Levels of Growth Factors and IgA in the Colostrum of Women from Burundi and Italy

Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-β (TGF-β) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (n = 23) and Italian (n = 76) women were collected at 0 to 6 days postpartum. A clinical chemistry analyser was used for IgA quantification and electro-chemiluminescence, for HGF and TGFβ1-3 assessment. A univariate analysis and multivariate linear regression model were used for statistical testing. The concentrations of TGF-β2 (p = 0.01) and IgA (p < 0.01) were significantly higher in the colostrum from the women residing in Burundi than in Italy, both in a univariate analysis and upon the adjustment for confounding factors. A similar trend is seen for HGF, reaching statistical significance upon a multivariate analysis. We found a moderate to strong positive correlation between the TGF-β isoforms and IgA concentration in both countries (p < 0.01), with stronger concentration in the colostrum from Burundi. The results of this study are in support of previous data, suggesting that concentration of the immune active molecules is higher in the human milk of women residing in developing countries. However, with a small sample size, caution must be applied, as the findings require further confirmation. Future work should also be focused on other factors (e.g., lipid and microbial composition), as well as the investigation into colostrum and between populations comparison, adjusting for potential confounders.

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Impact of Hyperbaric Oxygen Treatment on Time to Transfusion Independency Post-UCB Transplant

Blood ◽

10.1182/blood.v126.23.4333.4333 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4333-4333

Author(s):

Amy Rose Cantilena ◽

Tara L. Lin ◽

Siddhartha Ganguly ◽

Leyla Shune ◽

Anurag K. Singh ◽

...

Keyword(s):

Growth Factor ◽

Hyperbaric Oxygen ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Conditioning Regimen ◽

Small Sample ◽

Total N ◽

Post Transplant ◽

Transfusion Independence ◽

Transfusion Requirements

Abstract Background Limitations in umbilical cord blood (UCB) transplantations result from decreased cell numbers available for infusion at time of transplant. Delayed engraftment and higher rates of engraftment failure subsequently increase the need for post-transplant growth factor use and transfusion support. Hyperbaric oxygen (HBO) has been shown to improve engraftment in an animal model of UCB transplantation. These experiments proved sufficient to initiate a first-in-human trial of HBO for UCB transplantation. Objectives This study compared growth factor use and time to packed red blood cell (PRBC) and platelet transfusion independence between the HBO study population and historical UCB cases from the same institution. The effects of conditioning regimen and the number of cord units infused at time of transplant were analyzed. Study Design Subjects underwent HBO therapy at the University of Kansas Medical Center after reduced intensity conditioning (RIC) (n=9) or myeloablative conditioning (MAC) (n=6) regimens. Six hours following HBO therapy, they received single (n=8) or double (n=7) UCB units. Charts of HBO-treated patients and historical controls (n=44) were reviewed for post-transplant growth factor use and transfusion requirements. These were further stratified by preparative regimen and number of UCB units infused. Kaplan-Meier curves were compared between HBO and control subjects using log-rank tests as some observations were right-censored if the patient experienced relapse or expired within the first 100 days post-transplant. A small quantity was imputed to values of 0 to facilitate including these subjects in the analyses. Results By days +66 and +74 post-transplant, 100% of HBO-patients were PRBC and platelet independent, respectively. This compares to incomplete platelet (88.63%) and PRBC (86.36%) independence in the control cohort at day 100. Though time to transfusion independence (TTI) for PRBCs was consistently shorter in the HBO cohort, it was only statistically significant in the RIC setting and approached significance in the single cord setting (Table-1). TTI for platelets was shorter for the HBO cohort and approached statistical significance in the single cord setting. Similarly, the consecutive days of filgrastim support post-transplant were consistently fewer for HBO patients, with values approaching statistical significance in the MAC and single cord settings. Conclusions In vitro data with HBO and UCB showed improved rates of engraftment in animal models. Similarly, data in this small pilot study suggests that HBO facilitates less growth factor use and shorter TTI. However, these effects did not reach statistical significance in all settings, most likely due to small sample size of the HBO cohort. Further studies are needed to examine the effect of HBO on growth factor use, PRBC and platelet independence post-UCB transplantation. Table 1. A comparison of supportive transfusion means, between standard and HBO-UCB transplant recipients. These data are segregated for conditioning regimens and units of UCB infused for transplant. Group PRBC Units Platelet Units Days G-CSF Support TTI - PRBC TTI - Platelets HBO-total (n=15) 9 (p=0.30) 16.35 (p=0.31) 29.4 (p=0.08) 32.87 (p=0.07) 33.53 (p=0.11) Standard-Total (n=44) 9.29 17.14 35.02 56.09 54.8 HBO-Ablative (n=6) 5.43(p=0.23) 7.86 (p=0.16) 26.63 (p=0.07) 24 (p=0.53) 25.5 (p=0.45) Standard-Ablative (n=23) 11.93 22.29 35.65 66.13 67.78 HBO-RIC (n=9) 6.13 (p=0.66) 11.89 (p=0.78) 31.67 (p=0.44) 22.56 (p=0.02) 25.56 (p=0.11) Standard-RIC (n=21) 7.52 13.71 34.33 45.09 40.57 HBO-Single UCB (n=8) 5.43 (p=0.19) 7.87 (p=0.26) 26.63 (p=0.06) 24 (p=0.06) 25.5 (p=0.06) Standard-Single UCB (n=4) 10.25 24 36.2 74.4 70.2 HBO-Double UCB (n=7) 12.57 (p=0.87) 24.86 (p=0.95) 33.57 (p=0.70) 43 (p=0.74) 42.71 (p=0.95) Standard-Double UCB (n=40) 9.19 16.19 34.87 53.74 52.82 Disclosures No relevant conflicts of interest to declare.

