Development of ISB 1442, a CD38 and CD47 bispecific biparatopic antibody innate cell modulator for the treatment of multiple myeloma.

Antibody engineering can tailor the design and activities of therapeutic antibodies for better efficiency or other advantageous clinical properties. Here we report the development of ISB 1442, a fully human bispecific antibody designed to re-establish synthetic immunity in CD38+ hematological malignancies. ISB 1442 consists of two anti-CD38 arms targeting two distinct epitopes that preferentially drive binding to tumor cells and enable avidity-induced blocking of proximal CD47 receptors on the same cell while preventing on-target off-tumor binding on healthy cells. The Fc portion of ISB 1442 is engineered to enhance complement dependent cytotoxicity, antibody dependent cell cytotoxicity and antibody dependent cell phagocytosis. ISB 1442 thus represents a CD47-BsAb combining biparatopic targeting of a tumor associated antigen with engineered enhancement of antibody effector function to overcome potential resistance mechanisms that hamper treatment of myeloma with monospecific anti-CD38 antibodies. ISB 1442 is currently in a Phase I clinical trial in relapsed refractory multiple myeloma.

Instrumental assessment of dynamic postural stability in patients with unilateral vestibular hypofunction during straight, curved, and blindfolded gait.

PURPOSE: To characterise dynamic postural stability of gait in patients with vestibular hypofunction (PwVH) using a sensor-based assessment while performing dynamic tasks and to correlate the results of this evaluation with clinical scales. METHODS: This cross-sectional study involved 22 adults between 18 and 70 years old from a healthcare hospital centre. Eleven patients suffering from chronic vestibular hypofunction (PwVH) and eleven healthy controls (HC) were evaluated through a combined inertial sensor-based and clinical scale assessment. Participants were equipped with five synchronised inertial measurement units (IMUs) (128 Hz, Opal, APDM, Portland, OR, USA): three IMUs were located on the occipital cranium bone, near the lambdoid suture of the head, at the centre of the sternum, and at L4/L5 level, just above the pelvis, and were used to quantify gait quality parameters, while the other two were located slightly above lateral malleoli and used to perform stride and step segmentation. Three different motor tasks were performed in a randomized order: the 10-m Walk Test (10mWT), the Figure of Eight Walk Test (Fo8WT) and the Fukuda Stepping Test (FST). A set of gait quality parameters related to stability, symmetry and smoothness of gait were extracted from IMU data and correlated with the clinical scale scores. PwVH and HC results were compared to test for significant between-group differences. RESULTS: Significant differences were found for the three motor tasks (10mWT, Fo8WT and FST) when comparing PwVH and HC groups. For the 10mWT and the Fo8WT, significant differences between the PwVH and HC groups were found for the stability indexes. Considering the FST, significant differences between the PwVH and HC groups were also found in the stability and symmetry of gait. A significant correlation was found between the Dizziness Handicap Inventory and gait indices during the Fo8WT. CONCLUSIONS: In this study, we characterized the dynamic postural stability alterations during linear, curved, and blindfolded walking/stepping in PwVH combining an instrumental IMU-based with traditional clinical scales approach. Combining instrumental and clinical evaluation for dynamic stability of gait alterations in PwVH is useful in thoroughly evaluating the effects of unilateral vestibular hypofunction.

Clinical comparison of a xenogeneic collagen matrix versus subepithelial autogenous connective tissue graft for augmentation of soft tissue around implants.

Dental implant placement is a predictable therapy for replacing teeth. Nevertheless, mechanical, biological, and aesthetic complications frequently occur. The aim of this study was to compare the clinical outcomes of a xenogeneic collagen matrix (XCM) used at the time of implant placement as an alternative to a subepithelial connective tissue graft (SCTG), for soft tissue augmentation. This was a prospective clinical trial with 12 months of follow-up. In the control group, soft tissue augmentation at the time of implant placement was performed with a SCTG, while in the test group, a XCM was employed. At 12 months postoperative, all xenografts showed no postoperative complications. In both groups, a significantly greater thickness was observed on the buccal and occlusal sides from preoperative to 3 months postoperative (P<0.05). No statistically significant difference in pink aesthetic score (P=0.379, 6 months postoperative) or marginal bone loss (P=0.449 at 3 months postoperative, P=0.778 at 6 months postoperative) was observed between the groups. Statistically significant differences in pain perceived by the patients (P<0.0001) and the time to complete the surgical procedure (P=0.0008) were detected. At 12 months after surgery, XCM provided similar clinical results in terms of soft tissue augmentation on the buccal and occlusal sides as compared with the SCTG.

Malignant ventricular arrhythmias induction by programmed electrical stimulation of the right ventricular outflow tract only during type 1 Brugada ECG maximization.

OBJECTIVE: The role of electrophysiology study in Brugada syndrome (BS) sudden cardiac death risk stratification remains controversial and seems to depend on the phenotypic expression of the channelopathy. Ajmaline has a key role in the diagnosis of BS. We observed that programmed electrical stimulation (PES) of the right ventricular outflow tract (RVOT), only when type 1 BS ECG is unmasked by ajmaline administration, induces ventricular arrhythmias. CASE REPORT: We describe a case of ventricular fibrillation induction by PES of the RVOT when type 1 BS ECG is revealed by ajmaline, in a patient with a baseline dynamic intermittent type 1 and 2 BS ECG. CONCLUSIONS: The heterogeneous clinical presentations of BS are due to the underlying mechanisms. PES of the RVOT during positive ajmaline test maximizes the channelopathy and therefore sudden cardiac death risk-stratification in BS.

Inhaled ammonium persulphate inhibits non-adrenergic, non-cholinergic relaxations in the guinea pig isolated trachea.

BACKGROUND: Persulphates can act both as irritants and sensitizers in inducing occupational asthma. A dysfunction of nervous control regulating the airway tone has been hypothesized as a mechanism underlying bronchoconstriction in asthma. OBJECTIVES: It was the aim of this study to investigate whether inhaled ammonium persulphate affects the non-adrenergic, non-cholinergic (NANC) inhibitory innervation, the cholinergic nerve-mediated contraction or the muscular response to the spasmogens, carbachol or histamine, in the guinea pig epithelium-free, isolated trachea. METHODS: Male guinea pigs inhaled aerosols containing ammonium persulphate (10 mg/m(3) for 30 min for 5 days during 3 weeks). Control animals inhaled saline aerosol. NANC relaxations to electrical field stimulation at 3 Hz were evaluated in whole tracheal segments as intraluminal pressure changes. Drugs inactivating peptide transmission, nitric oxide synthase, carbon monoxide production by haem oxygenase-2 and soluble guanylyl cyclase were used to assess the involvement of various inhibitory neurotransmitters. Carbachol and histamine cumulative concentration-response curves were obtained. RESULTS: In both groups, nitric oxide and carbon monoxide participated to the same extent as inhibitory neurotransmitters. In exposed animals, the tracheal NANC relaxations were reduced to 45.9 +/- 12.1% (p < 0.01). The cholinergic nerve-mediated contractions to electrical field stimulation and the muscular response to histamine were not modified by ammonium persulphate exposure. The muscular response to carbachol was unaffected up to 1 microM. Conversely, the response to the maximal concentration of carbachol (3 microM) was increased (p < 0.01). CONCLUSION: Ammonium persulphate inhalation at high concentrations impairs the nervous NANC inhibitory control in the guinea pig airways. This may represent a novel mechanism contributing to persulphate-induced asthma.

Is rasburicase an effective alternative to allopurinol for management of hyperuricemia in renal failure patients? A double blind-randomized study.

Recent epidemiological studies provide a clear evidence that hyperuricemia is associated with hypertension, coronary heart disease, left ventricular hypertrophy and progression of renal disease. Aim of our study was to assess the effect of low dosage of recombinant urate oxidase on hyperuricemia in renal failure patients that already receiving allopurinol. Our study group consisted of 43 renal failure patients, 23 women and 20 men. The mean age was 74 years (range 36-90 years). The following variables were studied on admission: serum creatinine, blood urea nitrogen and serum uric acid. Intravenous rasburicase was administered at a dose of 0.02 mg/kg/day on 3 consecutive days in patients with serum uric acid between 8-10 mg/dl, on 5 consecutive days in patients with serum uric acid between 10-15 mg/dl and on 7 consecutive days in patients with serum uric acid > 15 mg/dl. Uric acid levels were assayed after 48 hours and 7 days after rasburicase treatment. Mean values of uric acid levels after 48 hours were 2.47 mg/dl (+/- 1.58) in men and 2.77 mg/dl (+/- 2.24) in woman, where'as mean values of uric acid levels after 7 days were 4.45 mg/dl (+/- 2.0) in men and 5.75 mg/dl (+/- 1.9) in woman. No significant relationship were found between uric acid and creatinine as before as well after therapy. There were no side effects in all patients included in the study. After 7 days, the rasburicase therapy showed more antihyperuricemic effect in men (59%) than in women (46%).

[Hyperhomocysteinemia and alternate vitamin supplementation]. / Iperomocisteinemia nei pazienti uremici: effetti della supplementazione alternata di acido folico e vitamina B 12.

