Distribution of Sibship Sizes and Correlation between Numbers of Male and Female Children in A Family: Evidence from Sub-Saharan Africa

This paper is concerned with the re-investigation of the distribution of sibship sizes as negative binomial distribution, truncated below one and computation of correlation between the numbers of boys and girls in a family. The distribution involves two parameters m and p and these are estimated by the method given in Brass (1958c) which has asymptotic efficiency more than 90 % in comparison to maximum likelihood. It is also found that the scoring method provides the similar estimates as given by Brass. The suitability of the distribution and correlation is tested using 10% sample of new DHS data gathered recently on 26 sub-Saharan African countries dividing in Western-Central, Eastern-Southern, implying a mean sibship size of 4.22 and 3.83 respectively which is significant at 1% level of probability. The observed and expected correlation coefficients are found to be the same in each country. Through the values of c2 at 1% and 5% level, we deem the fit to be very good except in few cases. The values of m and p will be useful to generate the underlying sibship sizes for the simulation study. Keywords: Sibship sizes,Negative binomial distribution,Maximum likelihood,Simulation,Correlation

Therapeutic Approaches to Aggressive Carcinomas Based on a Novel VEGF/Neuropilin Autocrine Pathway

Summary: Autocrine VEGF signaling in tumor cells contributes to de-differentiation and function of tumor initiating/stem cells. NRP2 is the nexus of a signaling pathway that promotes de-differentiation and sustains tumor initiating/stem sells. Anti-NRP2 therapy is worth pursuing, especially for high-grade cancers. Therapeutic Abs are available. This presentation was part of the retreat mini-symposium entitled: Biomarker Discovery and Targeted Therapeutics in Cancer

On K-Edge Fine Structure Spectra of Some Cu(I) Complexes

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Integrins in prostate cancer progression

Integrins, which are transmembrane receptors for extracellular matrix proteins, play a key role in cell survival, proliferation, migration, gene expression, and activation of growth factor receptors. Their functions and expression are deregulated in several types of cancer, including prostate cancer. In this article, we review the role of integrins in prostate cancer progression and their potential as therapeutic targets

The alpha6beta4 integrin promotes resistance to ferroptosis

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an enzyme that enriches membranes with long polyunsaturated fatty acids and is required for ferroptosis. Adherent cells lacking alpha6beta4 require an inducer, such as erastin, to undergo ferroptosis because they sustain GPX4 expression, despite their increase in ACSL4. In contrast, ECM detachment of cells lacking alpha6beta4 is sufficient to trigger ferroptosis because GPX4 is suppressed. This causal link between alpha6beta4 and ferroptosis has implications for cancer biology and therapy

Role of nonoperative treatment in managing degenerative tears of the medial meniscus posterior root

BACKGROUND: Tears of the medial meniscus posterior root can lead to progressive arthritis, and its management has no consensus. The aim of our study was to evaluate the effect of supervised exercise therapy on patients with medial meniscus posterior root tears. MATERIALS AND METHODS: Between January 2005 and May 2007, 37 patients with this tear verified by magnetic resonance imaging (MRI) and osteoarthritis grade 1–2 by radiographic examination were treated by a short course of analgesics daily for up to 6 weeks and then as required during follow-up, as well as a 12-week supervised exercise program followed by a home exercise program. Final analysis was performed for 33 patients, average age 55.8 (range 50–62) years and average follow-up of 35 (range 26–49) months. Patients were followed up at 3, 6, and 12 months and yearly thereafter using the Lysholm Knee Scoring Scale, Tegner Activity Scale (TAS), and visual analog scale (VAS). The analysis was performed using one-way analysis of variance (ANOVA) and Pearson’s correlation coefficient to determine the relationship between Lysholm score and body mass index (BMI). RESULTS: Patients showed an improvement in Lysholm score, TAS, and VAS, which reached maximum in 6 months and later was accompanied by a decline. However, scores at the final follow-up were significantly better than the pretherapy scores. There was also a progression in arthritis as per Kellgren and Lawrence radiographic classification from median 1 preintervention to median 2 at the final follow-up. A correlation between BMI and Lysholm scores was seen (r = 0.47). CONCLUSION: Supervised physical therapy with a short course of analgesics followed by a home-based program results in symptomatic and functional improvement over a short-term follow-up; however, osteoarthritis progression continues and is related to BMI

Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland

Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2. MMTV-Cre;NRP2(loxP/loxP) mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2(+/loxP) or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF(165), an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAK-dependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2(loxP/loxP) mammary glands compared with control glands. Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance

Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by beta1 integrins

We show here that beta1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The beta1A integrin forms a complex with the IGF-IR and insulin receptor substrate-1 (IRS-1); this complex does not promote IGF-I mediated cell adhesion to laminin (LN), although it does support IGF-mediated cell proliferation. In contrast, beta1C, an integrin cytoplasmic variant, increases cell adhesion to LN in response to IGF-I and its down-regulation by a ribozyme prevents IGF-mediated adhesion to LN. Moreover, beta1C completely prevents IGF-mediated cell proliferation and tumor growth by inhibiting IGF-IR auto-phosphorylation in response to IGF-I stimulation. Evidence is provided that the beta1 cytodomain plays an important role in mediating beta1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, beta1A associates with IRS-1 and beta1C with Gab1/Shp2. This study unravels a novel mechanism mediated by the integrin cytoplasmic domain that differentially regulates cell adhesion to LN and cell proliferation in response to IGF

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

SummaryVascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition