The miR-106b-25 cluster mediates breast tumor initiation through activation of NOTCH1 via direct repression of NEDD4L.

Tumor-initiating cells (TIC) represent a subset of tumor cells with increased self-renewal capability. TICs display resistance to frontline cancer treatment and retain the ability to repopulate a tumor after therapy, leading to cancer relapse. NOTCH signaling has been identified as an important driver of the TIC population, yet mechanisms governing regulation of this pathway in cancer remain to be fully elucidated. Here we identify a novel mechanism of NOTCH regulation and TIC induction in breast cancer via the miR-106b-25 miRNA cluster. We show that the miR-106b-25 cluster upregulates NOTCH1 in multiple breast cancer cell lines, representing both estrogen receptor (ER+) and triple negative breast cancer (TNBC) through direct repression of the E3 ubiquitin ligase, NEDD4L. We further show that upregulation of NOTCH1 is necessary for TIC induction downstream of miR-106b-25 in both ER + and TNBC breast cancer cells, and that re-expression of NEDD4L is sufficient to reverse miR106b-25-mediated NOTCH1 upregulation and TIC induction. Importantly, we demonstrate a significant positive correlation between miR-106b-25 and NOTCH1 protein, yet a significant inverse correlation between miR-106b-25 and NEDD4L mRNA in human breast cancer, suggesting a critical role for the miR106b-25/NEDD4L/NOTCH1 axis in the disease. Further, we show for the first time that NEDD4L expression alone is significantly associated with a better relapse-free prognosis for breast cancer patients. These data expand our knowledge of the mechanisms underlying NOTCH activation and TIC induction in breast cancer, and may provide new avenues for the development of therapies targeting this resistant subset of tumor cells.

Structural strength evaluation of driver's protective structures for self-propelled agricultural machines.

The high number of accidents due to rollovers of agricultural machines has increased the interest of researchers and organizations for standardization in this field. In the 1960s, standards to test rollover protective structures (ROPS) for tractors were designed and approved. Similar standards were introduced in the 1990s for earth-moving machinery, but ROPS standards were not defined for self-propelled agricultural machines. In the present work, the driver's protective structures of five different categories of self-propelled agricultural machines were analyzed with the goal of introducing ROPS with a strength level in accordance with the standards used for tractors while maintaining the same shape as the existing structure. The results show a low resistance level of the present structures on the machines selected for the tests. New structures that are able to sustain the loads specified by the tractor standard are not different in design from the existing structures, but an increase of the resistance of the materials or an increase of the thickness of the mountings is necessary.

Evidence of deterministic components in the apparent randomness of GRBs: clues of a chaotic dynamic.

Prompt γ-ray emissions from gamma-ray bursts (GRBs) exhibit a vast range of extremely complex temporal structures with a typical variability time-scale significantly short - as fast as milliseconds. This work aims to investigate the apparent randomness of the GRB time profiles making extensive use of nonlinear techniques combining the advanced spectral method of the Singular Spectrum Analysis (SSA) with the classical tools provided by the Chaos Theory. Despite their morphological complexity, we detect evidence of a non stochastic short-term variability during the overall burst duration - seemingly consistent with a chaotic behavior. The phase space portrait of such variability shows the existence of a well-defined strange attractor underlying the erratic prompt emission structures. This scenario can shed new light on the ultra-relativistic processes believed to take place in GRB explosions and usually associated with the birth of a fast-spinning magnetar or accretion of matter onto a newly formed black hole.

Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate.

Metronomic chemotherapy is an anticancer strategy which uses conventional cytotoxic drugs administered at very low dose in close intervals. We have designed a phase II trial to investigate the safety and antitumor activity of the newest metronomic chemo-hormonal-therapy with daily cyclophosphamide and twice daily megestrol acetate (mCM regimen) in patients with metastatic pretreated breast cancer.Twenty-nine pretreated post-menopausal patients with multiple metastatic sites were enrolled. four patients had a triple negative status, nineteen a positive hormonal ER and PgR status, and three ERB-B2 over-expression. Patients received treatment with cyclophosphamide (50 mg/daily day 1-21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall objective response rate was 31.0%, disease control rate 41.3%, mean time to tumor progression 7.4 months (CI 95%, 3.8-10.88, range 1-48 months) and mean overall survival 13.4 months (CI 95%, 7.24-17.18, range 1-53 months). The mCM regimen was active and well tolerated.

