PARP inhibition: A promising therapeutic target in ovarian cancer.

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane -based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer.

A focus on heme oxygenase-1 (HO-1) inhibitors.

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe⁺⁺), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.

Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase.

OBJECTIVE: To examine the long-term effects of treatment with recombinant human CuZn superoxide dismutase (rhSOD) in infants enrolled previously in two placebo-controlled trials. STUDY DESIGN: Records for 46 (88%) infants were examined, with 19 infants having received either single or multiple intratracheal (i.t.) doses of placebo, 12 having received a single i.t. dose of rhSOD, and 15 having received multiple i.t. doses of rhSOD. Mean age at follow-up was 28 months corrected age. Records were examined for neurologic dysfunction, developmental delay, and any significant medical disorders. RESULTS: Four placebo infants (21%) had evidence of neurodevelopmental abnormalities and four infants developed asthma. Four single-dose rhSOD infants (33%) had neurodevelopmental abnormalities and two infants developed asthma. One multiple-dose rhSOD infant had evidence of neurodevelopmental abnormalities and one developed asthma. No other differences were found between the placebo and rhSOD groups. CONCLUSION: Preliminary data suggest that rhSOD is safe and not associated with any long-term adverse effects. Further results will depend on the results of multicenter trials of rhSOD in preterm infants.

Early assessment of coronary reserve after bypass surgery by dipyridamole transesophageal echocardiographic stress test.

The evaluation of coronary reserve within a few hours of aortocoronary bypass surgery could be of extreme utility for the follow-up or therapeutical management of these patients. In 11 men patients who underwent aortocoronary bypass surgery, a dipyridamole echocardiography stress test was carried out before (1 to 3 days), early after (68 to 130 minutes), and 1 week after surgery. The first and third tests were performed using a standard transthoracic approach, while the second was performed by a transesophageal approach. Dipyridamole was administered intravenously at a dose of 0.56 mg/kg body weight (low dose) and eventually adding 0.28 mg/kg body weight (high dose), always in the absence of antiischemic therapy. An arbitrary wall motion score (0 = eukinesia; 1 = hypokinesia; 2 = akinesia; 3 = dyskinesia) was assigned to the seven different myocardial regions in which the left ventricle was divided in order to have a semiquantitative score. Under basal conditions wall motion score per patient in the three series of tests did not change significantly (1.6, 1.4, and 1.5, respectively), while the mean score during dipyridamole administration showed significant differences (3.6, 1.9, and 1.9, respectively), indicative of the results obtained by surgical repair. The test, positive in all patients before surgery, showed wall motion abnormalities and ischemic ECG changes in two patients immediately after surgery by the transesophageal approach. One patient who had a normal basal contraction pattern and an abnormal response after the test developed in the following days a perioperative myocardial infarction, while a second patient in the follow-up period developed low-level effort angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of malignant hypertension with an angiotensin converting enzyme inhibitor.

Malignant hypertension developed in an 18-year-old man whose primary hypertension had been diagnosed by chance. Standing blood pressure was 290/170 mmHg. Tests of renal function revealed high blood urea nitrogen and creatinine levels and low levels of both effective renal plasma flow and the glomerular filtration rate. Plasma renin activity and levels of angiotensin II and aldosterone were greatly elevated. Severe concentric left ventricular hypertrophy was noted. The patient received standard antihypertensive treatment with furosemide, propranolol, nifedipine, and prazosin, but his blood pressure did not decrease and there was no improvement in the clinical or biochemical measures. The patient was then given 20 mg of enalapril daily for one year. The inhibition of angiotensin converting enzyme immediately reduced blood pressure. Angiotensin II and aldosterone levels became normal, kidney function and hemodynamics improved, and echocardiograms revealed that the left ventricular hypertrophy had regressed. The results confirm the pathogenetic role of angiotensin II in the development of the malignant phase of hypertension.

[Liposarcoma of the spermatic cord (presentation of a case)]. / Liposarcoma del funicolo spermatico (presentazione di un caso).

Liposarcoma of the spermatic cord is a rare tumour, usually well differentiated, that generally resembles a lipoma and undergoes a slow, progressive enlargement. Most patients with liposarcoma do not experience any recurrence after local excision. Due to the rare occurrence of this tumour it seems appropriate to document one case that came to our observation in recent years.

[Cutaneous leiomyosarcoma (description of a case)]. / Leiomiosarcoma cutaneo (descrizione di un caso).

Cutaneous leiomyosarcoma is a rare tumour arising in dermis or subcutaneous tissue. Diagnosis is usually made by microscopic examination on the basis of marked cellular atypia and mitoses. We report one case of leiomyosarcoma of the gluteus with precocious lung metastases in a 65-year-old female.

[Physiopathological importance of renal ptosis evaluated by renography and photoscintigraphy]. / Importanza fisiopatologica della ptosi renale valutata a mezzo dell'indagine renografica e fotoscintigrafica.

After looking at the possible physiopathological role of renal ptosis in the pathogenesis of arterial hypertension and urinary inflammation, the results of an epidemiological study carried out on about 600 reno-scintigraphic investigations are reported. The study demonstrated the high frequency of the condition in males and its frequent association with monolateral changes in the renographic curve. The second part of the paper assesses the reversibility of renal ptosis and the renographic change in 13 patients in passing from the sitting to Trendelenburg's position. The results show that the change in flow, which may be the cause of the renographic change in the ptosic kidney, is reversible in many patients as it disappears or reduces as the kidney position is corrected. In other patients in whom this does not occur, it can be presumed that the reduction in flow has an organic genesis, namely fibromuscular dysplasia of the renal artery which, as the literature shows, may be looked on as a complication of ptosis.

[The value of electrophoretic studies of urinary proteins in clinical practice]. / Importanza dello studio elettroforetico delle proteine urinarie nella pratica clinica.

A brief account of the physiopathology of proteinuria is followed by a description of the diagnostic routine to be followed in such cases, with particular reference to the electrophoretic study of urinary proteins. In many cases, this simple method gives information on a par with that offered by biopsy, especially insofar as the planning of treatment is concerned. Several clinical cases are cited by way of illustration.