus or TNF-alpha from monocyte-derived macrophages. This model system can be used for further in vitro analysis of mechanisms that may relate to capillary leakage and the development of dengue haemorrhagic fever/dengue shock syndrome.

Cell Membrane Permeability↗

PubMed2003

Impact of myocardial contrast echocardiography on vascular permeability: an in vivo dose response study of delivery mode, pressure amplitude and contrast dose.

An in vivo rat model of myocardial contrast echocardiography (MCE) was defined and used to examine the dose range response of microvascular permeabilization and premature ventricular contractions (PVCs) with respect to method of imaging, peak rarefactional pressure amplitude (PRPA) and agent dose. A left ventricular short axis view was obtained on anesthetized rats at 1.7 MHz using a diagnostic ultrasound system with simultaneous ECG recording. Evans blue dye, a marker for microvascular leakage, and a bolus of Optison were injected i.v. Counts of PVCs were made from video tape during the 3 min of MCE. Hearts were excised 5 min after imaging and petechial hemorrhages, Evans blue colored area and Evans blue content were determined. No PVCs or microvascular leakage were seen in rats imaged without contrast agent followed by contrast agent injection without imaging. When PVCs were detected during MCE, petechial hemorrhages and Evans blue leakage were also found in the myocardium. Triggering 1:4 at end-systole produced the most PVCs per frame and most microvascular leakage, followed by end-systole 1:1, continuous scanning and end-diastole triggering 1:1. All effects increased with increasing Optison dosage in the range 25 to 500 microL kg(-1). Ultrasound PRPA was important, with apparent thresholds for PVCs at 1.0 MPa and for petechiae at 0.54 MPa. PVCs, petechial hemorrhages and microvascular leakage in the myocardium occur as a result of MCE in rats.

Albumins↗

PubMed2003

The role of Vif during HIV-1 infection: interaction with novel host cellular factors.

BACKGROUND: Current research suggests that human immunodeficiency virus type-1 (HIV-1) virion infectivity factor (Vif) acts during viral assembly in producer cells to ensure infectivity in target cells but the exact mechanism of action has not been defined. Vif interacts with Gag, viral protease and RNA and these interactions are proposed to be important for correct particle assembly and stability of the reverse transcription complex. OBJECTIVES: The existence of cells that are either permissive or non-permissive for replication of Vif deficient viruses suggests the involvement of host cellular factors in its function. Current research suggests an association of Vif with the intermediate filament protein, vimentin, and the tyrosine kinase, Hck, but the significance of these associations remains to be defined. More recently HP68, a cellular ATP binding protein, has been shown to be important for capsid formation and an interaction between Vif and HP68 has been shown. Our aim was to further identify host cellular factors involved in Vif function. STUDY DESIGN: We have employed the yeast 2-hybrid system to identify cellular proteins which interact with HIV-1 Vif. Sixteen clones were isolated from a high stringency yeast-2-hybrid screen of a human leucocyte cDNA library with Vif derived from the T-cell tropic HIV-1 strain NL4.3. Of these, 8 clones were confirmed as specifically binding Vif, fully sequenced and identified via GenBank homology searches. RESULTS: Thus far 3 of these clones, spermine/spermidine N1-acetyltransferase, Triad 3 and a novel gene which we have termed 'novel Vif binding protein', have been characterised and represent attractive candidates for mediating Vif action during HIV replication. CONCLUSIONS: Through identification and characterisation of cellular factors interacting with HIV-1 Vif we hope to unravel the mechanism of action of Vif which may ultimately aid therapeutic design.

Gene Products, vif↗

PubMed2003

Detection of resting myocardial perfusion defects by SonoVue myocardial contrast echocardiography.

BACKGROUND: SonoVue is a new microbubble contrast agent containing sulfur hexafluoride. We assessed the efficacy of SonoVue myocardial contrast echocardiography (MCE) to detect resting perfusion abnormalities. METHODS: Nineteen adult patients with a wall motion abnormality in a screening echocardiogram were studied. Each patient received up to four bolus injections of 2.0 mL SonoVue (Bracco Diagnostics, Inc.) during echocardiographic examination using either B-mode(n = 12)or power Doppler(n = 7)imaging. Each patient also had SPECT nuclear perfusion imaging performed. Segmental assessment of myocardial perfusion from SonoVue MCE images were compared with corresponding SPECT nuclear images. RESULTS: Using B-mode imaging, the mean number of views obtained with a single SonoVue injection ranged from 1.4 to 1.9, with 2 or 3 injections required for a complete examination. Ninety-four percent of segments were scored as diagnostic. Agreement between B-mode and SPECT images was 72% for segments with a perfusion defect, 86% for normal perfusion, and 80% for segments with either perfusion defect or normal perfusion (all views combined). Using power Doppler imaging, the mean number of views obtained with a single SonoVue injection ranged from 1.0 to 1.3, with 2 to 4 injections required for a complete examination. Sixty-eight percent of segments were scored as diagnostic. Agreement between power Doppler and SPECT images was 67% for perfusion defects, 53% for segments with normal perfusion, and 59% for segments with either perfusion defect or normal perfusion (all views combined). CONCLUSIONS: SonoVue MCE has the potential to assess myocardial perfusion at rest. B-mode imaging was more accurate than power Doppler imaging when compared with SPECT nuclear imaging.

Aged↗

PubMed2003

Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription.

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue.

Cell Nucleus↗

PubMed2003

Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells.

We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.

Animals↗

PubMed2003

Pathogenicity of GB virus C on virus hepatitis and hemodialysis patients.

