MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1.

ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.

Dysregulated responses to emotions among abstinent heroin users: correlation with childhood neglect and addiction severity.

The aim of this paper was to investigate the subjective responses of abstinent heroin users to both neutral and negative stimuli and the related hypothalamus-pituitary-adrenal reactions to emotional experience in relationship to their perception of childhood adverse experiences. Thirty male abstinent heroin dependents were included in the study. Emotional responses and childhood neglect perception were measured utilizing the State-Trait Anxiety Inventory Y-1 and the Child Experience of Care and Abuse Questionnaire. Neutral and unpleasant pictures selected from the International Affective Picture System and the Self-Assessment Manikin procedure have been used to determine ratings of pleasure and arousal. These ratings were compared with normative values obtained from healthy volunteers used as control. Blood samples were collected before and after the experimental sessions to determine both adrenocorticotropic hormone and cortisol plasma levels. Basal anxiety scores, cortisol and adrenocorticotropic hormone levels were higher in abstinent heroin users than in controls. Tests showed that anxiety scores did not change in controls after the vision of neutral slides, whilst they did in abstinent heroin addicts, increasing significantly; and increased less significantly after the unpleasant task, in comparison to controls. Abstinent heroin users showed significantly higher levels of parent antipathy and childhood emotional neglect perception than controls for both the father and the mother. Plasma adrenocorticotropic hormone and cortisol levels did not significantly increase after unpleasant slide set viewing among addicted individuals, because of the significantly higher basal levels characterizing the addicted subjects in comparison with controls. Multiple regression correlation showed a significant relationship between childhood neglect perception, arousal reaction, impaired hypothalamus-pituitary-adrenal axis response and addiction severity. Early adverse experiences seem to affect the entire interaction between hyper-arousal, reduced hormonal response to stress and addiction severity. Our findings, although obtained in a small number of subjects, indicate a significant link between the perception of parental style/care/support during childhood and the ability to cope with stressful emotional stimuli in adulthood and addiction severity.

Childhood neglect and parental care perception in cocaine addicts: relation with psychiatric symptoms and biological correlates.

UNLABELLED: Childhood neglect and poor child-parent relationships have been reported to increase substance use disorders susceptibility. Stressful environmental factors, including emotional neglect, could affect individual personality traits and mental health, possibly inducing stable changes in hypothalamic-pituitary-adrenal (HPA) axis and brain mono-amine function, in turn involved in addictive behavior vulnerability. Therefore, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH and cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in abstinent cocaine addicts, in relationship to their childhood history of neglect and poor parental care perception. METHODS: Fifty abstinent cocaine dependent patients, and 44 normal controls, matched for age and sex, were submitted to a detailed psychiatric assessment (DSM IV criteria). All patients and controls completed the Symptoms Check List-90 (SCL-90) and the Buss Durkee Hostility Inventory (BDHI), to evaluate psychiatric symptoms frequency and aggressiveness levels. The Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and Parental Bonding Instrument (PBI) have been used to retrospectively investigate parent-child relationships. Blood samples were collected to determine HVA, PRL, ACTH and cortisol basal plasma levels. RESULTS: Cocaine addicted individuals in general showed significantly lower HVA, and higher PRL, ACTH and cortisol basal levels respect to controls. In particular, neuroendocrine changes characterized cocaine addicts with childhood history of neglect and low perception of parental care. Obsessive-compulsive, depression and aggressiveness symptoms have been found related to poor parenting, inversely associated to HVA levels and directly associated to PRL, ACTH and cortisol levels. CONCLUSIONS: These findings suggest the possibility that childhood experience of neglect and poor parent-child attachment may partially contribute to a complex neurobiological derangement including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders susceptibility.

Homovanillic acid (HVA) plasma levels inversely correlate with attention deficit-hyperactivity and childhood neglect measures in addicted patients.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) seems to be a risk condition for substance use disorders, possibly in relationship to common neurobiological changes, underlying both addictive and externalising behaviour susceptibility. Although this vulnerability has been primarily attributed to gene variants, previous studies suggest that also adverse childhood experiences may influence neurotransmission, affecting in particular brain dopamine (DA) system and possibly concurring to the development of behavioural disorders. Therefore, we decided to investigate ADHD symptoms and plasma concentrations of the DA metabolite homovanillic acid (HVA) in abstinent addicted patients, in comparison with healthy control subjects, evaluating whether ADHD scores were related with HVA levels, as expression of DA turnover, and whether HVA values, in turn, were associated with childhood emotional neglect. METHODS: Eighty-two abstinent drug dependent patients, and 44 normal controls, matched for age and sex, completed the Wender Utah Rating Scale (WURS), measuring ADHD symptoms, and the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Blood samples were collected to determine HVA plasma levels. RESULTS: Addicted individuals showed significantly higher ADHD scores and lower HVA levels respect to control subjects. ADHD scores at WURS in addicted patients negatively correlated with plasma HVA values. In turn, plasma HVA levels were inversely associated with childhood neglect measures, reaching statistical significance with "mother-antipathy" and "mother neglect" scores. CONCLUSIONS: These findings suggest the possibility that childhood experience of neglect and poor mother-child attachment may have an effect on central dopamine function as an adult, in turn contributing to both ADHD and substance abuse neurobiological vulnerability.

Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction.

Variants of the opioid receptors are the obvious candidates underlying addiction. The kappa opioid receptor (KOR) system seems to play a role in stress responsivity, opiate withdrawal and responses to psycho-stimulants, inhibiting mesolimbic dopamine. KOR gene polymorphisms have been reported to contribute to predisposition to voluntary alcohol-drinking behavior in experimental animals. In humans, the 36G > T single nucleotide polymorphism (SNP) on KOR gene, that was recently identified, has been found associate with substance dependence, with inconclusive findings. In the present study, 106 heroin addicts (West European, Caucasians) and 70 healthy control subjects matched for race and gender, with no history of substance use disorder, have been genotyped. The frequency of KOR 36G > T SNP was significantly higher among heroin-dependent individuals compared with control subjects (Fisher's exact = 0.044; Pearson chi(2) = 4.2734, P = 0.039; likelihood ratio chi(2) tests = 4.6156, P = 0.032). Although KOR silent polymorphisms may apparently have no consequences on mRNA transcription, post-transcriptional mechanisms, such as mRNA stability, translation efficiency, and regulability may impair the function of kappa receptors system, with increased risk for substance use disorders. In specific, the neurobiological changes induced by mu-kappa opioid imbalance could underlie vulnerable personality traits and risk behavior.

[Laparoscopic rectopexy: our experience in the treatment of complete rectal prolapse]. / Rettopessi per via laparoscopica: nostra esperienza nel trattamento del prolasso rettale completo.

Surgical treatments of rectal prolapse still await a final arrangement. The aim of this work is to present Authors' experience with 12 female patients who underwent laparoscopic rectopexy. The patients, aged between 67 and 84 years, were suffering of a different degree of incontinence classified according to the Browing and Parks scale. Pneumoperitoneum was induced through the Veres needle end 5 trocars were placed. The technique used was the modified Orr-Loygue. One no death was observed and only two not serious intraoperative complications were registered, in both conversion to laparotomy was not necessary. Functional result as for incontinence has been really good (disappeared in 11 cases and improved in one). Whereas regarding the constipation, no improvement was observed in those in who in it was preexisting the operation, not appearing nevertheless, as on the contrary reported by other Authors, in those in whom it wasn't present before surgical treatment. The patients, all in follow-up (range between 10 and 36 months, average 25.08), still now experienced no relapse. In conclusion, on the base of Authors' experience, laparoscopic rectopexy is considered free of particular risks and excellent in the results even if, due to the slight number of series, any definitive judgement can be expressed.

[Calcium antagonist vs diuretics. Doppler velocimetric monitoring of the carotid flow in patients with essential hypertension]. / Calcioantagonisti versus diuretici. Monitoraggio velocimetrico Doppler del flusso carotideo nei pazienti con ipertensione essenziale.

BACKGROUND: In the period from 1995 to 1996, 19 patients with a range of 180-200 mmHg and 95-110 mmHg respectively for systolic and diastolic pressure, have been examined by Doppler monitoring. METHODS: Nine patients were treated with lacidipine (4 mg/die) and 10 were treated with idroclorotiazide + amiloride (50 mg every other day). The IPP and the IDC were end points to value the arterial compliance and the remodynamic flow in common carotid. RESULTS: The humeral blood pressure was valued every morning and Doppler monitoring of common carotid 30 and 60 day after treatment. The carotid blood flow and cerebral perfusion had a significant amelioration with calcium antagonists and an increase of IDC with a decrease of IPP were found. CONCLUSIONS: This study demonstrates the role of calcium antagonists not only as antihypertensive drug, but also to prevent, to check and to improve progression of ateromatic injury. The conclusions is drawn that Doppler monitoring is a satisfactory scientific method to obtain information on features of arterial wall without excessive cost.

