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Green building concept plays a fundamental role in reducing the use of resources and the impacts on human health and environment, during the whole building life cycle. Therefore, a method to measure the building sustainability rate is crucial for comparing various alternatives in terms of use of different materials, energy resources, production processes to reduce energy consumption and environmental impacts. Many protocols have been proposed to perform buildings’ sustainability evaluation; however, different operators applying these certification tools might need to make hypotheses, even different from each other, to complete the whole procedure. Hence, this work aims to evaluate whether and how the hypotheses formulated by each operator can influence the final certification level. To this end, a Round Robin Test among international partners was performed using different versions of LEED sustainability protocol to the same building with the same boundary conditions, comparing and analyzing the results provided by the participants. The final aim was to identify which issues have more influence on the final performance rate, giving to the users a deeper knowledge of the aspects included in these procedures. The results showed the potential of these building environmental certification systems, capable of offering a transversal level of environmental sustainability. © 2021 Elsevier Ltd

Although the Almone River, which runs for 6 km between the Roman Via Latina and Via Appia, inside the present Appian Way Regional Park, is a short tributary of the Tiber River, it played a crucial role among the cults for protection of the ancient city of Rome: the rite of lavatio (a ritual washing) of the lithic symbol of the Great Mother-Cybele goddess from Pessinus (the present village of Ballihisar, southwest of Ankara, Turkey) in the cold and fast-flowing water of the Almone River. In later times, the Almone River lost its sacrality and its flowing water got a new useful and hydraulic meaning. So it deeply characterised the local area and human settlements, enhancing their artisanal potential, especially in the Middle Ages and the Renaissance and in part until the 20th century. The river area has records of water mills and ‘valche’ (from the Longobard word walkan, rolling), i.e. wool-fulling mills. One of the latter (converted into a paper mill in the early 20th century) has been restored and is now used as the headquarters and visitors' centre of the Appian Way Regional Park, of which the Almone is one of the key attractions for its tourist, natural, historical and cultural value.

The expression of sigma-2 receptor (S2R) was assayed in blood and bladder samples from healthy cattle and in blood and bladder of cattle with deltapapillomavirus-associated urothelial tumors. Samples of bladder from cattle with neoplasia had significantly higher S2R than samples of bladder from healthy cattle (95% CI 0.31-0.82, P 0.05). In addition, significantly higher S2R was detected in the blood of cattle with bladder cancer than blood from healthy cattle (95% CI 0.22-0.41, P 0.05). The results provide evidence that increased expression of SR2 in blood could be useful as circulating biomarker for bladder cancer in cattle. PGRMC1 protein levels were also found to be increased in blood and bladder from cattle with cancer and increased expression of PGRMC1 transcripts was detected by quantitative real time PCR in samples from cattle neoplasia. Furthermore, electron microscopy revealed phagophores and numerous autophagosomes, ultrastructural hallmark of autophagy.

Activatable fluorescent probes share the unique feature of being turned on only under specific conditions: they are "silent" when not interacting with a specific target protein, microenvironment, or reactive species. Several activatable fluorescence probes have demonstrated their potential in cell biology study, disease study and diagnosis, and even in the rapidly expanding field of image-guided surgery. In this review, we will summarize progress in the design of activatable probes and their application in studying cell biology or in optical imaging. Some of the most effective examples of activatable fluorescent probes will be presented and their application will be discussed.

testo sul lavoro dell'artista Adelita Husny-Bey

In this paper two numerical procedures are presented: the first algorithm allows for the determination of the geometric characteristics of the maximum efficiency propeller for a given operative condition and profile distribution along the blade; the output of this numerical procedure is the chord distribution and twist angle of the blade, together with its efficiency and its torque and thrust coefficients for the prescribed operative condition. The aerodynamic characteristics of the optimum propeller when operating in a condition different from the design one are obtained by a second algorithm that allows for the evaluation of the efficiency, the thrust and torque coefficients of a propeller of known geometry, when the blade pitch and operative condition are varied.In the paper the formulation used for deriving the geometry of the optimum propeller and determining its performances when operating off-design is described in detail. The results obtained from the proposed propeller model have been validated by comparison with experimental data.

