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DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα–deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II–targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. Cancer Res; 77(16); 4217–27. ©2017 AACR.

Basal cell carcinoma is the most prevalent cancer in Caucasians worldwide. The aim of this study was to examine the overall risk of melanoma among patients diagnosed with basal cell carcinoma. This population-based retrospective cohort study included data from January 2010 to December 2018 from the databases of the Clalit Health Maintenance Organization and 2 major pathology laboratories in North District, Israel. The incidence and hazard ratio of melanoma in patients with a diagnosis of basal cell carcinoma were determined. Of 466,700 participants, 51% were women and the mean (standard deviation) follow-up was 6.7 (2.9; range 1–9) years. A total of 3,338 patients were diagnosed with basal cell carcinoma during the study period, 82 of whom subsequently developed melanoma. Patients with basal cell carcinoma had a significantly higher incidence of melanoma than patients without basal cell carcinoma (2.46% vs 0.37%; p

Background: The proper use of security accessories in cars has resulted in the reduction of morbidity and mortality both in adults and children. Improper use of abdominal seat belt is associated in some cases with severe abdominal injuries. Objectives: Investigation of the treatment outcomes of children who suffered complicated abdominal seat belt injuries between 1998 and 2013. Methods: We present five cases of children aged 6-14 years, who suffered complicated abdominal injuries due to improper use of the seat belt. Abdominal injuries included injuries to the liver, spleen, small bowel (duodenum, jejunum, and ileum), colon and aorta, mesenterial bleeding, retroperitoneal bleeding, bowel obstruction and pelvic fractures. Results: Three children were operated on within a few hours of admission due to peritoneal irritation, hemodynamic instability after fluid resuscitation, bowel injuries including perforation and bowel ischemia. Two children who were hemodynamically stable, were operated on after few days. One of them had a diagnosis of aortic injury and the other, bowel obstruction. The first child was treated in two stages: i. repair of duodenal rupture, and ii. repair of the aortic injury by using interposition Gore-Tex graft. For the child with bowel obstruction, segmental resection and primary anastomosis were performed. The operation and postoperative periods for all children were uneventful, and all five children are healthy today. Conclusion: 1) The abdominal seat belt should always be used in conjunction with the chest seat belt. 2) An abdominal seat belt sign should always raise the possibility of complicated abdominal injuries. 3) Gastrointestinal tract injuries are common in this setting. 4) Aortic injury is rare; however, it can easily be missed initially. 5) Abdominal aortic trauma is associated with duodenal injuries in almost all cases.

The presence of high-risk HPV in non-malignant tonsil tissues from patients who underwent tonsillectomy in the Galilee area might explain the low incidence of HPV-related oropharyngeal malignancy in the country. The aim of this retrospective study was to study the prevalence of human papillomavirus (HPV) in non-malignant tonsillectomy specimens of adults in the Galilee area. We conducted a retrospective analysis of all tonsil samples in our medical center. Tonsils from patients over 20 years of age who underwent tonsillectomy for the indication of recurrent tonsillitis and sleep apneas were eligible. Samples of formalin-fixed paraffin-embedded (FFPE) tonsillar tissue were tested for the presence of HPV DNA using polymerase chain reaction and by p16 immunohistochemistry. Of the 71 tonsil samples, age range 20–65, none were positive for HPV DNA. Fifty-two FFPE specimens of tonsil with HPV-positive cancer tested positive by the same method served as positive controls. HPV DNA is rare in non-malignant tonsil tissues of young adults and adults who underwent tonsillectomy in the Galilee area. Further research should be done in larger cohorts.

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.

E3 ubiquitin ligases (E3s) play essential roles in the maintenance of tissue homeostasis under normal and stress conditions, as well as in disease states, particularly in cancer. However, the role of E3s in the initiation of human tumors is poorly understood. Previously, we reported that genetic ablation of the HECT-type E3 ubiquitin ligase Smurf2 induces carcinogenesis in mice; but whether and how these findings are pertinent to the inception of human cancer remain unknown. Here we show that SMURF2 is essential to protect human dermal fibroblasts (HDFs) from malignant transformation, and its depletion converts HDFs into tumorigenic entity. This phenomenon was associated with the radical changes in chromatin structural and epigenetic landscape, dysregulated gene expression and cell-cycle control, mesenchymal-to-epithelial transition and impaired DNA damage response. Furthermore, we show that SMURF2-mediated tumor suppression is interlinked with SMURF2’s ability to regulate the expression of two central chromatin modifiers—an E3 ubiquitin ligase RNF20 and histone methyltransferase EZH2. Silencing these factors significantly reduced the growth and transformation capabilities of SMURF2-depleted cells. Finally, we demonstrate that SMURF2-compromised HDFs are highly tumorigenic in nude mice. These findings suggest the critical role that SMURF2 plays in preventing malignant alterations, chromosomal instability and cancer.

