Prenatal diagnosis of a likely pathogenic variant in ZBTB18: Natural evolution of fetal phenotype including the long bones and corpus callosum.

Pathogenic variants in ZBTB18 gene have been described only postnatally with a variable phenotypic spectrum that includes intellectual disability, microcephaly, hypotonia, poor growth, corpus callosum abnormalities, seizures, and dysmorphic facial features. These features overlap with the phenotype of 1q43-q44 deletion syndrome (OMIM #612337). There are several genes within the 1q43-q44 deletion region, and ZBTB18 is of particular interest due to its known involvement in neuronal differentiation and migration. We describe here a fetus presenting with an intrauterine growth restriction, diminished long bones growth, single umbilical artery, and a short corpus callosum. On mid pregnancy ultrasound, all biometric parameters including the corpus callosum were relatively small but still within the normal range. Only a targeted follow-up during the third trimester, including neurosonographic and MRI exams, revealed the full extent of the malformation, leading to amniocentesis and a genetic workup that led to the identification of a de novo likely pathogenic variant in ZBTB18 gene. This is the first description of the evolving phenotype of a ZBTB18-related disorder in a fetus, which emphasizes the challenging diagnosis of subtle findings, that mandates a high level of clinical suspicion and a targeted follow-up throughout pregnancy.

The prenatal detection of distal tracheoesophageal fistulas in fetuses diagnosed with esophageal atresia.

BACKGROUND: Esophageal atresia is a major anomaly of varying severity. The complexity of surgical correction depends on the presence of a distal fistula. OBJECTIVE: This study aimed to determine the feasibility and accuracy of prenatal ultrasound detection of the distal fistula in fetuses diagnosed with esophageal atresia. STUDY DESIGN: This was an observational study conducted at a single tertiary care center between 2019 and 2021. Included were pregnant patients carrying a fetus prenatally diagnosed with esophageal atresia that was confirmed postnatally during corrective surgery or at postmortem autopsy. During the scan, the performing investigator determined the presence or absence of a distal fistula by scanning the location of the lower esophagus during fetal breathing. Cases in which the lower esophagus was observed distending with amniotic fluid during breathing were deemed "fistula present," and the remaining cases "fistula absent." Test feasibility and performance indices, including sensitivity, specificity, and positive and negative predictive value were calculated. The offline clips and images were reviewed by 2 investigators for the assessment of interoperator agreement using Cohen's Kappa formula. RESULTS: Included were 16 fetuses with esophageal atresia scanned between 2019 and 2021. All fetuses were successfully scanned with sufficient resolution of the area of interest during at least 3 cycles of breathing. It took a median of 8.5 minutes to determine the presence or absence of a distal fistula. The feasibility of the test was 100% (16/16). The test's sensitivity, specificity, and positive and negative predictive values were 80% (95% confidence interval, 55-100), 100% (95% confidence interval, 60-100), 100% (95% confidence interval, 65-100), and 75% (95% confidence interval, 45-100), respectively. The Cohen's Kappa for interoperator agreement was calculated to be 1, P<.001, corresponding to a "perfect" level of agreement. CONCLUSION: Distal fistulas in esophageal atresia can be demonstrated prenatally by targeted scanning using appropriate technique. The method provided is feasible, reproducible, and has excellent performance indices. This novel technique and observations may improve the prenatal diagnosis and counseling of esophageal atresia.

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

Fetal Urinoma Due to Circulatory Disorders in an Umbilical Artery: Case Report.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

Enhanced expression of Galectin-3 in gestational diabetes.

BACKGROUND AND AIMS: Gestational diabetes mellitus (GDM), hyperglycemia diagnosed during pregnancy, is one of the most common medical complications of pregnancy, treated primarily by diet and pharmacotherapy, if indicated. It is well-established that GDM increases the risk of adverse pregnancy outcomes and long-term complications in mothers and infants. Galectin-3 (Gal-3) is important in processes of cell growth, differentiation, inflammation, and fibrosis. We evaluated Gal-3 expression in pregnancies complicated by GDM as a parameter that might explain how GDM influences early onset of future complications. METHODS AND RESULTS: Forty-four women with GDM and 40 with normal pregnancy (NP) were recruited during delivery admission. Blood samples were obtained from parturients and umbilical cords blood, as well as placental tissue for analysis. Gal-3 mRNA expression was increased in maternal blood samples and placental tissue of women with GDM compared to NP. In GDM, Gal-3 mRNA was decreased in cord blood compared to maternal blood and placental tissue. Gal-3 GDM placental protein expression was increased compared to NP. Immunostaining revealed that Gal-3 is upregulated in GDM placental extravillous trophoblast. ELISA of Gal-3 maternal serum levels between GDM and NP were similar. CONCLUSION: Gal-3 is strongly expressed at molecular levels (mRNA and protein expression) in GDM maternal blood and placental tissue, and decreased in cord blood. These findings highlight the role of the placenta in protecting the fetus from potential Gal-3 damage. Gal-3 expression at mRNA and protein levels might be influenced by diabetes, even if blood glucose is balanced by medication or diet.

