The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.

Cancer stem cells (CSCs) are proposed to drive tumor initiation and progression. Yet, our understanding of the cellular and molecular mechanisms that underlie CSC properties is limited. Here we show that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast CSCs. TAZ protein levels and activity are elevated in prospective CSCs and in poorly differentiated human tumors and have prognostic value. Gain of TAZ endows self-renewal capacity to non-CSCs. In epithelial cells, TAZ forms a complex with the cell-polarity determinant Scribble, and loss of Scribble--or induction of the epithelial-mesenchymal transition (EMT)--disrupts the inhibitory association of TAZ with the core Hippo kinases MST and LATS. This study links the CSC concept to the Hippo pathway in breast cancer and reveals a mechanistic basis of the control of Hippo kinases by cell polarity.

A MicroRNA targeting dicer for metastasis control.

Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery. In human breast cancer, high levels of miR-103/107 are associated with metastasis and poor outcome. Functionally, miR-103/107 confer migratory capacities in vitro and empower metastatic dissemination of otherwise nonaggressive cells in vivo. Inhibition of miR-103/107 opposes migration and metastasis of malignant cells. At the cellular level, a key event fostered by miR-103/107 is induction of epithelial-to-mesenchymal transition (EMT), attained by downregulating miR-200 levels. These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis.

A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.

Surgical anatomy of the sacral hiatus for caudal access to the spinal canal.

The sacral hiatus is used for access to the spinal canal in many neurosurgical and anesthesiologic procedures. The aim of the present paper is to give a review of its anatomical characteristics relevant to permit correct and uncomplicated accesses. The sacral hiatus is posteriorly closed by the superficial dorsal sacrococcygeal ligament (also called sacrococcygeal membrane) which has to be pierced in order to gain the sacral canal. The mean distance between the hiatal apex and the dural sac has been reported to be 45-60.5 mm in adults and 31.4 mm in children. The mean sacral space depth has been observed to be 4.6 mm in adults and 3.5 mm in infants. On the basis of anatomical measurements of the sacral hiatus, lower insertion angles have been suggested in infant with respect to adult subjects (21° vs. 58°).

Histotopographic study of the fibroadipose connective cheek system.

The purpose of this study was to investigate the morphology of the superficial musculoaponeurotic system (SMAS). Eight embalmed cadavers were analyzed: one side of the face was macroscopically dissected; on the other side, full-thickness samples of the parotid, zygomatic, nasolabial fold and buccal regions were taken. In all specimens, a laminar connective tissue layer (SMAS) bounding two different fibroadipose connective layers was identified. The superficial fibroadipose layer presented vertically oriented fibrous septa, connecting the dermis with the superficial aspect of the SMAS. In the deep fibroadipose connective layer, the fibrous septa were obliquely oriented, connecting the deep aspect of the SMAS to the parotid-masseteric fascia. This basic arrangement shows progressive thinning of the SMAS from the preauricular district to the nasolabial fold (p < 0.05). In the parotid region, the mean thicknesses of the superficial and deep fibroadipose connective tissues were 1.63 and 0.8 mm, respectively, whereas in the region of the nasolabial fold the superficial layer is not recognizable and the mean thickness of the deep fibroadipose connective layer was 2.9 mm. The connective subcutaneous tissue of the face forms a three-dimensional network connecting the SMAS to the dermis and deep muscles. These connective laminae connect adipose lobules of various sizes within the superficial and deep fibroadipose tissues, creating a three-dimensional network which modulates transmission of muscle contractions to the skin. Changes in the quantitative and qualitative characteristics of the fibroadipose connective system, reducing its viscoelastic properties, may contribute to ptosis of facial soft tissues during aging.

The ankle retinacula: morphological evidence of the proprioceptive role of the fascial system.

STUDY DESIGN: Research report. OBJECTIVES: To evaluate the anatomical characteristics of the ankle retinacula and their relationship with the fasciae and muscles in healthy subjects and in patients with ankle sprain outcomes. BACKGROUND: The role of the retinacula in proprioception has begun to emerge, but without clear anatomical bases or descriptions of their possible damage in patients with ankle sprain outcomes. METHODS: Dissection, histological and immunohistochemical analysis of 27 legs. An in vivo radiological study by MRI was also performed on 7 healthy volunteers, 17 patients with outcomes of ankle sprain, and 3 amputated legs. RESULTS: The retinacula are thickenings of the deep fascia presenting bone or muscular connections. They are formed of 2-3 layers of parallel collagen fibre bundles, densely packaged with a little loose connective tissue, without elastic fibres but many nervous fibres and corpuscles. By MRI, the retinacula appeared as low-signal-intensity bands with a mean thickness of 1 mm. In patients with outcomes of ankle sprain, MR findings were abnormal retinacula thickness, signal intensity, and full-thickness gap. DISCUSSION: The retinacula are not static structures for joint stabilisation, like the ligaments, but a specialisation of the fascia for local spatial proprioception of the movements of foot and ankle. Their anatomical variations and accessory bundles may be viewed as morphological evidence of the integrative role of the fascial system in peripheral control of articular motility.

Post-traumatic aneurysmal rupture involving the circle of Willis affected by fibromuscular dysplasia. A case report and systematic review.

The fatal rupture of a saccular aneurysm at the junction between the left anterior cerebral artery and anterior communicating artery affected by fibromuscular dysplasia (FMD) is a rare condition. Here is reported the case of a subject involved in a road traffic accident a few minutes before the death, which opened the debate on the real cause of death in a forensic setting. By autopsy, the examination of the brain revealed subarachnoid haemorrhage with flooding of the ventricles due to the breached saccular aneurysm of the junction between the left anterior cerebral artery and anterior communicating artery, in FMD mainly affecting the circle of Willis arteries. A spontaneous aneurysmal rupture was excluded on the basis of probabilistic analysis, in the presence of alternative hypotheses that could explain the facts. The passenger's delayed loss of consciousness may be explained as much by a hypertension-linked rupture of the aneurysm triggered by the emotional stress experienced, as by the traumatic shaking/impact of the aneurysm against the bony skull structures, in a subject predisposed to aneurysm frailty due to FMD. Overall, the concausal role of both the road traffic accident, typified by high kinetic energy, and the presence of a pre-existing aneurysmatic weakness due to FMD is fully recognized. The identification of anatomical variants, jointly with uncommon diseases at the examination of the brain base arteries in any case of isolated basal subarachnoid haemorrhage, may avoid wrong legal consequences even when the cause of death seems to be obviously of simple traumatic origin.

DNA copy number alterations correlate with survival of esophageal adenocarcinoma patients.

Despite recent advances in surgical and multidisciplinary treatment, prognosis for patients with esophageal adenocarcinoma remains poor, and the low prognostic significance of pTNM staging suggests that additional parameters are needed. To identify genomic abnormalities characteristic of esophageal adenocarcinoma, a panel of 33 samples obtained at surgery from previously untreated patients were analyzed by muliplex ligation-dependent probe amplification technique. We detected frequent gains of 6p, 8q, 13q, 17q, 20q, and losses of 4q, 5q, 15q, and 18q. When DNA copy number changes were correlated to clinicopathological features of patients no association was found between the number of chromosomal aberrations and gender, age, tumor grade or pTNM staging. However, interestingly, a significant correlation between patient survival and total number of chromosomal aberrations was found when esophageal adenocarcinoma cases were stratified according to the median of survival (20 months) (P=0.002) or the median of aberrations (12 aberrations) (P=0.014). Evaluation of the distribution of gains and losses at the level of single chromosomes indicated that gains on chromosomes 5, 6, 8, 11, 20 and losses on chromosomes 1, 3, 5, 11, and 18 were significantly different in the two survival groups. Furthermore, when single gene imbalances were analyzed in further details, we found that besides alterations that involve genes shared by both survival groups, a few genes (KIAA0170, EMS1, ABCC4, F3, and MIF) were altered only in samples from patients with poor survival. Thus, we established a good correlation between the total number of chromosomal alterations and survival, suggesting that the estimation of total imbalances might represent an additional indicator of disease outcome. In addition, the finding of alterations specific for the more aggressive esophageal adenocarcinoma subset might represent promising biomarkers to increase the accuracy of clinical outcome prediction.