Twenty-two women with metastatic breast cancer, previously submitted to one or more lines of chemotherapy, were treated with mitoxantrone as single agent delivered at full dosage (14 mg/m(2)) every other week (accelerated chemotherapy). This dose was possible with concomitant subcutaneous administration of granulocyte colony stimulating factor (G-CSF) on days 5 to 12 of each 14 day cycle. Although grade III-IV leukopenia, anemia and thrombocytopenia were observed in 50%, 13%, and 27% of cases, respectively, a complete recovery of neutrophils, due to G-CSF administration, permitted on time cycle delivery in the majority of cases. Partial response was observed in 6/22 patients (27%). In conclusion, accelerated chemotherapy with mithoxantrone plus G-CSF is both feasible and effective for patients with previously treated breast cancer.

A reversed phase high performance liquid chromatographic method has been developed for the simultaneous determination of the pro-drug 5′-deoxy-5-fluorouridine (5′-dFUR), its metabolite 5-fluorouracil (5-FU) and some fluorinated pyrimidines involved in the metabolic activation process of 5-FU. The method has been used to monitor the bioavailability of 5′-dFUR and 5-FU in patients undergoing anticancer chemotherapy. Serum sample treatment involves addition of internal standard (5-bromouracil), protein precipitation with saturated ammonium sulphate solution and liquid-liquid extraction with ethyl acetate-isopropanol (90 ∶ 10 v/v). Urine is simply diluted with mobile phase and injected. The average recovery from serum (at 0.5 μg/mL level) was 95.0%±1.4 for 5′-dFUR and 86.3%±3.5 for 5-FU. A linear response extending over four decades of concentration was observed. Detection limits in the low ng/ mL range were obtained using a 250 μL sample size and a 20 μL injection volume. Within-day and between-day coefficients of variation were below 4 and 10%, respectively.

A total of 1095 patients with operable breast cancer and en-rolled in a randomized clinical trial were analysed for estrogen (ER) and progesterone (PgR) receptor content of their primary tumor, and the relationships between steroid receptor status and several epidemiologic characteristics were studied. The proportion of ER+ and median ER levels increased with age: compared to women younger than 40, those aged 66 or more were approximately three times more likely to have an ER+ tumor (OR = 3.0, 95% C.I. = 1.6–5.7). This difference tended to be more marked after comparison between patients with ER > 100 fmol/mg protein and ER- within the same age groups: OR = 7.04, 95 % C.I. = 2.89–17.12. No association emerged between age and PgR. ER status and concentrations were independent of menopausal status after adjustment for age, whereas the proportion of PgR+ and PgR levels were significantly lower in postmenopausal patients of the same age. The distribution of ER and PgR profiles was similar in relation to family history of breast cancer, reproductive events and other selected epidemiologic characteristics of the patients.

Twenty-two patients affected by relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with a combination of ifosfamide (IFO) at the dose of 1.2 g/m2 intravenous (i.v.) (1 h infusion) for 5 consecutive days with mesna as uroprotector plus mitoxantrone (NOV) at the dose of 12 mg/m2 i.v. on day 1; both drugs were recycled every 3-4 weeks. Of 21 evaluable patients, overall response observed was 57% (38% complete response and 19% partial response with a median duration of response of 7 months (5-23+). Dose-limiting toxicity was represented by leukopenia (grade III-IV in 43% of cases); severe thrombocytopenia was observed less frequently (grade III-IV in 19% of cases). This hematologic toxicity prevented administration of therapy every 3 weeks as initially planned. However, the complete hematological recovery, usually observed at the fourth week, permitted therapy administration to all patients without dose reduction. Low-grade lymphomas responded to treatment as well as intermediate or high grade lymphomas. Moreover, patients treated with third- or fourth-line chemotherapy also responded. However, response was observed in 11/13 (85%) relapsed patients as compared to 2/8 (25%) refractory cases. The combination of IFO plus NOV is active in heavily pretreated patients with NHL. Nevertheless, the study of a larger number of patients is necessary to better define the exact role of this combination as "salvage" therapy for NHL.