White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology.

Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.

Human Oral Mucosal Stem Cells Reduce Anastomotic Leak in an Animal Model of Colonic Surgery.

BACKGROUND: Anastomotic leak is regarded as one of the most feared complications of bowel surgery; avoiding leaks is a major priority. Attempts to reduce or eliminate leaks have included alternate anastomotic techniques. Human oral mucosa stem cells (hOMSC) are self-renewing and expandable cells derived from buccal mucosa. Studies have shown that hOMSC can accelerate tissue regeneration and wound healing. The objective of this study was to evaluate whether hOMSC can decrease anastomotic leak rates in a murine model of colon surgery. METHODS: Two experiments were performed. In the first study, mice underwent colonic anastomosis using five interrupted sutures. hOMSC (n = 7) or normal saline (NS; n = 17) was injected into the colon wall at the site of the anastomosis. To evaluate whether hOMSC can impact anastomotic healing, the model was stressed by repeating the first experiment, reducing the number of sutures used for the construction of the anastomosis from five to four. Either hOMSC (n = 8) or NS (n = 20) was injected at the anastomosis. All mice that survived were sacrificed on postoperative day 7. Anastomotic leak rate, mortality, daily weight, and daily wellness scores were compared. RESULTS: In the five-suture anastomosis, there were no differences in anastomotic leak rate, mortality, or daily weight. Mice that received hOMSC had significantly higher wellness scores on postoperative day 2 (p < 0.05). In the four-suture anastomosis, there was a significant decrease in leak rate (70% [NS] vs. 25% [hOMSC], p = 0.029) and higher wellness scores in mice that received hOMSC (p < 0.05). CONCLUSION: Our study suggests that injecting hOMSC at the colonic anastomosis can potentially reduce anastomotic leak and improve postoperative wellness in a murine model of colon surgery.

Enhanced expression of αVß3 integrin in villus and extravillous trophoblasts of placenta accreta.

BACKGROUND: Placenta accreta is one of the most serious complications in obstetrics and gynecology. Villous trophoblasts (VT) and extravillous trophoblasts (EVT) play a central role in normal placentation. Placenta accreta is characterized by abnormal invasion of EVT cells through the uterine layers, due to changes in several parameters, including adhesion proteins. Although αvß3 integrin is a central adhesion molecule, participating in multiple invasive pathological conditions including cancer, data on placenta accreta are lacking. OBJECTIVE: To study the expression pattern of αvß3 integrin in placenta accreta in comparison with normal placentas. STUDY DESIGN: We collected tissue samples from placentas defined as percreta, the most severe presentation of placenta accreta and from normal control placentas (n = 10 each). The samples underwent protein extractions for analyses of αvß3 expression by Western blots (WB) and a parallel tissue assessment by immunohistochemistry (IHC). RESULTS: WB results indicated significantly elevated αvß3 integrin expression in the percreta samples compared to normal placentas. These elevated levels were mainly contributed by EVT cells, as demonstrated by IHC. αvß3 integrin demonstrated a classical membranal expression in the VT cells, whereas a uniformly distributed expression was documented in the EVT cells. These patterns of the αvß3 integrin localization were similar in both accreta and normal placental samples. CONCLUSIONS: Enhanced αvß3 integrin expression, mainly in extra villous trophoblasts of placenta percreta, implies for a role of this adhesion molecule in pathological placentation.

The association between maternal serum first trimester free ßhCG, second trimester intact hCG levels and foetal growth restriction and preeclampsia.

The purpose of this study was to analyse the association between free beta hCG (fßhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fßhCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fßhCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fßhCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fßhCG (>3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fßhCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fßhCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fßhCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fßhCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fßhCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as >3.00 MoM; additional studies are needed to explore the association between increased first trimester fßhCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester.

