Targeting of RAGE-ligand signaling impairs breast cancer cell invasion and metastasis.

The receptor for advanced glycation end products (RAGE) is highly expressed in various cancers and is correlated with poorer outcome in breast and other cancers. Here we tested the role of targeting RAGE by multiple approaches in the tumor and tumor microenvironment, to inhibit the metastatic process. We first tested how RAGE impacts tumor cell-intrinsic mechanisms using either RAGE overexpression or knockdown with short hairpin RNAs (shRNAs). RAGE ectopic overexpression in breast cancer cells increased MEK-EMT (MEK-epithelial-to-mesenchymal transition) signaling, transwell invasion and soft agar colony formation, and in vivo promoted lung metastasis independent of tumor growth. RAGE knockdown with multiple independent shRNAs in breast cancer cells led to decreased transwell invasion and soft agar colony formation, without affecting proliferation. In vivo, targeting RAGE shRNA knockdown in human and mouse breast cancer cells, decreased orthotopic tumor growth, reduced tumor angiogenesis and recruitment of inflammatory cells, and markedly decreased metastasis to the lung and liver in multiple xenograft and syngeneic mouse models. To test the non-tumor cell microenvironment role of RAGE, we performed syngeneic studies with orthotopically injected breast cancer cells in wild-type and RAGE-knockout C57BL6 mice. RAGE-knockout mice displayed striking impairment of tumor cell growth compared with wild-type mice, along with decreased mitogen-activated protein kinase signaling, tumor angiogenesis and inflammatory cell recruitment. To test the combined inhibition of RAGE in both tumor cell-intrinsic and non-tumor cells of the microenvironment, we performed in vivo treatment of xenografted tumors with FPS-ZM1 (1 mg/kg, two times per week). Compared with vehicle, FPS-ZM1 inhibited primary tumor growth, inhibited tumor angiogenesis and inflammatory cell recruitment and, most importantly, prevented metastasis to the lung and liver. These data demonstrate that RAGE drives tumor progression and metastasis through distinct tumor cell-intrinsic and -extrinsic mechanisms, and may represent a novel and therapeutically viable approach for treating metastatic cancers.

Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.

p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.

Perfectionism is multidimensional: a reply to Shafran, Cooper and Fairburn.

provided a cognitive-behavioural analysis of perfectionism that focused primarily on self-oriented perfectionism. They argued against studying perfectionism from a multidimensional perspective that they regard as inconsistent with prior work on perfectionism as a self-oriented phenomenon. We respond to by offering historical, empirical, and theoretical support for the usefulness and the importance of a multidimensional model of perfectionism involving both intrapersonal processes and interpersonal dynamics. It is concluded that a multidimensional approach to the study of perfectionism is still warranted.

Small bowel transplantation in the rat: ultrastructural changes during the early phases of rejection.

Small bowel transplantation has great potential for the treatment of short bowel syndrome, but the poorly understood rapid rejection of the bowel has hindered progress in this field. In this study, the rat model was used to evaluate the earliest detectable changes of bowel rejection. Eleven pairs of outbred rats underwent heterotopic transplantation of 10-15 cm segments of proximal jejunum on a pedicle of superior mesenteric artery and vein, anastomosed microsurgically to recipient aorta and inferior vena cava, respectively. The bowel extremities were exteriorized. Eight successfully transplanted rats were studied with serial punch biopsies, immediately post-transplantation and daily for 7 successive days. Biopsies were evaluated by light (LM) and transmission electron microscopy (TEM). Ultrastructural changes were evident before any gross or histologic changes. Endothelial damage, detected only by TEM, was common and resulted in exposure of the thrombus-promoting subendothelial components. Activated platelets as well as platelet aggregates adhered to these damaged areas. The lumen of some vessels was filled with tightly packed erythrocytes, at times showing intravascular hemolysis, suggestive of stasis. Extravascular features included edema and small numbers of immunocompetent cells. The epithelium showed a variable morphology depending on the degree of change in the underlying vessels and submucosa. The findings suggest that vascular damage and thrombosis as well as immunologic events are important in the early phase of the rejection process. Sustaining a viable segment of transplanted intestine may depend on suppressing both the microthrombotic aspect (with anticoagulants and/or antiplatelet agents) and the ensuing immunologic process with newer modalities such as cyclosporine.