[Trocar-induced complications in laparoscopy]. / Les complications dues aux trocarts en laparoscopie.

Trocar-related injury can occur if the different procedures, including distension of the abdomen, pneumoperitoneum or anesthesia, are insufficient. Such injuries can be prevented by proper handling and good angulation of the trocar on the abdomen. In case of suspected vascular injury, conversion to open laparotomy is required to explore the abdominal cavity. If abdominal adhesions are discovered after introducing the first trocar, a second trocar must be introduced at some distance from the first one to visually check the absence of any digestive injury. The degree of wound dehiscence depends on the size, site and direction of introduction of the trocar.

[Laparocele after laparoscopic surgery]. / Il laparocele dopo chirurgia laparoscopica.

The authors have reported two laparocele cases in the place of insertion of the umbilical trocar, on 156 laparoscopic accesses made by them. Both cases took place at the beginning of their experience when the navel fascial breach had not yet been stitched. The authors made an extensive review of the medical literature and have found out that such complication is rare and to prevent it, it is right to stitch the navel fascial defect, being careful for not englobing the epiploon or an intestinal loop in the suture.

[Warthin's tumor of the parotid gland]. / Il tumore di Warthin della parotide.

The Authors report 6 cases of Warthin's tumor of the parotid gland recently observed. In all cases the tumor was intraglandular, single, and no noteworthy disorders or symptoms except for a 2 to 5 cms tumefaction were present. At surgery all lesions appeared well-capsulated and the exeresis followed a cleavage plane easily identifiable which enabled the preservation of the residual glandular tissue as well as the surrounding nervous and vascular structures. All the patients, up to now, are free from relapse.

[Hypoxemia and pulmonary atelectasis after laparoscopic cholecystectomy]. / Ipossiemia ed atelettasia polmonare dopo colecistectomia laparoscopica.

The aim of this study is to evaluate, after laparoscopic (CL) or open (CO) cholecystectomy, the incidence of pulmonary atelectasis and hypoxaemia which are strictly related to the onset of pulmonary complications. Two groups of 20 consecutive patients affected by symptomatic and not complicated gallstone disease were cholecystectomized either using CO or CL. Hypoxaemia was assessed preoperatively and after operation. Postoperative determination was performed at the 4th, 8th, 12th and 24th hour and then every 12 hours until discharge from hospital. A not informed radiologist evaluated atelectasis through two X-rays, preoperatively and postoperatively at the 3rd day. Atelectasis cases were divided in micro, focal, segmental, lobar and of the entire lung. Statistic analysis was performed using the "t" Student test. No mortality or intraoperative complications occurred. The two groups were similar for age, sex, smoker percentage, obesity, preexisting pulmonary dysfunctions and anaesthesiological risk (ASA). Operative time resulted in longer in CL compared to CO patients although in an insignificant way. PO2 value resulted significatively reduced (P < 0.05) at 4th, 8th, 12th and 24th postoperative hour after CO, while subsequent measurements did not show significant differences. There was no evidence of PO2 significative reduction after CL. After operation atelectasis was found in 11 patients (55%) of CL group (P < 0.05) and in 17 patients (85%) of CO group (P < 0.001). Atelectasis observed in the group of 11 CL patients was represented by 7 micro and 4 focal types, while in the CO group 7 micro, 8 focal and 2 segmental types were found. This study suggests that CL alters the pulmonary function less than CO.

[Ulcerated carcinoma of the breast in an elderly woman. An unusual clinical case report]. / II carcinoma ulcerato della mammella nella donna anziana. Osservazioni su un caso clinico peculaire.

The authors analyze the most current methods for the treatment of ulcerated breast cancer in the elderly. They describe a peculiar case recently observed, characterized by an ulcerative lesion spreading from the hemiclavicle to the foreaxilla including the axillary cavity, causing a large phlebo-lymphaedema, anaesthesia and paresis of the homoteral upper limb. After an initial treatment with tamoxifen a scapulo-humeral disarticulation and a suture of the cutaneous wide defect were performed using a myo-skin graft which included the deltoid muscle. A radiotherapeutic treatment followed by tamoxifen therapy was carried out. No distant metastases and no local relapses were registered in the one year follow up. The Authors on the basis of their experience and according to the review of the Literature suggest that age itself is not a limiting factor to the therapeutic approach of ulcerated breast cancer.

[The laparoscopic approach: a technical note]. / L'accesso laparoscopico: nota di tecnica.

The authors report their laparoscopic access technique. It has to be considered a variation of the classical closed technique, with the introduction of the Veress needle and the first trocar directly at the level of the fascia which is kept in traction by two Kochers.