Primary Fetal Lung Hypoplasia (PFLH): Imaging and Clinical Characteristics.

Purpose To describe in utero and postnatal imaging and clinical characteristics of primary fetal lung hypoplasia (PFLH). Methods A retrospective review of fetuses and neonates diagnosed in one academic tertiary center during an eleven-year period. Results 12 cases of PFLH were identified. 4 were bilateral and 8 had unilateral involvement. Prenatal sonographic characteristics, postnatal magnetic resonance imaging (MRI), computerized tomographic angiography (CTA), and histologic findings are described. 3 of the 4 bilateral cases were evaluated during fetal live. 2 were terminated and 2 died shortly after delivery. Among the 8 cases with unilateral PFLH, 7 involved the right lung and 1 the left lung. In fetuses with right hypoplasia, 5 showed characteristic features of Scimitar syndrome, while associated gastrointestinal tract (GIT) anomalies were presented in 2 cases. In this group 3 were born alive and the other 5 were terminated. Conclusion Primary PFLH is a rare anomaly that lethal in its bilateral form and with variable prognosis in its unilateral variant. Targeted evaluation of lung vascularity and exclusion of associated anomalies, especially of the GIT, are important prognostic factors.

The magnitude of elevated maternal serum human chorionic gonadotropin and pregnancy complications.

This study assessed the correlation between the magnitude of the elevation in maternal serum human chorionic gonadotropin (MShCG) levels and pregnancy complications. Among 80,716 screened pregnancies, 120 with moderately elevated MShCG (3.00-5.99 MoM) were compared to 84 with extremely elevated MShCG >6.00 MoM. A control series of 120 women with normal MShCG (<3.00 MoM) were matched. Rates of intrauterine growth restriction, preterm labour, antepartum foetal death (APFD), pre-eclampsia, and placental abruption were analysed. We found that the study group had more adverse outcomes than the control group (73/204 [36%] vs. 18/120 [15%]; p < .0001). The rate was higher in the extremely elevated group than in the moderately elevated group (43/84 [51%] vs. 30/120 [25%]; p < .0001). All 12 cases of APFD (14%) occurred among the extremely elevated series. In conclusion, adverse pregnancy outcomes are more common in women with extremely elevated MShCG. The patients should receive counselling regarding this trend and undergo close pregnancy monitoring. Impact statement • What is already known on this subject?In addition to its contribution to Down syndrome (DS) screening, maternal serum human chorionic gonadotropin (MShCG) levels are a marker for pregnancy complications such as intrauterine growth restriction (IUGR), preterm labour (PTL), antepartum fatal death (APFD), pre-eclampsia (PE), placental abruption (PA) and fetal malformations with or without chromosomal aberrations. • What the results of this study add? We found that in the presence of elevated MShCG levels, the incidence of IUGR and PTL increased. PE increased clinically, but statistical significance was seen only when MShCG was extremely elevated (≥ 6.00 MoM). APFD and PA were associated with very high MShCG levels only. • What the implications are of these findings for clinical practice and/or further research? Women with high MShCG levels should be counselled. In case of very high levels (≥ 6.00 MoM), the risk of APFD and PA should be discussed. The pregnancy should be monitored for IUGR, PTL and PE. In view of the limited number of enrolled patients with very high levels of MShCG, the experience of other institutions is needed to corroborate these findings.

Is the ratio of maternal serum to amniotic fluid AFP superior to serum levels as a predictor of pregnancy complications?

PURPOSE: The use of maternal serum alpha fetoprotein (MSAFP) levels as a predictor of pregnancy complications (PC) is well established. We hypothesized that the ratio between the MSAFP/AFAFP levels (RATIO) will more accurately predict PC than MSAFP levels alone. METHODS: Women who had a MSAFP test followed by amniocentesis were divided into two groups: those who had PC comprised the study group and those who had an uneventful pregnancy served as the control group. Data regarding pregnancy and delivery course were collected. The RATIO between the study and the control groups was compared. RESULTS: 166 women were included in the study, of which 24 had PC. A significant correlation was found between the RATIO and intrauterine growth restriction (IUGR) and week of delivery. Six pregnancies had elevated MSAFP levels; two with RATIO below 2 had uneventful pregnancies. Among the other four pregnancies with RATIO above two, one had IUGR and the other, placental abruption. CONCLUSION: Our data suggest that the RATIO might serve as a predictor of IUGR and week of delivery. Although the number of patients in the current study was relatively small, the novelty of the proposed simple marker implies that a larger scale study is warranted. Such studies may confirm this finding and a possible advantage of using this RATIO instead of or in addition to MSAFP values for better prediction of pregnancies at risk for PC.