Cervical focal myositis in a child.

Focal myositis is a self limited, benign, inflammatory pseudotumor of skeletal muscle, which spontaneously regresses. A 10-year-old girl presenting with localized swelling of the left sternocleidomastoid muscle was seen with subsequent biopsy proven focal myositis. This is the second report of this distinct disease presenting in the neck and the first in the pediatric age group. Biopsy is the only diagnostic and therapeutic modality necessary.

Treatment of bilateral Wilms' tumors--a 22-yr experience.

A total of 157 children with Wilms' tumors were treated at the Children's Memorial Hospital during the years 1956-1978. Fourteen (or 9%) of these children had bilateral lesions. During the early years, treatment consisted of surgical excision of one kidney with radiation to the second tumor. During the second decade of this study a more aggressive approach to bilateral tumors was used consisting of nephrectomy on the side of the large tumor, with a heminephrectomy on the contralateral side and chemotherapy. More recently, we have attempted bilateral heminephrectomy when possible, together with increasingly aggressive chemotherapy. This series of patients allows us to compare the results of various treatment modalities among our own patients as well as those reported from other pediatric surgical centers.

Condyloma acuminata: an unusual presentation of child abuse.

Condyloma acuminata seen in childhood is a disease not well recognized as a sign of child abuse. These viral lesions are often diagnosed and treated without regard to their venereal mode of transmission. Four infants and children with condyloma acuminata ranging in age from 14 mo to 11 yr required surgical management. Two required multiple procedures for control of the lesions. Indications for surgical treatment include large, recurrent, or refractory lesions, as well as the need for histologic identification and acquiring tissue for immunotherapy when necessary. The follow-up care is often difficult because of the socioeconomic structure of the involved families. Careful and persistent medical and social care is necessary to adequately treat the disease and remove the source of infection and to protect children from sexual abuse.

Multifocal mesenchymal hamartoma of the chest wall in infancy.

The authors report on an infant who had multifocal mesenchymal hamartoma of the right posterior chest wall. The tumors were found incidentally, on a chest radiograph, during routine evaluation for upper respiratory tract infection. Resection of both lesions with chest wall reconstruction was performed, with a good result. Only 46 cases of this unusual tumor have been reported previously, and only two of them were multifocal.

Massive osteolysis of the chest in children: an unusual cause of respiratory distress.

Massive osteolysis, also called Gorham's disease, is an uncommon disease in which bone virtually disintegrates and is replaced by vascular fibrous connective tissue. The authors treated two children with massive osteolysis of the chest. Both conditions responded well to radiation therapy; one even showed evidence of reossification. Massive osteolysis should be considered in children who have spontaneous hemothorax. The bony structures should be examined for evidence of lytic lesions.

A modified technique for small-bowel transplantation in the rat.

The rat model for small-bowel transplantation is becoming increasingly popular. The currently accepted microsurgical technique, however, is complicated by extensive dissection in the donor rat vascular system requiring a great deal of manipulation of the vessels themselves, with consequent complications of thrombosis and vascular injury. We describe a procedure for small-bowel transplantation in the rat that simplifies the currently accepted technique. The peripheral portion of the superior mesenteric artery (SMA) and superior mesenteric vein (SMV) is used as the vascular pedicle of the segment of bowel to be transplanted rather than the SMA with an aortic cuff and the portal vein as previously described. The SMA and SMV are anastomosed to recipient aorta and inferior vena cava respectively. The bowel extremities are exteriorized, thus leaving access to the lumen for further studies. All anastomoses are performed with interrupted 10-0 nylon sutures. The procedure was performed in 11 animals. Good revascularization of the transplant was defined as immediate filling of the transplant vasculature with normal (pink) appearing bowel. Eight of the recipients had excellent revascularization. Venous occlusion was the cause of early failure in the remaining three animals. All animals were killed, autopsies performed, and the anastomoses examined. The longest survivors were killed at 7 months. Biopsies were obtained immediately and at daily intervals. Early ultrastructural changes of rejection in the transplanted bowel were studied by electron microscopy. Changes in the microvasculature were seen early after transplantation. Immunologic changes were apparent only later in the course of rejection. We conclude that this technique is successful in achieving functional small-bowel transplants in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Opsomyoclonus and neuroblastoma.