Starting from the previously reported 5-HT 7 receptor agents 4-7 with N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamide structure, the 1-(2-methylthiophenyl)-, 1-(2-diphenyl)-, 1-(2-isopropylphenyl)-, and 1-(2-methoxyphenyl)piperazine derivatives 8-31 were designed with the primary aim to obtain new compounds endowed with suitable physicochemical properties for rapid and extensive penetration into the brain. The affinities for 5-HT 7, 5-HT 1A, and D 2 receptors of compounds 8-31 were assessed, and several compounds displayed 5-HT 7 receptor affinities in the nanomolar range. Among these, N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (25) showed high 5-HT 7 receptor affinity (Ki = 0.58 nM), high selectivity over 5-HT 1A and D 2 receptors (324- and 245-fold, respectively), and agonist properties (maximal effect = 82%, EC 50 = 0.60 microM). After intraperitoneal injection in mice, 25 rapidly reached the systemic circulation and entered the brain. Its brain concentration-time profile paralleled that in plasma, indicating that 25 rapidly and freely distributes across the blood-brain barrier. Compound 25 underwent N-dealkylation to the corresponding 1-arylpiperazine metabolite.

BAL devices constitute an innovative therapeutic approach currently accepted as a bridge to liver transplantation for patients with liver failure. Usually, the patient’s blood or plasma is circulated extra-corporeally through a bioreactor that houses a metabolically active component which performs the functions of the damaged liver. Among these, ammonia detoxification is crucial because the accumulation of this metabolite is highly toxic to the central nervous system. Our first BAL prototype consisted of a hollow fiber-based cartridge perfused with goat blood through the fiber’s lumen. This device showed an effective ammonia depuration rate using isolated hepatocytes as cellular component. But, since the “ideal” biological component should contain all liver cell types for a maximum response, we became interested in evaluating LMOs: tissue slices that retain the basic micro architecture of the liver lobe. Therefore, we built up a flat-based BAL model, suitable to use fresh or cold preserved LMOs. Accordingly, we reported the development of a novel preservation solution (BG35) that showed the same efficacy as ViaSpan ® to protect LMOs against cold preservation injury for 48 h. So, the aim of the present work was to evaluate the performance of cold preserved rat LMOs in our new BAL model. LMOs were manually cut from rat livers (338 ± 27 μm thickness, n = 25) and stored in BG35 or ViaSpan ® solutions at 0 °C up to 48 h of preservation. Freshly cut LMOs were used as controls. After the preservation period, 1.5 g of LMOs was loaded into the BAL and an ammonia overload (1.06 ± 0.12 mM, n = 9) was added to the blood before initiating the system perfusion at 9 mL/min (blood volume = 35 mL). Samples of blood and extra-fiber fluid were taken after 60 and 120 min of perfusion. We determined LDH release (%) by LMOs in the extra-fiber fluid and ammonia detoxification capacity (% of the initial dose detoxified at different times) in the perfusing blood. After 120 min of perfusion, LMOs cold preserved in BG35 or ViaSpan ® were able to detoxify 57.4 ± 12.1 % and 51.9 ± 6.0 %, respectively, of the initial ammonia overload ( n = 3). No significant differences were found with Controls (49.3 ± 8.8%, n = 3). All groups showed a good maintenance of their viability: LDH release after 120 min was 10.5 ± 5.4 % and 9.2 ± 3.4% for BG35 and ViaSpan ® preserved LMOs, respectively, similar to Controls (6.1 ± 2.2%, n = 3). In conclusion, LMOs cold preserved in both solutions showed a good ammonia detoxification capacity that enables their use as biological component of a BAL device. These results confirm that the BG35 is as efficient as ViaSpan ® to protect rat LMOs against cold preservation injury and it is considerably less expensive and easy to prepare. Also, these experiments show that the BAL prototype developed constitutes a simple and inexpensive tool to investigate the effects of preservation, cryopreservation, or culture on the LMOs functions.