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Racial differences in the pattern of hematologic toxicity in the treatment of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.679 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 679-679

Author(s):

Olalekan O. Oluwole ◽

William Wu ◽

Steven N. Wolff ◽

Kenneth R. Hande

Keyword(s):

Colorectal Cancer ◽

Racial Differences ◽

Statistical Significance ◽

Dihydropyrimidine Dehydrogenase ◽

Univariate Analysis ◽

Small Sample ◽

Categorical Variables ◽

Hematological Toxicity ◽

Hematologic Toxicity ◽

Grade 3

679 Background: 5-fluorouracil (5-FU), a synthetic fluoropyrimidine, is a critical component of chemotherapy in many cancers. Its metabolites inhibit Thymidylate Synthetase (TS) causing cessation of DNA synthesis and are misincorporated into DNA and RNA causing ineffective DNA repair and faulty mRNA splicing. The rate limiting step in the catabolism of 5-FU is by the Dihydropyrimidine Dehydrogenase enzyme (DPD) which catabolizes over 80% of 5-FU. Patients with near total DPD enzymatic deficiency develop life threatening toxicity after a single administration and those with less severe deficiency will have delayed elimination of 5-FU and slowly accumulate active metabolites leading to toxicities. Methods: We conducted a pilot retrospective cohort study of African American (AA) and Caucasian patients treated for colorectal cancer over a 9 year period, 2000 – 2008, in this IRB approved study. The primary outcome of interest was the rate of development of grade 3 or 4 neutropenia (Absolute Neutrophil Count <1000/uL = grade 3 and <500/uL = grade 4). Descriptive and univariate analysis were done. To test for differences between AA and Caucasians, we computed independent t-test for continuous and Fisher’s exact test for categorical variables. Relative Risk (RR) and p-values were computed. All statistics were done with SPSS v19 software. Results: There were 66 evaluable patients (40 men, 26 women), 40 AA, 24 Caucasians and 2 of other races. Thirty-eight patients (15 Caucasians and 23 AA) received 5-FU containing chemotherapy. The two groups were comparable in baseline characteristics. AA were more likely to develop grade 3-4 hematological toxicity. Nine of 23 AA (39.1%) and one of 15 Caucasians (6.7%) developed grade 3-4 hematological toxicity. RR 8.56, 95% confidence interval 0.95 – 421.06 (p-value of 0.0561) Conclusions: These results suggest that AA were more likely than Caucasians to have severe hematologic toxicity with the use of 5-FU containing chemotherapy. This difference did not meet statistical significance due to small sample size and few numbers of events in the Caucasian arm. A larger prospective study is needed to further evaluate the observed difference.

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Transforming growth factor-beta and matrix protein expression in acute and chronic rejection of human renal allografts.

Journal of the American Society of Nephrology ◽

10.1681/asn.v62286 ◽

1995 ◽

Vol 6 (2) ◽

pp. 286-294

Author(s):

F S Shihab ◽

T Yamamoto ◽

C C Nast ◽

A H Cohen ◽

N A Noble ◽

...

