Small molecules targeted to the microtubule-Hec1 interaction inhibit cancer cell growth through microtubule stabilization.

Highly expressed in cancer protein 1 (Hec1) is a subunit of the kinetochore (KT)-associated Ndc80 complex, which ensures proper segregation of sister chromatids at mitosis by mediating the interaction between KTs and microtubules (MTs). HEC1 mRNA and protein are highly expressed in many malignancies as part of a signature of chromosome instability. These properties render Hec1 a promising molecular target for developing therapeutic drugs that exert their anticancer activities by producing massive chromosome aneuploidy. A virtual screening study aimed at identifying small molecules able to bind at the Hec1-MT interaction domain identified one positive hit compound and two analogs of the hit with high cytotoxic, pro-apoptotic and anti-mitotic activities. The most cytotoxic analog (SM15) was shown to produce chromosome segregation defects in cancer cells by inhibiting the correction of erroneous KT-MT interactions. Live cell imaging of treated cells demonstrated that mitotic arrest and segregation abnormalities lead to cell death through mitotic catastrophe and that cell death occurred also from interphase. Importantly, SM15 was shown to be more effective in inducing apoptotic cell death in cancer cells as compared to normal ones and effectively reduced tumor growth in a mouse xenograft model. Mechanistically, cold-induced MT depolymerization experiments demonstrated a hyper-stabilization of both mitotic and interphase MTs. Molecular dynamics simulations corroborate this finding by showing that SM15 can bind the MT surface independently from Hec1 and acts as a stabilizer of both MTs and KT-MT interactions. Overall, our studies represent a clear proof of principle that MT-Hec1-interacting compounds may represent novel powerful anticancer agents.

Biomechanical evaluation of scapular girdle in patients with chronic arm lymphedema.

The presence of arm lymphedema can induce alterations in motor functions and posture. Using an optoelectronic system (ELITE 2002), we evaluated these alterations during a set of tests involving walking, resting and fatigue. The results of our biomechanical analysis demonstrated a limited range of motion of the affected arm, particularly a reduction in swinging during walking tests, and in shoulder retroposition and abduction movements for all patients. After repeated cyclical movements, premature fatigue appeared in the pathological arm. Lymphedema does not appear to cause alterations to the posture of the spine in our study, but drooping of the shoulder homolateral to the lymphedema can occur. This kind of investigation, which is quick, easy, and comfortable for patients with lymphedema, can be a useful method to evaluate functional capacity, thus allowing a quantitative assessment of the loss of function and the optimizing of the rehabilitative protocol.

On-line sample preparation for high throughput reversed-phase LC/MS analysis of combinatorial chemistry libraries.

An on-line sample preparation method utilizing a time-programmed autosampler is described for high throughput liquid chromatography/mass spectrometry (LC/MS). This approach is particularly helpful for the LC/MS analysis of samples which require solvents incompatible with HPLC in the sample preparation process. The on-line sample preparation approach minimizes a bottleneck in throughput and improves sample recovery under some circumstances.

Structure-based design of six novel classes of nonpeptide antagonists of the bradykinin B2 receptor.

Six classes of nonpeptide bradykinin antagonists were designed using a template derived from structural studies of peptide antagonists. Several compounds from each class were synthesized and assayed for binding to the human bradykinin B2 receptor. Each family showed compounds active at the level of the smallest template peptide; three classes contained compounds with Kd < 8 microM. These results provide diverse leads for a medicinal chemistry-based optimization program.

Solitary plasmacytoma: a case report.

We report a case of solitary vertebral plasmacytoma that was peculiar in mode of onset and neurological course. The clinical and radiological evidence pointed to a generic diagnosis of epidural osteolytic process while electroimmunophoresis of blood narrowed the diagnosis to spinal plasmacytoma, confirmed at operation.

Growth factor (M-CSF) and antigenic properties of macrophages in meningioma.

In meningiomas, transformed meningeal cells can share morphological aspects (in hemangiopericytic meningioma) and antigenic properties (i.e.: HLA-DR antigens expression) with elements of the monocyte/macrophage lineage. In this report, we describe a case of a highly vascular meningioma where numerous tumor cells, studied with immunohistochemical methods, present phenotypic properties of macrophages. Moreover, the cerebrospinal fluid (CF) analysis disclosed, using a biological assay, a high level of a growth factor for monocytic elements, the Macrophages Colony Stimulating Factor (M-CSF). Our findings may confirm that transitional aspects between different mesenchymal cells could be present in meningiomas.

[Analgesic effect of Sandostatin (SMS 201-995) in acromegaly headache]. / Effetto analgesico della sandostatina (SMS 201-995) sulla cefalea dell'acromegalico.