The acute thrombosis of a bypass graft can always be a common and challenging problem for the vascular surgeon, since surgical revascularization procedures can often result in failure, limb loss and infection. Since over the past 15 years literature reports emphasize the efficacy of intraarterial thrombolytic therapy (IATT) in achieving clot lysis and initial patency of thrombosed arteries and grafts, the purpose of this study is to verify if IATT with urokinase represents a valid alternative procedure to surgery. From our experience of 18 cases of lower limb ischemia, 9 of which graft thrombosis and 9 native artery occlusions, 3 cases of acute thrombosis of lower extremity bypass grafts, successfully treated with IATT are considered. After arteriography proof of lower extremity artery or bypass graft occlusion, thrombolytic therapy with urokinase was delivered at a rate of 100,000 UI/hour for 24/48 hours. At the conclusion of the thrombolytic treatment, percutaneous transluminal angioplasty (PTA) was performed on any residual stenosis of the bypass graft. In all three cases complete clot lysis within 48 hours was obtained, with patency of the bypass graft at two years follow-up. Urokinase in our experience, has always given good results. In many cases restoration of normal blood flow was obtained in bypass grafts thrombosed a three days. Urokinase has also been helpful in defining the causes of the occlusion (stenosis proximal or distal to the bypass) or of the anastomosis itself. Regional urokinase thrombolytic therapy, even if expensive, represents a primary tool for the vascular surgeon, since excellent results may be obtained, especially in cases where surgery is of high risk.

Some 1-aryl-4-[(5-methoxy-1,2,3, 4-tetrahydronaphthalen-1-yl)-n-propyl]piperazines and their alkylamino and alkylamido analogues, previously studied as 5-HT1A ligands, were prepared in enantiomerically pure form, and their absolute configuration was determined by chemical correlation or by chiroptical properties. They were evaluated for in vitro 5-HT1A, D2, and alpha1 receptor affinity by radioligand binding assays, to study the influence of the chiral carbon atom of the tetrahydronaphthalene nucleus on the 5-HT1A affinity and selectivity. Results indicated that, as regarding the 5-HT1A receptor affinity, there was no difference in affinity between (-)- and (+)-enantiomers as well as the racemate of each compound. The stereochemistry, instead, influenced the selectivity: all (-)-enantiomers displayed affinity values higher than those of (+)-isomers at D2 receptors, and conversely, all (+)-enantiomers displayed affinity values higher than those of (-)-isomers at alpha1 receptors. As a result of this trend, it is not possible to predict the isomer with a better selectivity profile. However, compounds (S)-(+)-2, (S)-(+)-4, and (R)-(+)-6 displayed high affinity for the 5-HT1A receptor (IC50 values ranging between 7.0 and 2.3 nM) and good selectivity (/=250-fold) versus both D2 and alpha1 receptors. Furthermore, compounds (S)-(+)-4 and (R)-(-)-4 were submitted to the [35S]GTPgammaS binding assay for a preliminary evaluation of their intrinsic activity on the 5-HT1A receptor.

OBJECTIVES To evaluate the range of multiple swallowing in normal subjects by ultrasonography. METHODS Twenty-two normal subjects swallowed 5 or 10 ml of tap water or a semisolid meal. RESULTS With water multiple swallows were seen in 41% of the subjects examined and was related to the volume of the bolus:18% of the cases were 5 ml and 36% were 10 ml. Sixty-eight percent of subjects had multiple swallows with semisolid boluses. CONCLUSION These results differ from those reported with videofluoroscopy of modified barium swallowing. Ultrasonography should be used in future studies of normal and pathological oral swallowing.

A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl-[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective sigma 1 affinity. They were tested in radioligand binding assays on sigma 1, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma 1 affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [3H]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl] piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n- butyl]piperidine (26) reached the lowest Ki values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (Ki = 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, Ki = 3.9 nM on sigma 1 sites) caused an increase in 5-HT1A affinity (Ki0.14 nM).