Giant Sigmoid Diverticulum: A Rare Presentation of a Common Pathology.

Although colonic diverticulum is a common disease, affecting about 35% of patients above the age of 60, giant sigmoid diverticulum is an uncommon variant of which only relatively few cases have been described in the literature. We report on our experience with a patient affected by giant sigmoid diverticulum who was treated with diverticulectomy. Resection of the diverticulum is a safe surgical procedure, provided that the colon section close to the lesion presents no sign of flogosis or diverticula; in addition, recurrences are not reported after 6-year follow-up.

Physical-mechanical modifications of eggs for food-processing during storage.

Physical-mechanical properties of egg constituents and their modifications during storage and poststorage greatly influence the efficiency of food processing, such as the separation of white and yolk by mechanical shelling. Thick albumen height, Haugh unit, yolk index and vitelline membrane-yolk system strength of eggs from Hy-Line White and Lohmann Brown hens were analyzed during 7 mo of storage at 0 degrees C performing 3 poststorage treatments: i) immediately after refrigeration, T1; ii) after a further 6 h at 18 degrees C after refrigeration, T2; and iii) after a week at 18 degrees C after refrigeration, T3. For all qualitative parameters considered, this last poststorage treatment appeared to be the factor that produced the highest decrements; with respect to the first poststorage treatment, a further week at 18 degrees C after refrigeration can involve mean decreases of about 19, 14, 14, and 16% in thick albumen height, Haugh unit, yolk index, and vitelline membrane-yolk system strength (in terms of maximum force), respectively. During about 7 mo of storage at 0 degrees C, the latter parameter decreases, on average, by 10%. Increasing the storage time, physical-mechanical behavior was sometimes divergent from the observed trends.

Chemo-hormone therapy of non-well-differentiated endocrine tumours from different anatomic sites with cisplatinum, etoposide and slow release lanreotide formulation.

We report the results of a phase II trial in patients with metastatic endocrine tumours from different sites, which aimed to evaluate the anti-tumour activity and toxicity of a cisplatinum and etoposide regimen administered in combination with the somatostatin agonist lanreotide given in slow release formulation. Between January 1999 and November 2003, 27 patients with histological diagnoses of endocrine tumours with different degrees of differentiation, excluding well differentiated carcinoid neoplasms, received intravenous (i.v.) administration of cisplatinum (30 mg m(-2)) and etoposide (100 mg m(-2)) on days 1-3 and intramuscular administration of 60 mg lanreotide on day 1, in a 21-day cycle. All of the patients were evaluable for toxicity and response. The treatment was very well tolerated as no grade 4 toxicity was observed. Four patients achieved a complete response, six a partial response, 12 experienced disease stabilisation and five disease progression. The average time to progression and to survival were 9 and 24 months respectively. These results suggest that this chemo-hormone therapy regimen is well tolerated and active in patients with non-well differentiated endocrine tumours.

[Withdrawing or discontinuing chronic dialysis in adult patients]. / Non avvio o sospensione del trattamento dialitico cronico nell'adulto: considerazioni cliniche, relazionali, bioetiche e legislative.

Dialysis treatment leads chronic uremic patients to a prolonged survival; incidence and prevalence of dialysis patients are increasing, the population is getting older and many comorbidities coexist, such as diabetes, heart diseases, vasculopathies, neoplasia. The question often arises of whether to start or continue dialysis treatment in compromised patients. Withdrawing and/or discontinuing dialysis represents a therapeutic option with different ratios among countries, due to various cultural, religious, legal and social aspects. Italy shows a low prevalence, but a future increase is likely to appear. The crucial issue is the doctor-patient relationship: thanks to recent legal regulations, the patient has started to play an active role in the therapeutic decision making, by signing or not the informed consent regarding the therapeutic options suggested. In the Piemonte Region we evaluated the behavior of the nephrology operating units, through a consultant- and head nurses team-oriented survey. Most interviewees assert that starting a dialysis treatment is not always mandatory for every patient. The choice of per-forming dialysis should always be based on patient informed consent and in agreement with the physician in charge, the family and the patient himself. It is fundamental to choose to discontinue dialysis consistently with patients' prognosis and their concept of quality of life. It is mostly believed to be a legal and deontological duty to continue dialysis treatment, should any clear patient's will declaration lack.

Gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) in patients with different gastroenteric malignancies.

This phase II clinical trial was performed in order to evaluate the pharmacokinetics, toxicity and anti-tumor activity of a novel combination of gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) designed on a specific translational basis. Every 4 weeks, 44 patients with various gastroenteric malignancies, 29 of whom had pancreas carcinoma, received a short intravenous (i.v.) infusion of FA (100 mg/m2) and 5-FU (400 mg/m2) on days 1-5, and GEM 1000 mg/m2 on days 1, 8 and 16. Our results suggest that, although this treatment leads to hematological and gastroenteric toxicity, it is very active in patients with pancreatic carcinoma. We therefore believe that an improved version would merit further investigation in larger scale trials.

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma.

Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase I-II clinical trial testing the GOLF regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1-3 received 600 mg m(-2); patients # 4-6 received 850 mg m(-2); while patients # 7-29 received 1000 mg m(-2)) on the day 1, levo-folinic acid (100 mg m(-2)) on the days 1 and 2; 5-fluorouracil (400 mg m(-2)) in bolus injection, followed by a 22-h continuous infusion (800 mg m(-2)) on the days 1 and 2, and oxaliplatin (85 mg m(-2)), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade I-II haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease, and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer.

[Steroids, interferon-alpha and ribavirin treatment of cryoglobulinemic glomerulonephritis concurrent with HCV infection]. / Terapia con steroidi, interferone-alpha e ribavirina in corso di glomerulonefrite crioglobulinemica HCV correlata.

The treatment of mixed cryoglobulinemia concurrent with HCV infection is still under debate. We report the case of a patient referred to our unit for a membranoproliferative glomerulonephritis associated with HCV infection. A nephrotic syndrome and a slight reduction of glomerular filtration rate were present. We treated him with alpha-interferon for six months and prednisone for two months. We achieved a remission of the nephrotic syndrome without any significant reduction of the viral load. One year after the therapy had been suspended, the nephrotic syndrome relapsed and subsequently responded to a combined treatment with interferon ribavirin and prednisone. HCV-RNA became suddenly and persistently negative.

Initial experience with laparoscopic adjustable gastric banding and pouch dilatation: two cases.

BACKGROUND: Late proximal pouch dilatation (LPPD) has occurred occasionally following gastric banding for morbid obesity. At present, laparoscopic conservative resetting and oversuturing of the band is considered the standard procedure for pouch dilatation without any important posterior component. METHODS: Two cases of LPPD are presented, which occurred in our initial experience with the Lap-Band, corrected via a laparoscopic approach. RESULTS: The reintervention was necessary in both patients, with conservative laparoscopic repositioning and oversuturing of the band in the first case and laparoscopic substitution of the gastric band in the second. We have not observed further complications, and weight loss has been maintained in a midterm outcome in both cases (30 and 18 months follow-up). CONCLUSIONS: LPPD can be corrected with a conservative laparoscopic surgical approach, without complications and negative functional effects on mid-term outcome.

Prediction of lymph node status by analysis of prognostic factors and possible indications for elective axillary dissection in T1 breast cancers.