BACKGROUND: Treatment with folic acid and vitamin B 12 appears to be effective in lowering total plasma Homocysteine (tHcy) concentration, but whether vitamin B 12 alone decreases tHcy in patients with normal vitamin B 12 status is still unknown. The aims of the present study were to explore the effect of alternate vitamin supplementation with folic acid or vitamin B 12 on tHcy concentrations in haemodialysis (HD) patients, and to compare changes in tHcy concentrations with MTHFR genotype. METHODS: 74 patients, 44 men and 30 women, were recruited and randomized blindly into two groups of 37 subjects each. The first group was initially treated with vitamin B 12 for two months, and with folic acid for the following two months; the second group was supplemented in the reverse order. In both groups the treatment was followed by a 2-month washout period. tHcy levels were measured at the beginning of treatment (T0), after two months (T1), four months (T2), and at the end of the washout period (T3). Vitamin B 12 and folate were taken at T0 and T3. RESULTS: The genotype frequency was: C/C 37%, C/T 34%, T/T 29%. tHcy decreased in both groups following the alternate vitamins therapy. This decrease was greater for the T/T genotype (p<0.05) and was more significant when the treatment start-ed with folic acid (p<0.01). Moreover, after the washout period, tHcy increased remarkably without significant differences between diffusive and convective techniques. Folate levels at the end of study appeared to be reduced in haemodialysis patients. Vitamin B 12 concentration significantly increased in patients on diffusive haemodialysis, confirming the fundamental role of membrane performance. CONCLUSION: The alternate vitamin treatment demonstrated the importance of folate therapy and the secondary contribution of vitamin B 12 in lowering tHcy in HD patients.

Postpartum thyroiditis is associated with fluctuations in transforming growth factor-beta1 serum levels.

Postpartum thyroiditis (PPT) is characterized by a rapid evolution and recovery of euthyroidism. Therefore, it can represent a good model to study early cytokine fluctuations in autoimmune thyroid diseases. TGFbeta1 is an immunosuppressive cytokine, as it inhibits T and B cell proliferation, natural killer cell cytotoxic activity, and the generation of T cell cytotoxicity. The aim of this study was to assess serum concentrations of TGFbeta1 during pregnancy and to study possible serum fluctuations of this cytokine during the different phases of PPT. Thyroid biochemical pattern, antithyroid autoantibodies (ATA), and total and active TGFbeta1 (aTGFbeta1) serum concentrations were evaluated in 63 pregnant women. Thirty-four of them were ATA(+), and 29 were ATA(-). Twenty of the 34 ATA(+) women were followed in the postpartum year. Nine of these 20 women developed PPT; 11 remained euthyroid. All of the PPT women became euthyroid during the follow-up. Our results showed 1) detectable serum levels of aTGFbeta1 in 50% of ATA(+) pregnant women, suggesting that the presence of autoantibodies may characterize a favorable condition for TGFbeta1 activation; and 2) decreased total TGFbeta1 and increased aTGFbeta1 serum levels during the active phase of PPT in ATA(+) women. This seems to suggest that inflammation may be responsible for TGFbeta1 activation and autoantibody increase because of antigen release. Although further studies of women with persistent hypothyroidism after the postpartum year are needed, the possibility that the enhanced activation of TGFbeta1 may contribute to resolution of thyroid inflammation postpartum cannot be excluded.

[Effects of the combined deficiency of selenium and iodine on thyroid function]. / Effetti della deficienza combinata di selenio e iodio sulla funzionalità tiroidea.

Recent studies reported the role of several trace elements in health and disease. The role of iodine deficiency in thyroid dysfunction is well known. Also the selenium deficiency has been reported to be correlated to thyroid dysfunctions. In fact, although the major role of selenium is related to the glutathione peroxidase system, which protects cellular structures from oxidative damages, selenium plays also an important role in thyroid hormone metabolism as an essential component of the three deiodinase. These regulate inter-conversion of active and inactive forms of iodothyronines. Several studies have been carried out to establish the role of combined selenium and iodine deficiency. This review aims to provide information on the relationship between selenium and iodine intake and thyroid function. Furthermore, the state of art on the effects of the combined deficiency of selenium and iodine is also provided.

[Adrenal metastasis of choroidal melanoma: a case report]. / Metastasi surrenalica da melanoma della coroide: descrizione di un caso clinico.

We report on the case of a 32 years old man submitted to right eye enucleation twelve years before for a choroidal melanoma. We observe a metastases located in the left adrenal gland. The blood-tests, the TAC of the abdomen did not show other localizations, while during laparotomy were discovered metastases in the pancreas and in the omentum. In this case, the age of tumor's development, the age of clinical manifestation, the period between the enucleation and the appearance of the metastases and their localization are exceptions to the normal biological behaviour of the choroidal melanoma.

Neuropathy secondary to vitamin E deficiency in acquired intestinal malabsorption.

A patient with acquired intestinal malabsorption developed a motor-sensory polyneuropathy with a recurrent remittent course, normal CSF and reduced motor and sensory conduction velocities. Nerve biopsy showed axonal changes. Serum DL-alpha-tocopherol was abnormally low. Six months supplementation with vitamin E was followed by normalization of DL-alpha-tocopherol serum levels and clinical and electrophysiological improvement.