This paper describes DANIELA a neuro-fuzzy system for control applications. The system is based on a custom neural device that can implement either multilayer perceptrons, radial basis functions or fuzzy paradigms. The system implements intelligent control algorithms mixing neuro-fuzzy paradigms with finite state automata and is used to control a walking hexapod.

The synthesis of some o-methoxyphenylpiperazines with a benzamide moiety on N-4 alkyl chain was accomplished and their affinity for dopamine and serotonin receptor subtypes was assayed by in vitro receptor binding. The results show that several derivatives had a good affinity both on D-2 and 5-HT1A receptors, the IC50s ranging from 10(-7) to 10(-8) M.

Bioartificial livers (BAL) were designed as a bridge to maintain patients with liver failure until they recover or receive a liver transplant. In these devices, the patient’s blood or plasma is circulated extra-corporeally through a bioreactor that houses a metabolically active component, as isolated hepatic cells or cultured cells. In this work, we tested LMOs from rat liver. LMOs are tissue slices that retain the microarchitecture of the liver lobe and its physiological characteristics. The use of LMOs is also attractive because it obviates the stages of cell isolation and cultivation. So, our group has set up a technique to manually obtain LMOs and constructed a flat-based BAL model suitable to use fresh LMOs. Moreover, we have developed a novel preservation solution, BG35, with similar efficacy than ViaSpan ® to protect LMOs against cold preservation injury. This would allow having the biological component viable, functional and ready to be used when is needed for our BAL. Ammonia accumulates in the blood of patients with liver failure, causing metabolic and neurological disturbances, being crucial that any cell or tissue to be employed in a BAL can perform this task. Since the Urea Cycle is the major pathway of ammonia removal, the objective of this work was to study gene expression and activity of Carbamoyl Phosphate Synthetase I (CPSI) and Ornithine Transcarbamylase (OTC), two key enzymes, after LMOs preservation in BG35 and ViaSpan ® (0 °C, 48 h). We have assayed in vitro the LMOs ability to detoxify an overload of ammonia in order to evaluate them for their successive application into a BAL. LMOs were manually cut (338 ± 27 μm thickness, n = 25). 50 LMOs were stored at 0 °C in 60 mL of BG35 or ViaSpan ® . Freshly-cut LMOs were used as controls. After cold storage, LMOs were rewarmed (37 °C, Krebs Henseleit Rewarming solution, 120 min) in a Dubnoff metabolic shaker under 95%O 2 :5% CO 2 atmosphere. Samples were taken after 60 and 120 min. All groups showed a good maintenance of their viability. After 120 min, the amount of LDH released by LMOs cold preserved in BG35 (20.1 ± 5.6%) and ViaSpan ® (23.4 ± 5.5 %) was similar to Controls (16.0 ± 4.4 %, n = 3). The preservation conditions did not affect ammonia metabolism: after 2 h of rewarming, LMOs cold preserved in BG35 and ViaSpan ® could detoxify 29.3 ± 7.9% and 25.7 ± 4.9% of the initial overload, similarly than Controls (29.7 ± 10.7%, n = 6). Though there were differences in relative mRNA levels between Controls and the two preserved groups, the values of CPSI and OTC enzymatic activity were comparable in all studied groups. In summary, we have shown that our preservation conditions did not affect ammonia metabolism and cold preserved LMOs maintain the physiological and biochemical liver functions tested, which allows their use as biological component of a BAL system.

The aim of the study was to identify a number of sonographic landmarks in the evaluation of the oral phase of swallowing. Forty non-dysphagic adults (average age 38 years) and 20 normal bottle-fed newborns (average age 13 days) were submitted to videorecorded sonographic examination using two types of transducers (5 and 7.5 MHz). The adults were asked to swallow a 20 ml bolus of water and the newborns were examined while sucking from a bottle containing milk. Preliminary transverse scans of the neck were obtained to evaluate laryngeal movements during swallowing. The mouth was examined through the submental window using sagittal and coronal scans. In the newborn, additional transbuccal scans were employed. In both adults and newborns highly significant and reproducible images of single-element motor events involved in swallowing were obtained. Normal sonographic images of the oral stage of deglutition form the baseline from which abnormal patterns may then be recognized.