Family history of cancer rather than p53 status predicts efficacy of pegylated liposomal doxorubicin and oxaliplatin in relapsed ovarian cancer.

BACKGROUND: The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations. METHODS: Seventy-two women received a median of 7.5 courses of PLD at 30 to 35 mg/m2 plus oxaliplatin at 70 mg/m2, and associations between BRCA1/2 and TP53 status and overall survival (OS) were determined. Thirty-eight had a short platinum-free interval (PFI; <12 months), and 34 had a long PFI (> or =12 months). RESULTS: Nine patients had BRCA1 mutations, and 1 had a BRCA2 mutation. Platinum sensitivity was associated with OS (P = 0.0001). At a median follow-up of 9.3 months, objective response rate, median time to progression, and OS were 47.3%, 5.8 months, and 12.9 months, respectively, in short PFI compared with the 76.5%, 11.5 months, and 47.7 months in long PFI. p53 status did not correlate to these parameters. The median time to progression was 11.5 months for high-risk patients versus 6.5 months for patients with sporadic cancer (P = 0.0188), and the median OS from the start of treatment was 48.7 and 16.2 months (P = 0.0032), respectively. Toxicity was mostly grade 1 or 2. CONCLUSIONS: High response rates in the long-PFI patients indicate that this treatment is beneficial and well tolerated. Platinum sensitivity and positive family history and/or a BRCA1/BRCA2 mutation are a useful predictor of response.

The palmaris longus muscle and its relations with the antebrachial fascia and the palmar aponeurosis.

The palmaris longus (PL) is a muscle of the forearm with a long distal tendon that is continuous with the palmar aponeurosis (PA). It is generally assumed that the muscle lies deep to the antebrachial fascia from origin to termination, but a detailed description is lacking. The relationship of the PL tendon with the antebrachial fascia was studied in 30 dissections. The PL was completely absent in six specimens (20%), whereas the PA was identified in all. Average length of the forearm was 25.5 cm (SD: 2.1 cm, range 22-29 cm), overall length of the PL muscle 26.9 cm (SD: 2.6 cm, range 22.5-31.5 cm), muscular belly 13.8 cm (SD: 3.4 cm, range 9.5-23 cm), tendon 13.1 cm (SD: 3.3 cm, range 8-15.5 cm). Proximally, the PL was situated deep to the antebrachial fascia, then in the lower third of the forearm its tendon perforated the antebrachial fascia (at 4.7 +/- 1.7 cm from the bistyloid line) moving to a suprafascial plane, inserting in the PA. The PA could be divided into two layers: the superficial one formed by longitudinal fibers and adherent to the skin, the deep one formed by transverse fibers continuous laterally with the deep fascia of the hand. The PL tendon was found to be in continuity only with the longitudinal fibers of the PA. Based on the anatomical findings, it may be suggested that the superficial part of the PA is situated in the subcutaneous planes of the palm, and that the muscle should be considered as a tensor of the superficial fascial system of the subcutaneous tissue.

The expansions of the pectoral girdle muscles onto the brachial fascia: morphological aspects and spatial disposition.