Keyword(s):

Growth Factor ◽

Acute Rejection ◽

Transforming Growth Factor Beta ◽

Chronic Rejection ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Statistical Significance ◽

Tgf Beta ◽

Plasminogen Activator Inhibitor 1 ◽

Pai 1

Because the increased tissue expression of TGF-beta underlies fibrosis in many diseases, it was hypothesized that sustained elevated transforming growth factor (TGF)-beta overexpression might be responsible for fibrosis in chronic rejection of the renal allograft. To test this hypothesis, biopsies were obtained from 5 patients with acute rejection, 5 patients with chronic rejection, 10 normal individuals, and 10 patients with kidney disease. The tissues were examined by immunofluorescence for the three TGF-beta isoforms (1, 2, and 3) and the two matrix proteins induced by TGF-beta that serve as markers of fibrosis: fibronectin extradomain A positive (EDA+) and plasminogen activator inhibitor-1 (PAI-1). The tubulointerstitium from all cases of acute rejection and chronic rejection showed highly significant increases in immunostaining for the three TGF-beta isoforms (P < 0.001), fibronectin EDA+ (P < 0.005), and PAI-1 (P < 0.001). In the glomeruli, only TGF-beta 1 expression achieved statistical significance (P < 0.005) in acute rejection, whereas in chronic rejection, all three TGF-beta isoforms (p < 0.001) in addition to fibronectin EDA+ (p < 0.001) and PAI-1 (p < 0.001) were elevated. There was both cellular and matrix staining of the TGF-beta isoforms. In striking contrast, control kidney tissues were negative or only weakly positive. Because TGF-beta was present both in acute and in chronic rejection but not in control tissues and because acute rejection episodes are a good predictor for chronic rejection, these results suggest that TGF-beta may play a role in the pathogenesis of fibrosis in chronic rejection.

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Impact of fibroblast growth factor receptor 1 (FGFR1) amplification on the prognosis of breast cancer patients

Breast Cancer Research and Treatment ◽

10.1007/s10549-020-05865-2 ◽

2020 ◽

Vol 184 (2) ◽

pp. 311-324

Author(s):

Ramona Erber ◽

Matthias Rübner ◽

Simon Davenport ◽

Sven Hauke ◽

Matthias W. Beckmann ◽

...

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor Receptor ◽

Statistical Significance ◽

Growth Factor Receptor ◽

Small Sample ◽

Fibroblast Growth ◽

Luminal B ◽

The Impact

Abstract Purpose Various aberrations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3 are found in different cancers, including breast cancer (BC). This study analyzed the impact of FGFR amplification on the BC prognosis. Methods The study included 894 BC patients. The amplification rates of FGFR1, FGFR2, and FGFR3 were evaluated on tissue microarrays using fluorescence in situ hybridization (FISH). Associations between these parameters and prognosis were analyzed using multivariate Cox regression analyses. Results FGFR1 FISH was assessable in 503 samples, FGFR2 FISH in 447, and FGFR3 FISH in 562. The FGFR1 amplification rate was 6.6% (n = 33). Increased FGFR2 copy numbers were seen in 0.9% (n = 4); only one patient had FGFR3 amplification (0.2%). Most patients with FGFR1 amplification had luminal B-like tumors (69.7%, n = 23); only 32.6% (n = 153) of patients without FGFR1 amplification had luminal B-like BC. Other patient and tumor characteristics appeared similar between these two groups. Observed outcome differences between BC patients with and without FGFR1 amplification did not achieve statistical significance; however, there was a trend toward poorer distant metastasis-free survival in BC patients with FGFR1 amplification (HR = 2.08; 95% CI 0.98 to 4.39, P = 0.05). Conclusion FGFR1 amplification occurs most frequently in patients with luminal B-like BC. The study showed a nonsignificant correlation with the prognosis, probably due to the small sample size. Further research is therefore needed to address the role of FGFR1 amplifications in early BC patients. FGFR2 and FGFR3 amplifications are rare in patients with primary BC.

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Breast Milk Transforming Growth Factor β Is Associated With Neonatal Gut Microbial Composition

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/mpg.0000000000001585 ◽

2017 ◽

Vol 65 (3) ◽

pp. e60-e67 ◽

Cited By ~ 21

Author(s):

Alexandra R. Sitarik ◽

Kevin R. Bobbitt ◽

Suzanne L. Havstad ◽

Kei E. Fujimura ◽

Albert M. Levin ◽

...

Keyword(s):

Growth Factor ◽

Breast Milk ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Microbial Composition

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Characterization of the Luminal and Mucosa-Associated Microbiome along the Gastrointestinal Tract: Results from Surgically Treated Preterm Infants and a Murine Model

Nutrients ◽

10.3390/nu13031030 ◽

2021 ◽

Vol 13 (3) ◽

pp. 1030

Author(s):

Ingeborg Klymiuk ◽

Georg Singer ◽

Christoph Castellani ◽

Slave Trajanoski ◽

Beate Obermüller ◽

...