OBJECTIVE: To identify those patients with T1 breast cancers with lower risk of nodal metastases who can safely be spared axillary dissection. DESIGN: Retrospective study. SETTING: University hospital, Italy. SUBJECTS: Review of clinical records and histopathological slides of 547 patients with T1 breast cancer, operated on between 1984 and 1997. MAIN OUTCOME MEASURES: Incidence of axillary metastases in relation to age, menopausal status, diameter and grade of tumour, vascular invasion, DNA ploidy, S-phase fraction and hormone receptor state, by univariate and multivariate analysis. RESULTS: Axillary metastases were present in 159 patients (29%). On univariate analysis, diameter of tumour 10 mm or less (pT1a/pT1b cancers), no vascular invasion, and grade 1 tumour were significantly correlated with a lower risk of nodal metastases, but only vascular invasion (p = 0.0001, odds ratio = 3.1) and diameter of tumour (p = 0.04, odds ratio = 1.6) were independent predictors on multivariate analysis. Among 34 pT1a/pT1b cancers, with low grade of tumour and no vascular invasion, only 2 (6%) had axillary metastases. When only one favourable predictive factor was associated with diameter of tumour of 10 mm or less, the incidence of axillary metastases ranged from 12% for 43 patients with grade 1 cancers to 13% for 76 patients with no vascular invasion. CONCLUSIONS: Axillary dissection may be avoided in pT1a and pT1b breast cancers (< or = 10 mm), with low grade of tumour or no vascular invasion. T1 breast cancers 10 mm or less in diameter should be treated by a two-step approach, first wide excision of the tumour and then axillary dissection or not depending on pathological examination of the primary tumour.

Decay of the GRB 990123 optical afterglow: implications for the fireball model

Broad-band (ultraviolet to near-infrared) observations of the intense gamma ray burst GRB 990123 started approximately 8.5 hours after the event and continued until 18 February 1999. When combined with other data, in particular from the Robotic Telescope and Transient Source Experiment (ROTSE) and the Hubble Space Telescope (HST), evidence emerges for a smoothly declining light curve, suggesting some color dependence that could be related to a cooling break passing the ultraviolet-optical band at about 1 day after the high-energy event. The steeper decline rate seen after 1.5 to 2 days may be evidence for a collimated jet pointing toward the observer.

The Millimeter-Wave Spectrum of DCCNC

The millimeter-wave spectrum of deuteroethynylisocyanide has been observed and analyzed in the ground and in the first excited vibrational states (v4, v5, v6, v7) = (0100), (0010), and (0001). Rotational, centrifugal distortion, and l-type doubling constants are given. Copyright 1998 Academic Press.

Photometry and spectroscopy of the GRB 970508 optical counterpart

An optical transient within the error box of the gamma ray burst GRB 970508 was imaged 4 hours after the event. It displayed a strong ultraviolet excess, and reached maximum brightness 2 days later. The optical spectra did not show any emission lines, and no variations on time scales of minutes were observed for 1 hour during the decline phase. According to the fireball and afterglow models, the intensity should rise monotonically before the observed optical maximum, but the data indicate that another physical mechanism may be responsible for the constant phase seen during the first hours after the burst.

Synthesis and antimicrobial activity of N, N-dialkyl-2-substituted-5-diazo-imidazole-4-carboxamides.

A series of 2-substituted-5-diazoimidazole-4-carboxamides has been synthesized, and their antimicrobial activity has been tested in vitro. Some of the compounds show antifungal activity related to the presence of small groups on the 4-carbox-amido moiety, while the presence of substituents in position 2 was detrimental.

[Original procedure of functional plasty of primary inguinal hernias]. / Procédé original de plastie "fonctionnelle" des hernies inguinales primaires.

We describe a novel autoplasty method we developed for primary inguinal hernia repair and report our results in nearly 150 operations. The method is based on novel principles: priority given to an individual stato-dynamic conception of the inguinal region; effect on physiological defense mechanisms of the inguinal canal; absence of tension on the sutures by autoplastic repair.

[A case of pancreatic somatostatinoma]. / Considerazioni su un caso di somatostatinoma a localizzazione pancreatica.

The authors describe a case of somatostatinoma localized in the body and tail of the pancreas. They emphasize the rarity of this finding (only 33 cases with certain pancreatic localization are reported in literature) and the absence of a distinctive syndrome, which could direct to an early diagnosis, the authors are in doubt about the real incidence of this disease. The absence, generally, of a distinctive syndrome, the poor condition of these patient and then the lack of surgical treatment and histological examination, could lead to a lower valuation. Delayed diagnosis and then the local extension of this neoplasm often make surgical treatment vain. Nevertheless since somatostatinoma has more possibilities of radical resection than pancreatic cancer, it's required to know its features and course so to increase possibilities of an early diagnosis. In fact disregarding surgical treatment, the survival of these patients, one year after diagnosis, is about 48%. This result is better than the survival of patients with pancreatic or biliary duct cancers. Current diagnostic procedures are reported.