Three cases of neuroblastoma with opsomyoclonus are reported, reconfirming favorable prognostic significance of the association. In one case, computed tomography of the abdomen was the only confirmatory diagnostic study. Two of the cases also were unusual in that the patients had a concomitantly inherited genetic disorder not known to be associated with childhood cancer.

Bridging the gap between attachment and object relations theories: a study of the transition to motherhood.

An empirical study of the relations between assessments of adult attachment styles and object representations was performed in the context of first-time mothers' emotional ties to their unborn babies. We assumed that, while conceptualizations of attachment behaviour and internal working models grasp the early basic patterns of interpersonal relationships and affect regulation, object representations indicate current transformations of these patterns in an individual's internal world. Participants were a sample of 120 women in the third trimester of their first pregnancy. Participants' representations of their own mothers were found to fully mediate the association between internal working models and antenatal ties to their babies. Similarities and differences between theoretical conceptualizations and empirical operationalizations of attachment and object relations theories are discussed.

Effects of organotins on rat brain astrocytes in culture.

The interaction of triethyltin (TET) and trimethyltin (TMT) with rat brain astrocytes in vitro was investigated. Both compounds are highly neurotoxic after in vivo application, cause neurobehavioral changes, and elicit neuronal and glial responses in the CNS. In this study, 5-week-old cultures were exposed to TMT or TET (0.1-2.5 microM) for 24 h. A concentration-dependent cytotoxicity was observed for both agents by vital dye uptake assay using neutral red (NR). The order of potency for half-maximal cytotoxicity (NR-50) was TET (0.7 microM) > TMT (2.5 microM), in agreement with results found after in vivo administration. TET and TMT caused similar morphological changes: large holes extending through the plasma membrane appeared initially in the flattened cell bodies, cytoplasmic extensions were retracted, and long cellular processes formed. Later, the cell bodies rounded up and had only a few extremely long and thin processes. Indirect immunofluorescence staining using anti-vimentin and anti-glial fibrillary acidic protein (GFAP) antibodies revealed that the orderly array of the intermediate filament system was severely disturbed. At lower concentrations, an increased bundling was observed, and at higher concentrations the disassembly of the intracellular framework was seen, and cellular staining appeared rather diffuse. Western blot analysis of cellular extracts was carried out to determine the protein levels of GFAP and vimentin. In this culture system, TET and TMT caused an almost two-fold increase in the levels of GFAP at concentrations around and below NR-50, indicating that astrocytes react to organotins independently of neuronal signals.(ABSTRACT TRUNCATED AT 250 WORDS)

Pneumoperitoneum in the extremely low-birth-weight infant: successful nonoperative treatment.

Pneumoperitoneum without associated pulmonary air leak occurred in two extremely preterm, low-birth-weight infants. These infants were considered too critically ill to tolerate surgical exploration. Accordingly, they were treated medically and supportively, with excellent results.

Nursing responsibility in the diagnosis, care, and treatment of the child with gastroesophageal reflux.

Gastroesophageal reflux (GER) has been known to occur in infants but was thought to be normal. As a result of increased recognition of GER and a clear documentation of GER with extended (18 to 24 hour) esophageal pH monitoring, several severe complications of GER in children have become apparent. An immature cardiorespiratory system is susceptible to some complications of GER such as apnea, choking, recurrent cough or wheezing, and recurrent aspiration pneumonia. Noncardiorespiratory complications include weight loss, esophagitis, anemia, irritability, posturing, malnutrition, and developmental delays. Nursing assessment contributes to a complete clinical picture and the subsequent treatment choice of the physician. To form an accurate assessment of the child with suspected GER, the nurse must be aware of the symptoms and complications of this condition and must precisely execute diagnostic studies, particularly extended esophageal pH monitoring. Nursing responsibilities also include providing a safe yet stimulating environment for the child, teaching parents to participate in the child's care, supporting parents through hospitalization, and preparing both the parents and child for discharge and follow-up care at home.

Experiences of stigmatization play a role in mediating the impact of disease severity on quality of life in psoriasis patients.