BACKGROUND/AIMS: The aim of this study was to analyse the relationships between the expansions of the pectoral girdle muscles, i.e. pectoralis major, latissimus dorsi and deltoid, and the brachial fascia. METHODS: Thirty shoulder specimens from 15 unembalmed adult cadavers were studied by dissection and in vivo radiological studies were performed in 20 patients using magnetic resonance (MR) imaging. RESULTS: The clavicular part of the pectoralis major muscle sent a fibrous expansion onto the anterior portion of the brachial fascia, its costal part onto the medial portion and medial intermuscular septum. The latissimus dorsi muscle showed a triangular fibrous expansion onto the posterior portion of the brachial fascia. The posterior part of the deltoid muscle inserted muscular fibres directly onto the posterior portion of the brachial fascia, its lateral part onto the lateral portion and the lateral intermuscular septum. In MR images, the brachial fascia appeared as a low-signal-intensity sinuous line of connective tissue, sharply delineated in T(1)-weighted sequences. CONCLUSION: The expansions of the pectoral girdle muscles onto the brachial fascia were present in all the subjects and showed a quite constant course with a specific spatial organization. During the various movements of the arm, these expansions stretch selective portions of the brachial fascia, with possible activation of specific patterns of fascial proprioceptors.

Histo-topographic study of the longitudinal anal muscle.

The longitudinal anal muscle (LAM) has been described as a vertical layer of muscular tissue interposed between the circular layers of the internal (IAS) and external (EAS) anal sphincters. There is, however, no general agreement in the literature on its composition and attachments. The aim of this study was to investigate the histological structure, attachments, and topography of the LAM in order to evaluate its role in continence and defecation, thus enhancing knowledge of the surgical anatomy of this region. After in situ formalin fixation, the pelvic viscera were removed from eight male and eight female cadavers (age range: 52-72 years). Serial macrosections of the bladder base, lower rectum and anal canal, cervix and pelvic floor complex, cut in the transverse (six specimens) and coronal (six specimens) planes, underwent histological and immunohistochemical studies. Four specimens were studied using the E12 sheet plastination technique. The LAM was identified in 10/12 specimens (83%). Transverse and coronal sections made clear that it is a longitudinal layer of muscular tissue, marking the boundary between the internal and external anal sphincters. From the anorectal junction it extends along the anal canal, receives fibers from the innermost part of the puborectalis and the puboanalis muscles, and terminates with seven to nine fibro-elastic septa, which traverse the subcutaneous part of the external anal sphincter, reaching the perianal dermis. In the transverse plane, the mean thickness of the LAM was 1.68 +/- 0.27 mm. Immunohistochemical staining showed that the LAM consists of predominantly outer striated muscle fibers and smaller numbers of inner smooth muscle fibers, respectively coming from the levator ani muscle and from the longitudinal muscular layer of the rectum. The oblique fibers suggest that the LAM may represent the intermediate longitudinal course of small bridging muscle bundles going reciprocally from the striated EAS to the smooth IAS and vice versa. The spatial result is the helical course of striated and smooth muscle fibers between the EAS and IAS, which contribute not only to the narrowing but also to some shortening of the anal canal during sphincter contraction. Thus, rather than being a boundary, the LAM gives anatomical evidence of a functional connection between two muscle systems with different structures and topography.

Three cases of pancreatic serous cystadenoma and endocrine tumour.

AIMS: To report three cases of serous cystadenoma and endocrine tumour in the same pancreas, to review the literature and to evaluate the clinicopathological features of the tumours. CASES: Three women (71, 57 and 31 years old) were admitted to hospital, two for diseases unrelated to the pancreas and the third for increasing obstructive jaundice in von Hippel-Lindau disease. Preoperative examination showed two distinct lesions in the first patient and only cystic lesions in the other two. RESULTS: Histological examination of the pancreas showed one serous oligocystic adenoma associated with a benign, well-differentiated endocrine tumour, one serous oligocystic adenoma associated with an endocrine microadenoma, and a von Hippel-Lindau-related cystic neoplasm with a well-differentiated endocrine carcinoma. CONCLUSIONS: Serous cystadenoma associated with endocrine tumour shows some clinicopathological differences with respect to the two tumours considered separately, and with respect to von Hippel-Lindau-related cases, although there is no convincing evidence at present to justify considering this association as a separate entity.

Maspin expression in adenocarcinoma of the ampulla of Vater: relation with clinicopathological parameters and apoptosis.