Keyword(s):

Individual Differences ◽

Gastrointestinal Tract ◽

Preterm Infants ◽

Bacterial Colonization ◽

Statistical Significance ◽

Small Sample ◽

Intestinal Microbiome ◽

Gi Tract ◽

Microbial Composition

Environmental factors, including nutritional habits or birth mode, are known key determinants for intestinal microbial composition. Investigations of the intestinal microbiome in different species in a multiplicity of studies during recent decades have revealed differential microbial patterns and quantities along the gastrointestinal (GI) tract. Characterization of the microbial pattern in various aspects is a prerequisite for nutritional interventions. In this 16S rRNA amplicon-based approach, we present a characterization of the mucosa-associated microbiome in comparison with the luminal community of four infants at the time of the closure of ileostomies and perform a systematic characterization of the corresponding luminal and mucosal microbiome from jejunal, ileal and colonic regions, as well as collected feces in mice. The most dominant taxa in infant-derived samples altered due to individual differences, and in the mucosa, Enterococcus, Clostridiumsensustricto1, Veillonella, Streptococcus and Staphylococcus were the most abundant. Two less abundant taxa differed significantly between the mucosa and lumen. In murine samples, relative abundances differed significantly, mainly between the intestinal regions. Significant differences between mouse mucosa- and lumen-derived samples could be found in the observed species with a trend to lower estimated diversity in mucosa-derived samples, as well as in the relative abundance of individual taxa. In this study, we examined the difference between the mucosal and luminal bacterial colonization of the gastrointestinal tract in a small sample cohort of preterm infants. Individual differences were characterized and statistical significance was reached in two taxa (Cupriavidus, Ralstonia). The corresponding study on the different murine intestinal regions along the GI tract showed differences all over the intestinal region.

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Characteristics of Neuropeptide-Containing Innervation, Tissue Remodeling, Growth, and Vascularity in Noses of Patients With Cleft Lip and Palate

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665620904519 ◽

2020 ◽

Vol 57 (8) ◽

pp. 948-956

Author(s):

Evija Balode ◽

Mara Pilmane

Keyword(s):

Growth Factor ◽

Connective Tissue ◽

Cleft Lip ◽

Transforming Growth Factor ◽

Cleft Lip And Palate ◽

Transforming Growth Factor Β1 ◽

Nerve Fibers ◽

Strong Positive Correlation ◽

Pgp 9.5 ◽

Affected Tissue

Objective: To detect the appearance and distribution of factors regulating remodeling, innervation, growth, and vascularity of the nasal tissue affected by cleft lip and palate (CLP). Design: Morphological analysis of human tissue. Setting: Cleft and craniofacial center. Participants: Fifteen patients who underwent CLP rhinoplasty, 7 control patients. Interventions: Rhinoplasty. Main Outcome Measures: Immunohistochemistry was performed with protein gene product (PGP) 9.5, transforming growth factor β1 (TGFβ1), vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), matrix metalloproteinase 2 (MMP2), MMP9, and tissue inhibitor of metalloproteinase 2 (TIMP2). The results were evaluated semiquantitatively. Spearman rank order correlation coefficient and Mann-Whitney U test were used for statistical analysis. Results: Cleft lip and palate–affected tissue revealed dense and loose connective tissue, adipose cells, and hyaline cartilage, along with numerous CD34-positive endotheliocytes and regions of VEGF-positive neoangiogenesis. We observed moderate to numerous PGP 9.5-positive nerve fibers. Transforming growth factor β1, MMP2, MMP9, and TIMP2 were found in cartilage and connective tissue. Cleft lip and palate–affected tissue compared to control samples showed a statistically significant difference in PGP 9.5 ( P = .006), VEGF ( P = .001), MMP2 ( P = .002), MMP9 ( P = .013), and TIMP2 ( P < .001) expression. We observed a strong, positive correlation between VEGF and MMP9 ( P = .027; r S = 0.705). Conclusions: The moderate expression of TGFβ1 and increased distribution of VEGF, MMP2, MMP9, and TIMP2 demonstrate an active extracellular matrix remodeling and angiogenesis, performed by proteases. The cartilaginous septum of the nose is an example of balance between tissue degradation and its suppression, demonstrated by the relationship between MMPs and TIMPs and the presence of VEGF.

