Zoledronic acid boosts γδ T-cell activity in children receiving αß+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor.

We demonstrated that γδ T cells of patients given HLA-haploidentical HSCT after removal of αß+ T cells and CD19+ B cells are endowed with the capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance γδ T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. γδ T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of Vδ2-cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in Vδ2 cells, but not in Vδ1 lymphocytes in those patients given more than one treatment. Proteomic analysis of γδ T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, p = 0.008). Our data indicate that ZOL infusion in pediatric recipients of αß T- and B-cell-depleted HLA-haploidentical HSCT promotes γδ T-cell differentiation and cytotoxicity and may influence the outcome of patients.

Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo.

Interleukin (IL)-23 and IL-27 are pro-inflammatory cytokines that share functional and structural similarities and may exert anti-tumor activities against solid and hematological malignancies. Here, we asked whether IL-23 and IL-27, alone or in combination, may act directly against human follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) cells. In this study, we demonstrated for the first time that human primary FL and DLBCL cells expressed complete and functional IL-23 and IL-27 receptors (R) and that IL-23 and IL-27 exerted anti-tumor activities in vitro and in vivo through different and complementary mechanisms. In vivo studies using severe combined immunodeficiency /non-obese diabetic mice-injected subcutaneously with human SU-DHL-4 cell line revealed that IL-23 inhibited directly tumor-cell proliferation, whereas IL-27 impaired the angiogenic program of lymphoma cells resulting in strong reduction of cell growth. In addition, combined treatment of IL-23 and IL-27 amplified the anti-tumor effects in vivo as compared with administration of each cytokine alone. These anti-tumor mechanisms were confirmed by in vitro experiments performed with primary lymphoma cells and cell lines. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of the IL-23 and IL-27 in lymphoma patients.

Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model.

B-acute lymphoblastic leukemia (B-ALL) represents the most common pediatric hematological tumor that derives from the aberrant proliferation of early B lymphocytes in the bone marrow. Although most of the B-ALL children take advantage from current therapeutic protocols, some patients relapse and need alternative therapies. With this background, we investigated whether interleukin (IL)-27, an immunomodulatory cytokine with antitumor properties, may function as an antitumor agent against pediatric B-ALL cells. Here we show for the first time that pediatric B-ALL cells functional IL-27R and that IL-27 dampens directly tumor growth in vivo and in vitro through mechanisms elucidated in this study. The novelty of these results deals with the first demonstration that (1) B-ALL cells from pediatric patients injected intravenously (i.v.) into NOD/SCID/Il2rg(-/-) (NSG) mice gave rise to leukemic spreading that was severely hampered by IL-27; (2) IL-27-treated mice, compared with controls, showed significant reduction of putative B-ALL-initiating cells and blasts in the peripheral blood (PB), bone marrow (BM) and spleen; and that (3) IL-27 reduced in vitro B-ALL cell proliferation and angiogenesis, induced apoptosis and downregulated miR-155. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of IL-27 in childhood B-ALL patients.

Recent advances in targeted anti-vasculature therapy: the neuroblastoma model.

Novel anti-vasculature strategies that are emerging for the treatment of cancer and for the inhibition of angiogenesis may be a promising new tool for the adjuvant therapy of malignant tumours. Over the last fifteen years, several reports have been published concerning the relationship between tumour progression and angiogenesis in experimental models of neuroblastoma in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumour growth on active angiogenesis. Here, we present an overview of the most recent advances in anti-vasculature therapy of neuroblastoma, and describe some preclinical results as well as future perspectives.

Cervical changes throughout pregnancy as assessed by transvaginal sonography.

OBJECTIVE: To evaluate changes in cervical dimensions by transvaginal ultrasound in non-randomly selected pregnant women. METHODS: This longitudinal study included 154 pregnant women undergoing transvaginal ultrasound assessment of the cervix at a mean gestational age of 12, 16, 20, 25, and 31 weeks. On each occasion, the longitudinal and anteroposterior diameters of the cervix were measured. The rate of prematurity in the series was 1.9%, and the mean gestational age at delivery was 38.7 weeks. RESULTS: Overall, cervical length (mean 4.3 cm; 95% confidence interval 4.1-4.3) did not change significantly (P = .06), whereas the anteroposterior diameter of the cervix at its midportion shortened throughout the investigated period of gestation. Multiparous women had longer and thicker cervices than primigravidas or women with previous cesareans or first-trimester abortions. Gestational age at delivery did not correlate with cervical dimensions at any stage of pregnancy. CONCLUSIONS: The cervix undergoes a change in shape from cylindrical to conic, more marked in primigravidas than in parous women. Women who had previous cesarean deliveries had cervical characteristics similar to primigravidas; therefore, it appears that mechanical, rather than hormonal, factors have a greater effect in determining changes of cervical dimensions throughout pregnancy.

Measurements of fetal limb bones in early pregnancy.

The fetal humerus, radius/ulna, femur, tibia/fibula and foot were measured in 296 pregnant women at 64-108 days' menstrual age, using vaginal sonography. All limb measurements correlated significantly with gestational age and biparietal diameter independently. Ratios of limb segment lengths did not change with gestation. Reference ranges (mean and 95% data intervals) were constructed for each limb segment. These data may prove useful in prenatal diagnosis of skeletal dysplasias and in the antenatal assessment of patients at risk of chromosomal abnormalities.

Transvaginal sonography for fetal measurement in early pregnancy.

OBJECTIVE: To establish reference ranges for fetal size by gestation in the first trimester as indicated by cephalic, abdominal and limb measurements using transvaginal sonography. DESIGN: A prospective descriptive study. SETTING: Two antenatal clinics in Milan, Italy. SUBJECTS: 270 women with normal singleton pregnancies at 42-108 days gestation. All had regular cycles and certain dates. INTERVENTIONS: Vaginal ultrasound examination including inspection of fetal structures and lasting 5-15 min. MAIN OUTCOME MEASURES: As many of the following fetal measurements as possible according to gestational age and ease: crown-rump length (CRL), biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur and foot lengths. RESULTS: CRL was measured in 183 fetuses, BPD in 201, HC in 162, AC in 160, femur length in 133 and foot length in 62. The best description of the relation of CRL to gestational age was achieved by a quadratic function (y = -3.98 - 0.308x + 0.0117x2). Mean values thus derived were virtually identical to those obtained by Robinson & Fleming in 1975 with transabdominal static scanning. Fetal BPD, HC, AC and femur length correlated more closely with CRL than gestational age. Reference ranges (mean and 95% data intervals) were constructed for each biometrical measurement in relation to gestational age and CRL. The HC/AC and femur/foot length ratios did not show any significant variation with gestational age or CRL. CONCLUSIONS: These data may be useful in the early detection of genetic disorders affecting the growth of fetal head, trunk and limbs. Genetic and/or environmental variables play an appreciable role in the modulation of early fetal growth.

[Analysis of the performance of several technicians in the echographic evaluation of the uterus]. / Analisi del comportamento di diversi operatori nella valutazione ecografica dell'utero.

The reproducibility degree in echographic biometry of uterus, studied by three diameters (longitudinal, transverse and antero-posterior), is mainly influenced by the anatomic characteristics of the structures. Starting from this observation a study about if and how much the understanding difficulties can influence differently the evaluation by four operators has been performed. Data, obtained from ten women, have been elaborated for appraising precision and accuracy of the four operators. Results show an almost univocal interpretation of the images and also that the data inhomogeneity in the less reproducible diameters valuation is caused by real difficulty in the interpretation of the pictures.

Fitting growth curves to head and abdomen measurements of the fetus: a multicentric study.

Three different mathematical models were fitted to ultrasonic measurements of the biparietal diameter, head circumference, and abdomen circumference obtained from 1,426 healthy fetuses. The linear cubic function gives coefficients comparable with most previous studies, but it does not thoroughly explain fetal growth throughout pregnancy. Both the exponential-power function and the logistic-logarithmic function fit the raw data well and theoretically reflect the biological phenomena of human fetal growth. The characteristics of each model are discussed.

Quantitative characterization of the growth of the fetal kidney.

The time-dependent changes in the antero-posterior (A-P) diamter and length (L) of fetal kidneys has been evaluated by means of statistical analysis of measurements made during the third trimester in a normal population. Two hundred eighty pregnant women were examined between 22 and 40 weeks of gestation. Differences between operator-scanner combinations were evaluated. The relationships of the A-P diameter and length to menstrual age were determined in cross-sectional and longitudinal studies of kidney growth. The results obtained confirmed that measurements of fetal kidney can be used as an additional parameter in the routine assessment of fetal well being and to rule out kidney malformations characterized by changes in kidney size.

[Prenatal diagnosis of a case of familial recurrence of unilateral diaphragmatic agenesis]. / Diagnostic prénatal d'un cas de répétition familiale d'agénésie unilatérale du diaphragme.

Prenatal diagnosis of different fetal malformations have been performed by echography. The authors report a case of recurrence of monolateral diaphragmatic agenesy in sibs. The diagnosis was achieved at the 23 degrees week of gestation. Some methodological details are also proposed to improve the possibility of early diagnosis. Embryological and epidemiological data have been evaluated.

Gluconeogenesis in developing rat kidney cortex.

1. Gluconeogenesis in developing rat kidney cortex was studied by assaying the activities of two enzymes, glucose 6-phosphatase and phosphoenolpyruvate carboxykinase, and by measuring glucose formation in tissue slices. 2. Glucose 6-phosphatase and phosphoenolpyruvate carboxykinase are present in late foetal (21-22-day-old) tissue and increase rapidly postnatally. Maximum activity of phosphoenolpyruvate carboxykinase occurs at 7 days of age, followed by a decline to the adult level. Glucose 6-phosphatase activity rises during the first 2 postnatal weeks and then declines. 3. Late foetuses synthesize glucose from both pyruvate and l-glutamate. The rate increases during the first 2 weeks to above adult levels. Synthesis is always higher from pyruvate than from glutamate. 4. The effect of 24hr. starvation was studied in perinatal animals. The results indicate that the ability to increase the rate of glucose synthesis as a result of starvation is not present at birth, but develops some time after the second postnatal day.