AIM: Maspin is a unique serine proteinase inhibitor which has tumor suppressor activity. The aim of the present study was to investigate the role of maspin in ampullary adenocarcinomas, its correlation with apoptosis and its value as a prognostic marker. PATIENTS AND METHODS: Twenty-three cases of ampulla of Vater adenocarcinoma were collected from archival material. For each sample, maspin, M30, p53 and Mib1 immunohistochemical reactivity were evaluated and results compared with clinicopathological parameters. RESULTS: A statistical relation was found between nuclear maspin and M30 (Spearman's Q = 0.46, p = 0.02), and p53 (Kruskal-Wallis = 0.03); a trend was found between nuclear maspin and pT (Kruskal-Wallis = 0.09), and pM (Mann-Whitney = 0.08) and pN status (Fisher's mid-point test: p = 0.070). CONCLUSION: The present study evaluated the role of maspin in ampullary adenocarcinomas and for the first time demonstrated its association with apoptosis, tumor growth and metastasis.

Expression of survivin, p53, and caspase 3 in Barrett's esophagus carcinogenesis.

The regulation of apoptosis, as a distinctive form of programmed cell death, in multistep Barrett's esophagus (BE) carcinogenesis is poorly understood. The aim of this study was to investigate, in the intestinal metaplasia-dysplasia-carcinoma sequence, the role of survivin, an inhibitor of apoptosis; the p53 protein, a tumor suppressor gene involved in cell cycle control; and caspase 3, a protease-inducing apoptosis and inhibited by survivin. Immunohistochemical expression was tested in 40 cases of BE, including 11 low-grade and 19 high-grade dysplasias (HGD), and samples were obtained from 40 surgical specimens of esophagectomy performed for HGD or Barrett's adenocarcinoma. To define the deregulation time of the proteins, overexpression was evaluated in relation to the proliferative and/or maturative compartment. In BE, cytoplasmic expression of survivin and caspase 3 (100% of cases) was significantly higher than expression of p53 (25%). The latter increased with increasing grade of dysplasia. In BE, the expression of survivin, p53, and caspase 3 mainly involved the proliferative compartment, whereas in LGD and HGD, the 3 proteins were coexpressed in both proliferative and maturative compartments. These results indicate that survivin overexpression is an early event in the proliferative compartment of BE, preceding both p53 accumulation and dysplastic changes. Cytoplasmic survivin location may indicate an initial antiapoptotic, more than proliferative, role in the early phases of Barrett carcinogenesis. Expression of caspase 3 in BE and dysplasia may be ascribed to accumulation of the nonactivated form, as the antibody used detects both cleaved and uncleaved caspase 3.

Mitochondrial DNA D-loop in pancreatic cancer: somatic mutations are epiphenomena while the germline 16519 T variant worsens metabolism and outcome.

We ascertained the frequency of mitochondrial DNA (mtDNA) D-loop region somatic mutations in pancreatic cancer (PC) and verified whether polymorphisms were linked to diagnosis, prognosis, and PC-associated diabetes mellitus (DM) in 99 PC cases, 42 chronic pancreatitis (CP) cases, 18 pancreatobiliary tract tumors, and 87 healthy control subjects (CSs). Tissue samples were obtained from 19 patients with PC and 5 with CP. The D-loop region was sequenced from all tissue samples and from blood DNA of the same patients and 12 CSs. D-loop somatic mutations were found in 3 PC tissue samples (16%). Four single nucleotide polymorphisms (SNPs; T152C, T16189C, T16519C, A73G), more frequently found in PC than in CS, were analyzed by denaturing high-performance liquid chromatography-restriction fragment length polymorphism using blood DNA as the starting template in all cases. The T allele of 16519 SNP correlated with DM. The survival of patients with PC correlated with tumor stage and grade and with DM at diagnosis. When survival analysis was performed considering only patients with locally advanced disease, the T allele of mtDNA 16519 SNP correlated with shorter life expectancy. mtDNA D-loop somatic mutations, rarely found in PC, cannot be considered causative events for this tumor type and probably are epiphenomena; the mtDNA D-loop 16519 variant, which worsens PC prognosis, seems to be a predisposing genetic factor for DM.