[Complications of the laparoscopic access]. / Le complicanze dell'accesso laparoscopico.

The Authors analysed the complications observed during 156 laparoscopic accesses. In 38 cases following the classic closed technique, two pneumoderma, one pneumoscrotum, one pneumoepiploon and two laparoceles were observed in the umbilical area. In 30 patients the laparascopic access was performed according to the open technique, registering a significant loss of gas during the operation though not compromising it in 4 patients, and two infections of the umbilical incision. In 88 cases the modified closed technique was used and only one infection in the umbilical trocar insertion area was observed. After discussing the incidence, the etiopathogenesis, the diagnosis and the treatment of complications related to the laparoscopic access, the Authors emphasize the fact that in patients with surgical scars near the naval or patients who have already undergone laparascopy, or those with a positive history of affections causing abdominal adherence, the laparoscopic access must be performed using the open technique.

[The clinical evaluation of acetoxyethylcefuroxime in dentistry]. / Valutazione clinica dell'acetossietilcefuroxima in campo odontoiatrico.

The study examines the use of an oral antibiotic with a wide spectrum of action tested in dentistry belonging to the cephalosporin class: acetoxyethylcefuroxime. The pharmaceutical industry has succeeded in synthesising a prodrug of parenteral cephalosporin "Metoxyrinic cefuroxime sodium", thus resolving the problems presented by earlier molecules such as: scarce bioavailability, poor palatability and collateral effects at a gastroenteric level. This is a 2nd generation cephalosporin whose mechanism of action consists in the capacity to selectively block the synthesis of the peptidoglycan, a fundamental component of the cell wall of both Gram+ and Gram- bacteria. The study, which was performed in the Division of Odontostomatology of the Mauriziano Hospital in Turin, examined 59 patients suffering from some of the most commonplace dental pathologies such as: apical periodontitis-alveolitis-odontogenic abscesses-eighth teeth in dysodontiasis-maxillary cysts. The following clinical parameters were evaluated in both outpatients and those undergoing surgery: swelling, pain, lymphoadenopathy at the start of treatment, and at days 3 and 5 of treatment. A 250 mg tablet was administered every 12 hours for 5 days. Owing to the rapid resolution of symptoms and the limited collateral effects observed, the authors conclude that the drug may be regarded as the elective form of treatment.

[Paget's disease with an exclusively maxillary location. A case report]. / Malattia di Paget ad esclusiva localizzazione mascellare. Descrizione di un caso.

The authors illustrate a case report of Paget's disease in an exclusively cranio-facial localisation. Paget's disease is a dystrophy of an osteo-condensing type. Excess bone remodelling activity, due primarily to hyperclastic hyperactivity, leads to accelerated resorption and excess tissue formation. This marked alteration of the metabolism causes the hypertrophy of the bones involved, with zones of greater density and increased vascularisation. Its clinical manifestations include morphological deformations and painful symptoms in the areas affected. Complications may include pathological fractures, medullary or radicular compression, heart failure (rare), sarcomatous transformation (approximately 1% of cases). The case reported here describes a 70-year-old who was admitted to the out-patient clinic of the Odontostomatological Division of the Ospedale Mauriziano in Turin for a dental check up. The patient had had 6 teeth removed during the past 2 weeks in a private clinic. At the time of the control a mucous crater was present, also involving the underlying bone, at the level of the extracted 2.6 tooth. The patient had kept the teeth which had been removed some of which showed that the roots were surrounded by alveolar bone. A dental panoramic x-ray and cranial x-ray were performed using 3 projections and showed the remodelling of the cranial theca and upper jaw. The suspicion of Paget's disease was confirmed by hematochemical tests, bone scintigraphy with calcium phosphate and by the histologic examination of the alveolar bone fragments adhering to the root surface of the extracted teeth.(ABSTRACT TRUNCATED AT 250 WORDS)

Children's knowledge of auditory/articulatory correspondences: phonologic and metaphonologic.

Forty-five normally developing children, 15 within each group of mean ages 5, 6, and 7, participated in a metaphonologic study examining the knowledge of auditory/articulatory correspondences. Tasks included (a) a nonverbal identification of correspondences by selecting the appropriate side of a split video screen display, and (b) a verbal explanation of the cues used to motivate this choice. With development, there were significant increases in numbers of correct responses on the nonverbal task and corresponding changes in relative proportions of verbal explanation types. No significant relationship between level of performance on metaphonologic tasks and phoneme production skill was found.