Somatostatin analogue (Sandostatin; SMS 201-995) is utilized as a therapy in acromegaly because of its efficiency in inhibiting GH secretion; it induces some clinical improvements, such as headache remission in acromegalic patient, which seem to be unrelated to Gh normalization. We have examined 8 acromegalic patients, suffering from headache, after injection of saline solution and subsequently of SMS 201-995 (100 y), in order to study the mechanism of analgesic effect induced by Sandostatin administration. Headache, by autovaluation test, heart rate frequency, PAO, sistolic and diastolic blood velocity in medial cerebral artery, by utilizing Transcranial Doppler Sonography (SDSV), have been measured before and after saline and after SMS 201-995. GH and beta-endorphin have been also assayed in plasma samples. All patients have shown a rapid and complete improvement in headache after Sandostatin administration. At the same time we have observed an increase in SDSV and a parallel slight increase in PAO values, more evident in the diastolic phase. Plasma beta-endorphin assay has shown rather conflicting results after SMS 201-995 administration. Our results confirm an important and rapid analgesis effect of Sandostatin on acromegaly headache unrelated to GH normalization. The cerebral emodinamic changes suggest their involvement in Sandostatin induced analgesia.

Pineal germinoma: diagnosis, treatment and tumor response.

We report the case of pineal germinoma in a 25 year old man. The neurological signs and symptoms were insidious in onset; Parinaud syndrome allowed a topical diagnosis, confirmed by CT scan. Computerized Tomography and CSF cytological examination were of the utmost importance to diagnosis and treatment and it confirmed the success of radiotherapy.

Therapeutic effect of lisuride in advanced Parkinson's disease.

The therapeutic effects of lisuride hydrogen maleate, a central dopamine agonist, were examined in 15 patients with advanced Parkinson's disease no longer satisfactorily responding to levodopa. A significant improvement (p less than 0.01) in the total Parkinson's disease disability score was obtained by the addition of lisuride to levodopa therapy. The clinical assessment in the follow-up was performed with 2 different disability scales that yielded a more precise evaluation of the efficacy of lisuride, an efficacy that, as with other dopaminergic drugs, showed a slight decrease in time after a mean of 3 months. No important adverse effects were noticed. The only limitation of the use of lisuride was the occurrence of reversible psychic disturbances. It is concluded from this study that lisuride is a valuable tool in the management of advanced Parkinson's disease that allows for a reduction of the side effects of levodopa therapy in the long-term treatment of the disease.

Effect of lymphocytapheresis plus cyclophosphamide on the course of a chronic progressive form of multiple sclerosis.

We report a case of a 16 year old boy with a chronic progressive form of Multiple Sclerosis treated with lymphocytapheresis and a low dose regimen of cyclophosphamide. A progressive improvement in the disability index and slowing of the clinical course were obtained. No side effects were observed. Depletion of lymphocytes and their pharmacological suppression point to their possible role in the induction of an immunoregulation of the disease process.

[Neoplasms of the brain stem: clinico-pathologic correlations]. / Neoplasie del tronco encefalico: correlazioni clinico-patologiche.

We report here the clinico-pathological data about 4 patients with brainstem tumors. Clinical symptoms were variable but allowed a correct topical diagnosis. On the other hand, all the neuroradiological examinations, especially CT scan of the brain, resulted always negative or without diagnostic value. Good results for the diagnosis were given by pneumoencephalography and ventriculography. The neuropathological examination revealed one spongioblastoma, two malignant astrocytomas and one pontine metastasis of carcinoma of esophagus. Diagnostic troubles, even with modern and sophisticated techniques are stressed here. The clinician should not overweight negative results obtained with these techniques and every time include in the differential diagnosis brainstem tumors.

Wernicke-Korsakoff syndrome after subtotal gastrectomy.

A case of Wernicke-Korsakoff syndrome is a nonalcoholic patient after gastric surgery provides support for the theory that nutritional deficiencies play an important part in the pathogenesis of the disease.

Alzheimer's disease and senile brains: an immunofluorescence study.

The results obtained with direct immunofluorescence techniques on normal, senile and Alzheimer's disease brains are reported. The antisera used were directed against C3c, IgG (gamma chain), IgG Fc., kappa and lambda light chains and anti-Ig (total). The brain samples were prepared in different ways: formalin-fixed and paraffin embedded; fresh frozen samples and alcohol fixed, paraffin-embedded samples. The images obtained with the different processing methods did not coincide. In order to obtain a more complete picture, we suggest the use of different methods on the same samples. In Alzheimer's disease brains, abundant but probably not monoclonal Ig antigenic determinants were found. Ig were found diffusely in the tissue, connected to amyloid (both in senile plaques and blood vessel walls), in glial cells and neurons. The significance of such data in relation to the genesis of brain amyloid are discussed.