Adrenomedullin immunoreactivity in the human carotid body.

We studied by immunocytochemistry the expression of AM in human carotid bodies, sampled at autopsy from 16 adult subjects (mean age+/-S.D.: 44.3+/-3.4 years) and from six fetuses (mean gestational age+/-S.D.: 167+/-11 days). No AM immunoreactivity was visible in the type II cells of both series. The percentage of immunoreactive type I cells was higher in the adult subjects (32.3+/-7.7%) with respect to the fetuses (11.8+/-2.7%, P < 0.001). Dark cells showed a higher percentage of positive immunoreaction with respect to light cells, both in adult subjects (61.7+/-13.4% versus 19.2+/-5.2%) and in fetuses (25.3+/-4.4% versus 6.2+/-2.0%). AM may play a role in the regulation of chemoreceptor discharge through paracrine releasing action and/or vasodilator effect. The low expression of AM in fetuses may be ascribed to the absence of pulmonary respiration with lack of regulatory role of the carotid body during the prenatal period.

Immunohistochemical mapping of adrenomedullin in the human medulla oblongata.

We studied by immunocytochemistry the expression of adrenomedullin (AM) in the human medulla oblongata, sampled from 13 adult subjects (mean age: 38 years), whose medical history was negative for neurological and neurovascular pathologies. Immunoreactive neurons were found in the medulla oblongata with statistically significant differences among the various nuclei (one-way ANOVA, P < 0.001). The hypoglossal nucleus showed higher AM expression than that of the spinal tract of the trigeminal nerve (P < 0.05), solitary tract nucleus (P < 0.05), nucleus intercalatus (P < 0.05), and area postrema (P < 0.05). The arcuate nucleus and inferior olivary nuclear complex showed lower AM expression than the hypoglossal nucleus (P < 0.001), vestibular nuclei (P < 0.01), cuneate and gracile nuclei (P < 0.05), lateral column of the reticular formation (P < 0.05), and nucleus ambiguous (P < 0.05). Furthermore the nuclei were grouped with reference to their function, into somatic sensitive nuclei, somatic motor nuclei, visceral nuclei, reticular formation, and nuclei involved in cerebellar functions. The ANOVA revealed statistically significant differences (P < 0.001) in mean AM scores among the different groups. Nuclei involved in cerebellar function showed the lowest mean AM score (P < 0.05). The difference in AM score between somatic motor nuclei and visceral nuclei was also statistically significant (P < 0.05). Widespread AM immunoreactivity in the nuclei of the medulla oblongata may account for the role of the peptide in neuronal function and regulation of regional blood flow. Differences in the expression of AM in the nuclei studied indicate the different involvement of AM in neurotransmission and neuromodulation.

Leptin and leptin receptor expression in the myometrium and uterine myomas: Is leptin involved in tumor development?

Leptin, the product of the obesity (ob) gene, along with its receptors (Ob-Rs), is expressed in several tissues and organs. Evidence has been provided that leptin, in addition to being involved in obesity development, plays a role in the regulation of the female reproductive system, angiogenesis and tumor growth. Uterine myoma is a rather common disease that develops more frequently in obese than lean women, where plasma leptin concentrations are elevated. RT-PCR and Western blotting showed that leptin was expressed, as mRNA and protein, in several uterine myomas but not in normal myometrium, while leptin receptors were expressed in both tissues. Immunocytochemistry indicated that leptin-immunoreactivity was located in both myometrial cells and blood-vessel walls of uterine myomas. Leptin(22-56), at concentrations of 10(-7) and 10(-6) M, enhanced the proliferative activity of both the normal myometrium and myoma cells in primary culture. Taken together, our findings allow us to suggest that leptin, acting through autocrine-paracrine mechanism(s), may be involved in the development of uterine myomas.