The synthesis of some arylpiperazines with a benzamide moiety on N-4 alkyl chain was accomplished and their dopaminergic and serotonergic affinity was assayed by in vitro receptor binding. The results of such investigation showed a moderate affinity on D-2 receptors and a lack of 5-HT receptor affinity.

In this study we treated 19 patients with relapsed ovarian cancer with malignant peritoneal effusion. All patients were previously treated with cisplatin-containing regimens. Intraperitoneal mitoxantrone was administered at a dosage of 20-30 mg/mq repeated every 28 days if ascites was still present. No patient was treated with systemic chemotherapy during the study. In 15 of 19 patients progressive ascites reduction was obtained. Moreover, in 4 of 15 responsive patients, a progressive reduction of the quantity of ascites was observed even though the abdominal masses demonstrated an increase in volume. Serum concentrations of Mitoxantrone (MXN) were determined, in ten patients, by high performance liquid chromatography with spectrophotometric detection, and low serum levels (1-30 ng/ml) with a maximum at the first or second hour were revealed. In conclusion, in patients with ovarian carcinoma and recurrent neoplastic ascites, palliative treatment with mitoxantrone was effective and well tolerated. The reduction of ascites and frequency of paracentesis represents a marked advantage for these patients and improves their quality of life.

Seven patients with inflammatory and 11 with metastatic breast cancer were treated with high dose FEC chemotherapy plus GM-CSF; 5-fluorouracil and cyclophosphamide were administered at 500 mg/m2/iv/day 1, epirubicin at three dose levels: 100 mg, 120 mg and 140 mg/m2/iv/day 1 every three weeks (six patients per level). GM-CSF was administered at a dosage of 5 mg/kg/sc from day 5 to 12 of each cycle. The overall response rate was 83% (95% CI: 66%-100%) with 22% complete response. The median response duration for patients with metastatic disease was 7 months (range: 4-10). The hematological toxicity was moderate but reversible due to GM-CSF rescue; mucositis represented the dose limiting toxicity. In conclusion, the increase of dose intensity resulted in a higher response rate but not longer response duration, which must be taken into account when administering high-dose chemotherapy with growth factor rescue.

Bulky mediastinal involvement is a challenging presentation of Hodgkin's disease (HD). Radiotherapy alone has provided a good response rate but also a high percentage of recurrences, and therefore many studies have been initiated to evaluate combined modality treatment.In a prospective study 23 stage IIA/IIIB HD patients treated with ABVD/MOPP alternating chemotherapy and radiotherapy were evaluated with regard to overall (OS) and disease-free survival (DFS), acute and long-term toxicity.A 95% CR rate was obtained. Ten-year actuarial OS and DFS were 83 and 91%, respectively. Two patients (8.8%) relapsed 8 and 9 months after achieving CR. One patient (4.4%) died following severe bone marrow failure 25 months after diagnosis. No clinically evident acute or chronic cardiac or pulmonary toxicity was evident, and no second malignancies were observed. At the end of therapy 7/14 evaluable women became amenorrheal and remained so at their last follow-up. Two male patients were considered azoospermic on the basis of laboratory evaluation at the end of therapy, and after 68 and 122 months, respectively; 4 of 5 male patients had sexual intercourse freely but did not fertilize their partners.In our opinion and in agreement with available literature, chemotherapy has a fundamental place alongside radiotherapy in the treatment of bulky mediastinal HD. Combined modality treatment improves the disease-free survival obtained with radiotherapy or chemotherapy alone. In our experience a high percentage of patients (83%) can be considered cured without the need for second-line therapy. However, long-term and especially gonadal toxicity greatly influence the quality of life of these patients. Therefore treatment must be personalized according to age, sex, cardiopulmonary status and desire to preserve reproductive function.