Evaluation of peritoneal CEA levels following colorectal cancer surgery.

BACKGROUND: Peritoneal carcinoembryonic antigen (pCEA) levels in the early postoperative period following a curative resection of colorectal cancer (CRC) have not been previously studied. METHODS: Postoperative peritoneal fluids of 36 CRC patients followed by 24 benign colonic disease patients were evaluated for CEA levels and tumor cell presence. Serum CEA levels were also evaluated prior and after surgery. RESULTS: Although high postoperative pCEA levels were observed in some benign patients, more CRC patients exhibited significant elevation of postoperative pCEA (>5 ng/ml) compared to benign patients (50% vs. 23%, P = 0.039). Postoperative median pCEA levels of CRC patients were significantly higher compared to benign patients (5.4 vs. 2 ng/ml, P = 0.011). Specifically, pCEA levels in CRC patients were significantly elevated when measured during the first 24 hr after surgery. Postoperative pCEA levels were associated with colon tumor location compared to rectal location. However, no correlation was found with known risk factors for cancer recurrence or with serum CEA levels. CONCLUSIONS: Postoperative pCEA levels may be significantly elevated following a curative resection for CRC. Its significance within patient's prognostic evaluation remains to be studied. Inclusion of patient's follow-up data may reveal the significance of elevated pCEA levels following CRC resection.

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

[Osteoarthritic changes in hip joint in patients with fractures of femoral neck].

BACKGROUND: Fractures of proximal femur are common among elderly people. They are associated with considerable morbidity and mortality. Identification of etiopathogenetic factors associated with fractures might facilitate prevention. Osteoporosis is commonly present in the heads of femurs. The prevalence of osteoarthritic changes in hip joints is controversial. Some authorities report low prevalence and even speculate on the protective effect of osteoarthritis against fractures. OBJECTIVE: The goal of the study was to examine the association between osteoarthritic changes (radiologic and histologic) and fractures of the neck of the femur. METHODS: The patient population included 41 patients undergoing replacement of femoral head for subcapital fracture; their ages ranged from 61 - 93 years of age. Radiologic criteria for osteoarthritis included: (a)narrowing of joint space (b) subchondral sclerosis (c) deformation of head of femur (d) subchondra cysts and (e] osteophytes. RESULTS: Osteoarthritic changes, usually mild, were present in 22 (54%) patients, regardless of age and gender The frequency of radioLogical changes was similar to the general population. HistoLogic findings included subchondral fibrosis and subchondral cysts. Mild subchondral fibrosis was present in 78% of cases. CONCLUSION: The findings support lack of association between osteoarthritic changes in hip joint and fracture of proximal femur, without a protective effect.

[Autopsies for fetal anomalies].

BACKGROUND: Fetal autopsies are effective in identifying the cause and/or mechanisms leading to death in cases of intrauterine fetal death. Autopsies for fetal anomalies are different. OBJECTIVE: To summarize our experience with 569 autopsies of fetal anomalies which were performed during an 18-year period. METHODS: A retrospective analysis of 569 autopsies of fetal anomalies was conducted, out of a total of 1067 fetal autopsies. The pregnancy weeks were 14 - 41. RESULTS: Among 569 cases, 88% were termination of pregnancies, 10% intrauterine death and 2% perinatal deaths. The diagnosis of a syndrome or disease process was made when a constellation of gross and/or histologic findings was met. Specific diagnoses were offered in cases of cystic diseases of kidneys, types of dwarfism, tumors and fetal hydrops. Teratogenic (acquired) processes, such as congenital infections, thrombosis and cerebral hemorrhages, were differentiated from malformations. In cases of multiple congenital anomalies, documentation of the entire spectrum of malformations facilitated the genetic counseling. DISCUSSION: First and foremost, the autopsy is performed in the interest of the parents, with their written consent and in accordance with limitations and requests which they pose. Autopsy results provide feedback to the prenatal imaging. They assist in focusing the genetic counseling. Autopsy reports provide tools of control for the health authorities. Autopsies for fetal anomalies are time consuming. They require skill and experience. They are helpfuL when the prenatal diagnosis raises differential diagnosis. They are Less helpful when the diagnosis is clear, i.e. chromosomal trisomy.

The effect of hypotensive drugs on intraocular lenses clarity.