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Prognostic utility of inflammation biomarkers in a PDAC trial involving the human anti-CTGF antibody pamrevlumab.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.752 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 752-752

Author(s):

Mark D. Sternlicht ◽

Dongxia Li ◽

Viet-Tam Nguyen ◽

Mairead Carney ◽

Duo Zhou ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Cox Model ◽

Performance Status ◽

Univariate Analysis ◽

Locally Advanced ◽

Tissue Growth ◽

Cox Models ◽

Prognostic Utility ◽

Pre Treatment

752 Background: Pancreatic ductal adenocarcinomas (PDAC) often exhibit desmoplasia, elevated CTGF (connective tissue growth factor) expression and inflammation. The influence of inflammation on patient outcomes was examined in a dose-ranging trial of the anti-CTGF antibody pamrevlumab in combination with a fixed regimen of gemcitabine and erlotinib in locally advanced or metastatic PDAC patients (NCT01181245; Picozzi et al. J Cancer Clin Trials 2017 2:123; n = 75). Methods: The prognostic utility of pre-treatment plasma levels of C-reactive protein (CRP), transforming growth factor β1 (TGFβ1), albumin, CTGF and CA 19-9 were assessed by univariate and multivariate Cox analysis. Demographic parameters, treatment cohort, and pamrevlumab exposure determined on treatment day 15 were also evaluated, as were changes in biomarker levels over the first four weeks of treatment. Results: Elevated baseline CTGF and CRP were prognostic for shorter overall survival (OS) by univariate analysis (HR = 3.2 for CRP > 10 mg/L, p= 0.00002 and HR = 1.6 for CTGF > 10 ng/mL, p= 0.045). In a five-factor multivariate Cox model that included CRP and TGFβ1 as continuous Ln-transformed variables, performance status, age, and pamrevlumab treatment cohort, cohort assignments associated with increasing pamrevlumab exposure predicted improved OS (HR = 0.87, p= 0.03). Removing CRP from this model reduced the prognostic utility of pamrevlumab cohort assignment and exposure, indicating an important contribution of inflammation to interpretation of treatment outcome. Changes in inflammation biomarkers over the course of treatment were also evaluated, but were not prognostic in this study. Conclusions: In multivariate Cox models, assessment of pre-treatment CRP levels improved ability to detect significant differences in PDAC patient survival outcomes associated with pamrevlumab treatment. Our results emphasize the utility of accounting for pre-treatment CRP levels as an independent prognostic factor in PDAC treatment effect models.

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Headache in patients with a meningioma correlates with a bone-invasive growth pattern but not with cytokine expression

Cephalalgia ◽

10.1111/j.1468-2982.2009.01945.x ◽

2009 ◽

Vol 30 (4) ◽

pp. 413-424 ◽

Cited By ~ 11

Author(s):

CJ Schankin ◽

M Krumbholz ◽

P Sostak ◽

VM Reinisch ◽

R Goldbrunner ◽

...

Keyword(s):

Risk Factors ◽

Growth Factor ◽

Antiepileptic Drugs ◽

Growth Pattern ◽

Transforming Growth Factor ◽

Univariate Analysis ◽

Correct Prediction ◽

Binary Logistic Regression Analysis ◽

Invasive Growth ◽

History Of

We included 58 patients with meningioma in a prospective study to analyse the prevalence of and risk factors for different types of meningioma-associated headache. Twenty-three patients (40%) had meningioma-associated headache. Of these, the pain was migraine-like in five (22%) and tension-type headache (TTH)-like in 13 (57%). Sixteen of 21 (76%) experienced relief of pain intensity of at least 50% after 18–24 months. Univariate analysis revealed bone-invasive growth pattern ( P = 0.007) as a risk factor for headache and intake of antiepileptic drugs ( P = 0.04) or large surrounding oedema ( P = 0.04) as possible protective parameters. For migraine-like headache, risk factors were a positive history of migraine ( P = 0.009) and bone-invasive growth pattern ( P = 0.046) and, for TTH-like headache, only bone-invasive growth pattern ( P = 0.009). Binary logistic regression analysis added to assess predictability and interaction effects could not identify a single factor predicting the occurrence of headache in the presence of a meningioma (correct prediction in 74% by a model consisting of bone-invasive growth pattern, history of head surgery, intake of antiepileptic drugs, temporal tumour location and moderate and large surrounding oedema). Analysis of 38 tumour specimens could not confirm the hypothesis that the occurrence of headache correlates with the expression magnitude of signal substances known to be present in meningiomas [stroma cell-derived factor 1, interleukin (IL)-1β, IL-6, vascular endothelial growth factor A] or thought to be relevant to headache/pain pathophysiology [prostaglandin-endoperoxide synthase 2, calcitonin-related polypeptide alpha, nitric oxide synthase (NOS) 1, NOS2A, NOS3, transforming growth factor-alpha, tumour necrosis factor, tachykinin, vasoactive intestinal peptide]. The affection of bone integrity and the expression of molecules thought to be relevant to headache pathophysiology might be important for meningioma-associated headache in predisposed individuals.

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