s / Cancer Treatment Reviews 36S3 (2010) S95–S119 S109 47 BIOLOGICAL CHARACTERIZATION OF MC70, AS POTENT INHIBITOR OF ABC TRANSPORTERS INVOLVED IN MULTIDRUG RESISTANCE A.E. Quatrale, L. Porcelli, N.A. Colabufo, F. Berardi, R. Perrone, A. Paradiso, A. Azzariti. Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Chemical and Pharmaceutical Department, University of Bari, Bari, Italy Background: Multidrug resistance (MDR) is a major limitation in the cancer chemotherapy. The most important mechanism involved in MDR is the overexpression and the increased activity of several ATP-dependent efflux pump namely ATP-Binding Cassette (ABC) transporters, such as Pglycoprotein (P-gp), Breast Cancer Resistant Protein (BCRP) and MultiDrug Resistant Proteins (MRPs). Methods: We characterized one potent P-gp inhibitor MC70, a 6,7 dimethoxytetrahydroisoquinoline derivative, in MCF7/ADR and Caco-2, a breast and a colon cancer cell line, respectively. Initially, we investigated P-gp inhibition by our compound in MCF7/Adr cells, analyzing its ability to interfere with Rhodamine-123 active efflux which was highly inhibited by MC70 probably through P-gp blockage. In the same cells, our compound was not able to induce consistent cell death or cell growth inhibition, conversely, it strongly enhanced the citotoxicity induced by doxorubicin when cells were pre-exposed to our P-gp inhibitor, with an increase of cell growth inhibition of about 66%. This strong activation of doxorubicin activity probably was not dependent, only, from P-gp inhibition and other cellular targets should be involved. Results: To identify the mode of action of our compound, microarray analysis, cell cycle determination and western blotting were carried out. Cells were exposed to 20m MC70 for 2 days, mRNA was extracted and processed on Affymetrix GeneChip Human Gene 1.0 ST. Data suggested that this agent did not modulate mRNA expression probably acting at a post-transcriptional step. Cell cycle modulation by MC70 evidenced an early increase of cell accumulation in G2/M phase that seemed to recover the baseline cell cycle rate after 2 days drug exposure. Western blot analysis demonstrated that our agent stimulated Akt activation without affecting p-ERK1/2 phosphorylation. In Caco-2 cell, MC70 behaviour was quite different. This compound showed a strong antiproliferative activity when given alone and conversely it did not enhance doxorubicin cytotoxicity. The cell cycle perturbation by MC70 evidenced an accumulation of cells in S phase after 1 day exposure instead of G2/M phase, and its ability to stimulate Akt activation was confirmed. Furthermore, preliminary data suggested that MC70 was able to modulate other MDR transporter than P-gp as BCRP. Conclusions: These evidences show that this agent, designed and synthesized as a pure P-gp inhibitor, enhanced conventional chemotherapeutics efficacy also through other mechanisms.

Two series of compounds, 8-methoxy- and p-dimethoxy derivatives of 1-aminoethylhetero-tetralins, I, were evaluated for D-2, 5-HT1 and 5-HT2 receptors affinity. No significant serotoninergic affinity was observed, whereas p-dimethoxy-derivatives 7b e 11b showed a moderate D-2 affinity.

The Authors describe a case of gastric metastases from breast cancer. The staging procedures in breast cancer do not usually include the endoscopic examination of the gastroenteric tract; nevertheless the complaint of persistent gastric disorders in patients affected by metastatic breast cancers must not be underestimated. In this case the finding of gastric neoplastic involvement led to effective treatment of the above mentioned disorders and consequently to an improvement in the patient's quality of life. Moreover, the evaluation of this clinical case shows that chemotherapeutic treatment of this metastatic localisation does not differ from that of metastases in other sites.