OBJECTIVES: To assess the effect of hypotensive drugs on light absorbance, discoloration, opacification and precipitate formation of IOLs. METHODS: In this laboratory study, four types of IOLs (two hydrophilic-acrylic-L1 and L2, and two hydrophobic-acrylic-B1 and B2) were soaked in solutions containing Timolol-maleate 0.5%, Dorzolamide 2%, Brimonidine-tartrate 0.2%, Latanoprost 0.005%, Brimonidine-tartrate/Timolol-maleate 0.2%/0.5% and Dorzolamide/Timolol-maleate 2%/0.5%. Non-treated IOLs and IOLs soaked in balanced salt solution (BSS) served as controls. All Treated lenses were sealed in containers and placed in an oven at 82 degrees Celsius for 120 days. Each IOL was examined using four different techniques: light microscopy imaging, light absorbance measurements at 550 nanometers through the optic's center, assessment of by a scanning electron microscope (SEM), and energy dispersive Xray spectrometry (EDX). RESULTS: Ninety-eight IOLs were included. All BSS-soaked IOLs appeared clear with no significant discoloration or precipitate-formation. Light absorbance in these lenses was comparable to that of non-soaked, non-heated IOLs. No calcium or phosphate were detected in either of these groups. Light absorbance differed significantly between the four treated IOL types. The drops most affecting light absorbance differed between IOLs. Gross examination revealed brown and yellow discoloration of all IOLs soaked in Dorzolamide and Brimonidine-tartrate solutions, respectively. SEM demonstrated precipitates that differed in size, morphology and distribution, between different IOL-solution combinations. EDX's demonstrated the presence calcium and phosphor in the majority of precipitates and the presence of sulfur in brown discolored IOLs. CONCLUSIONS: In vitro, interactions between hypotensive drugs and IOLs induce changes in light absorbance, discoloration and precipitate formation.

Exploring multisite heterogeneity of human basal cell carcinoma proteome and transcriptome.

Basal cell carcinoma (BCC) is the most common type of skin cancer. Due to multiple, potential underlying molecular tumor aberrations, clinical treatment protocols are not well-defined. This study presents multisite molecular heterogeneity profiles of human BCC based on RNA and proteome profiling. Three areas from lesions excised from 9 patients were analyzed. The focus was gene expression profiles based on proteome and RNA measurements of intra-tumor heterogeneity from the same patient and inter-tumor heterogeneity in nodular, infiltrative, and superficial BCC tumor subtypes from different patients. We observed significant overlap in intra- and inter-tumor variability of proteome and RNA expression profiles, showing significant multisite heterogeneity of protein expression in the BCC tumors. Inter-subtype analysis has also identified unique proteins for each BCC subtype. This profiling leads to a deeper understanding of BCC molecular heterogeneity and potentially contributes to developing new sampling tools for personalized diagnostics therapeutic approaches to BCC.

BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.

OBJECTIVE: The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression. METHODS: BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting. RESULTS: We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells. CONCLUSIONS: BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

NF-kappa B expression in resected specimen of colonic cancer is higher compared to its expression in inflammatory bowel diseases and polyps.

NF-Kappa B has a significant role in inflammatory processes as well as in colorectal cancer. The aim of this study was to compare the expression of NF-kappa B in colonic adenocarcinoma specimen, colonic adenomas and inflammatory colonic tissues. Patients with colorectal cancer (CRC), colonic adenomas and inflammatory processes undergoing surgery were recruited. Following a routine pathological evaluation tissue samples were stained using anti NF-κB monoclonal antibodies. Expression of NF-κB was quantified using IMAGEJ program for immunohistochemistry staining. Samples were also stained and quantified for CEA expression. Fifty-six patients were included. 30 cancers, 6 polyps and 20 inflammatory processes. Expression of NF-κB was similar between polypoid and inflammation etiologies. However, it was significantly higher in CRC compared to both (p < 0.05). In cancer patients, NF-κB expression in the resection margins was correlated with positive node status. CEA expression was higher in the cancer group, less in the IBD group and the lowest in the colonic non diseased margins. Our results provide a supportive evidence that NF-κB pathway is strongly involved in colon cancer development and metastasis. Interestingly, expression of NF-κB in benign polypoid lesions was as high as in inflammatory etiologies. This support the role of NF-κB early in the adenoma to carcinoma sequence. Further research is needed to evaluate the exact role of NF-κB in tumor progression in order to look for diagnostic and therapeutic possibilities.