BACKGROUND: Psoriasis may have a severe impact on patients' quality of life (QOL) in several ways, an impact mediated by the mental or physical difficulties they have to deal with during the course of the disease and the various treatment regimens. In addition, psoriatic patients often suffer from experiences of stigmatization (EOS) related to the disease. OBJECTIVES: This study was designed to test the hypotheses that psoriasis patients report higher levels of stigmatization than a comparison group, and that their EOS play a role in mediating the impact of the severity of psoriasis on their QOL. METHODS: One hundred patients with psoriasis (study group) and 100 patients with mixed skin problems (comparison group) were matched according to age, sex and education. All subjects answered questionnaires on EOS and QOL. A dermatologist diagnosed the diseases and measured severity scores. The Psoriasis Area and Severity Index score was used for psoriasis and a linear severity score for the comparison patients. The mediating effect of EOS was analysed using structural equation modelling (SEM). SEM is a multivariate statistical method used to examine the consistency of a theory relating one group of variables (termed a 'latent construct') to another: in the present study, the relationship between EOS and QOL. RESULTS: Psoriatic patients were found to report significantly higher levels of EOS related to the disease, compared with the comparison group. No significant differences were found regarding QOL or severity of disease. Clinical severity of psoriasis was found to correlate negatively with QOL in psoriasis patients. EOS were found to have a complete mediating effect for the severity of disease on the QOL in patients with psoriasis. This result was not found among the comparison group patients. CONCLUSIONS: The results of this study indicate that psoriasis patients experience higher levels of stigmatization than do other dermatological patients, and that these EOS mediate the association between disease severity and patients' reported low levels of QOL. Treatment of psoriatic patients should consider these results and should include tools for psychosocial intervention.

Nursing responsibility in the diagnosis, care, and treatment of the child with gastroesophageal reflux.

Gastroesophageal reflux (GER) has been known to occur in infants but was thought to be normal. As a result of increased recognition of GER and a clear documentation of GER with extended (18 to 24 hour) esophageal pH monitoring, several severe complications of GER in children have become apparent. An immature cardiorespiratory system is susceptible to some complications of GER such as apnea, choking, recurrent cough or wheezing, and recurrent aspiration pneumonia. Noncardiorespiratory complications include weight loss, esophagitis, anemia, irritability, posturing, malnutrition, and developmental delays. Nursing assessment contributes to a complete clinical picture and the subsequent treatment choice of the physician. To form an accurate assessment of the child with suspected GER, the nurse must be aware of the symptoms and complications of this condition and must precisely execute diagnostic studies, particularly extended esophageal pH monitoring. Nursing responsibilities also include providing a safe yet stimulating environment for the child, teaching parents to participate in the child's care, supporting parents through hospitalization, and preparing both the parents and child for discharge and follow-up care at home.

Formation of focal adhesion-stress fibre complexes coordinated by adhesive and non-adhesive surface domains.

Cell motility consists of repeating cycles of protrusion of a leading edge in the direction of migration, attachment of the advancing membrane to the matrix, and pulling of the trailing edge forward. In this dynamic process there is a major role for the cytoskeleton, which drives the protrusive events via polymerisation of actin in the lamellipodium, followed by actomyosin contractility. To study the transition of the actin cytoskeleton from a 'protrusive' to 'retractive' form, we have monitored the formation of focal adhesions and stress fibres during cell migration on a micro-patterned surface. This surface consisted of parallel arrays of 2 microm-wide, fibronectin-coated gold stripes, separated by non-adhesive (poly(ethylene glycol)-coated) glass areas with variable width, ranging from 4-12 microm. Monitoring the spreading of motile cells indicated that cell spreading was equally effective along and across the adhesive stripes, as long as the non-adhesive spaces between them did not exceed 6 microm. When the width of the PEG region was 8 microm or more, cells became highly polarised upon spreading, and failed to reach the neighboring adhesive stripes. It was also noted that as soon as the protruding lamella successfully crossed the PEG-coated area and reached an adhesive region, the organisation of actin in that area was transformed from a diffuse meshwork into a bundle, oriented perpendicularly to the stripes and anchored at its ends in focal adhesions. This transition depends on actomyosin-based contractility and is apparently triggered by the adhesion to the rigid fibronectin surface.