The DNA content and S-phase fraction (SPF) of pathological paraffin-embedded lymph node tissue from 47 patients with poor prognosis non-Hodgkin's lymphoma (NHL) were analyzed by flow cytometry (FCM). Fifteen of 42 evaluable cases proved to be aneuploid. The DNA aneuploidy was not correlated with age, histology, stage, presence of systemic symptoms, clinical response or overall survival (OS) of patients. Mean SPF evaluated in 35 cases was 22.9%. After 78 months of follow-up, nine patients with diploid low SPF tumors had a significantly longer disease-free survival (DSF) with respect to the group of patients (33 cases) with aneuploid or diploid high SPF tumors (100% vs 59%; log rank test, p = 0.04).

The authors reports his personal experience in performing intraluminal drainage of the common biliary duct by a two-way "Gastroduodenal-choledochal" tube, specifically realized. The author has been using this biliary drainage technique in some patients and prefers this suction method as an alternative to other in carrying out some biliary surgical procedures.

Replacement of the oxygen atom at 1-position in the hexahydronaphthoxazines (4, PHNO) with a sulfur or nitrogen atom leads to the hexahydronaphthiazines (6, PHNT) and octahydro-benzoquinoxalines (5, POBQ) respectively and the 9-OH-PHNT shows to have a high affinity towards D-2 dopamine receptors in the binding assays; the racemic 9-OH-PHNT was then resolved and its absolute configuration was determined by CD. Inactivity on D-2 receptors of (+)-9-OCH3-PHNT 12 confirms the validity of the McDermed receptor model.

Objective. —To assess prospectively the impact on survival and health-related quality of life of two follow-up protocols in patients with early breast cancer. Design. —Randomized controlled clinical trial. Setting. —Multicenter study involving 26 general hospitals in Italy. Patients. —A consecutive sample of 1320 women younger than 70 years with stage I, II, and III unilateral primary breast cancer. Intervention. —Patients were randomly assigned to an intensive surveillance, which included physician visits and performance of bone scan, liver echography, chest roentgenography, and laboratory tests at predefined intervals (n=655), or to a control regimen (n=665), in which patients were seen by their physicians at the same frequency but only clinically indicated tests were performed. Both groups received a yearly mammogram aimed at detecting contralateral breast cancer. Main Outcome Measures. —Primary end points were overall survival and health-related quality of life. Results. —Compliance to the two follow-up protocols was more than 80%. At a median follow-up of 71 months, no difference was apparent in overall survival with 132 deaths (20%) in the intensive group and 122 deaths (18%) in the control group. No significant differences were apparent in time to detection of recurrence between the two groups. Measurements of health-related quality of life (ie, overall health and quality-of-life perception, emotional well-being, body image, social functioning, symptoms, and satisfaction with care) at 6,12, 24, and 60 months of follow-up did not show differences by type of care received. Conclusions. —Results of this trial support the view that a protocol of frequent laboratory tests and roentgenography after primary treatment for breast cancer does not improve survival or influence health-related quality of life. Routine use of these tests should be discouraged. (JAMA. 1994;271:1587-1592)

Rupture of the pericardium due to closed thoracic trauma is a very rare event which is hard to diagnose. It occurs in the form of two main clinical pictures: 1) severe chest trauma with massive haematoma requiring surgery and which permits diagnosis, and 2) precordial pain and clinical signs of pericardiac origin. Surgery is essential in view of the risk of lethal complications from cardia luxation. Operation consists of closure of the pericardiac lesion.

In order to study the influence on dopaminergic activity of the exchange of X in rigid dopamine congeners of structure 1, the synthesis of octahydrobenzo [f] trans-quinoxalines (VII c, d) and trans-hexahydro-4H-naphtho[1,2-b][1,4]thiazines (X c, d), is reported.

A simple synthetic route that leads to three isosters of octahydrobenzo[g]quinolines (IA), in which the carbon atom in 4-position is replaced by an oxygen, a sulfur or a nitrogen atom, to give hexahydronaphth-[1,4]oxazine (VIII a) and -[1,4]thiazine (VIII b), and octahydrobenzo[g]quinoxaline (VIII c) respectively, is here reported. These compounds can be considered as new structural models of dopamine agonists.

The epoxide (I) is converted to the tetrahydronaphthazirine (IV) which reacts with glycine ethyl ester (V) to give the tricyclic lactam (VI).