AIM: To determine the pathogenicity of GB virus C (GBV-C) on liver and the effects of its co-infection on the clinical features and prognosis of patients with hepatitis B and C. METHODS: Cross-sectional study was carried out in 413 patients with acute, chronic hepatitis B or liver cirrhosis, and in 67 hemodialysis patients. A 20-month prospective cohort study was carried out in 95 hepatitis B and 80 hepatitis C patients. A reverse transcriptase nested polymerase chain reaction (RT-nPCR) of the 5'-noncoding region was used to detect circulating GBV-C RNA. Liver function was determined by an automated analyzer for all patients. RESULTS: The prevalence of GBV-C in the high-risk populations with the virus transmitted via blood was high, ranging from 16.2 to 28.8 %. Co-infection with GBV-C in hepatitis B patients did not affect the clinical features of the disease or liver function. The dialysis patients infected with GBV-C alone did not develop functional changes to the liver. Prospective cohort study showed that GBV-C co-infection did not affect the clinical features, prognosis or negative serum conversion rate of chronic hepatitis B and C. CONCLUSION: The results suggest that GBV-C has no marked pathogenicity on liver, so it may not be a hepatitis virus.

Cohort Studies↗

PubMed2003

Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast.

CONTEXT: Medullary carcinoma (MC) is a special type of breast cancer that has a better prognosis than atypical medullary carcinoma (AMC) and high-grade invasive ductal carcinoma (HGIDC) with prominent lymphocytic infiltrates. What accounts for the different clinical courses of these carcinomas, despite their similar histology, is unknown. To address this issue, we performed a comparative study of amplification and overexpression of HER-2/neu and expression of several other important biochemical markers (p53, MIB1, and estrogen receptor [ER]/progesterone receptor [PR]) in these 3 cancer groups. OBJECTIVE: To evaluate HER-2/neu, p53, MIB1, and ER/PR as markers in the differential diagnosis of MC, AMC, and HGIDC.Design.-Nine cases of MC, 13 cases of AMC, and 16 cases of HGIDC with prominent lymphocytic infiltrates were identified according to strict histologic criteria. All tests were performed on formalin-fixed, paraffin-embedded archival tissues. HER-2/neu gene amplification was examined by fluorescence in situ hybridization using PathVysion HER-2 DNA probes. Expression of HER-2/neu, p53, MIB1, and ER/PR was detected by immunohistochemistry. chi2 and Student t tests were applied for statistical analyses. RESULTS: None of 9 cases of MC examined had either amplification or overexpression of HER-2/neu (0%). In contrast, HER-2/neu amplification was observed in AMC (46%, P <.025) and HGIDC (56%, P <.005). All 3 categories of tumors had similar percentages of expression of p53 (78% of MC, 77% of AMC, and 69% of HGIDC) and MIB1 (89% of MC, 92% of AMC, and 94% of HGIDC). Immunostaining for ER/PR was rarely positive in either MC or AMC, and there were no significant differences of expression of ER/PR between these 2 lesions (P >.05). However, the expression rate of ER/PR (31%/44%) in HGIDC is higher than in both MC (P =.05) and AMC (P =.01). CONCLUSIONS: Medullary carcinoma of breast is distinct from AMC and HGIDC with prominent lymphocytic infiltrates in amplification and overexpression of HER-2/neu. This difference may account for its different clinical and biological behavior, and may potentially aid in diagnosis and management of these groups of patients.

Adult↗

PubMed2003

[Expression of constructed eukaryotic vectors carrying encoding gene of soluble human interleukin-1 receptor in mammalian cells].

OBJECTIVE: This study is to make sure if the constructed pcDNA3 carrying encoding gene of sIL-1R can be expressed in mammalian cells in vitro. METHODS: COS-1 cells and CHO cells were respectively transfected with recombinant plasmid pcDNA3/sIL-1R by liposome. The protein expression products were detected by ELISA. RESULTS: The results indicated that the protein expression products could be detected in the cell plasma and the cell culture supermatant. The expression level in experimental groups was much higher than that in control groups(P < 0.05). CONCLUSION: The constructed pcDNA3/sIL-1R can express interest protein in mammalian cells and this establishes the basis for future investigation on gene therapy of periodonititis and other inflammatory diseases.

Animals↗

PubMed2002

Tuberous sclerosis in a 19-week fetus: immunohistochemical and molecular study of hamartin and tuberin.

Tuberous sclerosis complex (TSC) is a genetically heterogeneous disease caused by mutations of TSC1 or TSC2 genes. It involves multiple organ systems resulting in mild to lethal hamartoma formation due to gene mutation in the germ line and loss of heterozygosity (LOH) in somatic cells. Hamartin (TSC1) and tuberin (TSC2) are expressed broadly. However, little is known about tissue susceptibility to hamartomas when equal or similar amounts of TSC gene expression are present. In this study, we present a 19-week gestational age fetus with pathological features of TSC, which was confirmed by finding LOH of TSC2 in a cardiac rhabdomyoma. Developmental expression of hamartin and tuberin in the TSC fetus, an age-matched non-TSC fetus, and a 26-week gestational age non-TSC fetus were analyzed by immunohistochemistry. We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues. In general, hamartin and tuberin are mainly expressed in epithelial cells, myocytes, and neural tissues. By comparing the incidence of the hamartomas in early childhood and gene expression in tissues, it appears that tissues with co-expression of hamartin and tuberin are prone to a higher incidence of hamartomas than those expressing only one protein, or two proteins but in different patterns of cellular localization.

Adult↗