SMURF2, an E3 ubiquitin ligase and suggested tumor suppressor, operates in normal cells to prevent genomic instability and carcinogenesis. However, the mechanisms underlying SMURF2 inactivation in human malignancies remain elusive, as SMURF2 is rarely found mutated or deleted in cancers. We hypothesized that SMURF2 might have a distinct molecular biodistribution in cancer versus normal cells and tissues. The expression and localization of SMURF2 were analyzed in 666 human normal and cancer tissues, with primary focus on prostate and breast tumors. These investigations were accompanied by SMURF2 gene expression analyses, subcellular fractionation and biochemical studies, including SMURF2&rsquo, s interactome analysis. We found that while in normal cells and tissues SMURF2 has a predominantly nuclear localization, in prostate and aggressive breast carcinomas SMURF2 shows a significantly increased cytoplasmic sequestration, associated with the disease progression. Mechanistic studies showed that the nuclear export machinery was not involved in cytoplasmic accumulation of SMURF2, while uncovered that its stability is markedly increased in the cytoplasmic compartment. Subsequent interactome analyses pointed to 14-3-3s as SMURF2 interactors, which could potentially affect its localization. These findings link the distorted expression of SMURF2 to human carcinogenesis and suggest the alterations in SMURF2 localization as a potential mechanism obliterating its tumor suppressor activities.

Summary A‐lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A‐lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease‐associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson‐Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose‐ and E3 ligase‐dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic–lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A‐lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2–lamin A axis in age‐related diseases such as cancer.

Medical tourism is defined by the active act of traveling from a patient’s country of origin to a different country, specifically to receive medical treatment. Globalization has made a tremendous change in the field of medical tourism. Medical tourism statistics revealed an anticipated growth of the industry from about $40 billion in 2004 to $100 billion by 2012, as estimated by the McKinsey Company (Shetty, 2010). The size of the global medical tourism market increased about 2.5 times from 2004 to 2012 by approximately USD 10 billion, and it is expected to reach approximately USD 33 billion by 2019 (Seo & Park, 2018). Israel has emerged as a medical tourism destination due to the advantages it can offer. Israel’s facilities are recognized throughout the world, and provide high quality of care at reasonable prices. But, Israel has a socialized health care system. This means that the national health insurance program is financed mainly by the government from public sources, such as health insurance tax that is collected by the general payroll and other general tax revenues, but also directly from the public through out-of-pocket money and private complementary health insurances. In comparison to OECD countries, Israel’s hospitals are characterized by a very low bed to population ratio, an extremely low average length of stay, a high rate of admissions per 1000 population, and a high occupancy rate, which means this is already a very “lean” and effective system, that is on the verge of collapse due to a lack of funding. In relation to this medical tourism raises a lot of ethical, moral and economic issues for the Israeli health system. In the current article we try to shed some light upon these problems and suggest feasible solutions for them.We suggest that countries should adopt an ethical code and health policy, which will be used by local hospitals to maintain the delicate balance between medical services to the local population and medical tourism.

DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα–deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II–targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. Cancer Res; 77(16); 4217–27. ©2017 AACR.

Object Microfibrillar collagen hemostat (MCH; trade name Avitene) is a partially water-insoluble acid salt of purified bovine corium collagen. This agent has been widely used to control hemorrhage at surgery, and especially during pediatric neurosurgeries at the authors' institution. Despite its effectiveness, rare case reports detailing adverse inflammatory reactions to MCH have been documented. Based primarily on MR imaging, postoperative reactions have most commonly elicited clinical differential diagnoses of tumor recurrence or abscess. According to the literature, MCH induces a very characteristic mixed inflammatory response that is rich in eosinophils; in light of these observations, many authors have suggested an allergy-based pathogenesis. Methods The authors retrospectively reviewed 3 pediatric neurosurgical cases treated at their institution, wherein a common histomorphological inflammatory reaction to MCH was elicited at the site of prior craniotomy. Results Case 1 is that of a 10-year-old girl whose diagnosis was a right temporal lobe ganglioglioma, classified as WHO Grade I. Case 2 is that of a 9-year-old boy whose diagnosis was a left parietal lobe anaplastic ependymoma, classified as WHO Grade III. Finally, Case 3 is that of a 15-year-old girl whose diagnosis was focal cortical dysplasia Type IIA affecting the left occipital lobe. Each patient presented with new or recurrent seizures 5–6 weeks after the initial resection. The postsurgical reactions incited by MCH mimicked the radiological appearance of either an abscess (Cases 2 and 3) or recurrent tumor (Case 1). Histologically, the mixed inflammatory infiltrate was typified by the presence of MCH-centric necrotizing granulomas that were surrounded by a palisade of macrophages and often several eosinophils. Conclusions The findings are in keeping with previous case reports describing the clinicopathological features of adverse reactions occurring due to MCH. Based on the authors' observations, the possibility of an idiopathic inflammatory reaction to MCH should be considered when either seizures, a typical radiological appearance (that is, consistent with tumor recurrence or abscess formation), or both arise shortly after initial surgery. A conservative treatment approach to this type of inflammatory lesion appears to be the most appropriate management strategy.

The present study was aimed to compare term versus preterm placental pathologies associated with fetal growth restriction (FGR).A retrospective cohort study was performed, including all singleton deliveries of FGR with placental pathology examination. Comparison of placental findings was performed between neonates who were born at term versus preterm. Preterm was defined as37 completed weeks of gestation, and34 weeks gestation in another analysis. When one or more of the following pathology was found in microscopic examination of the placental tissue, the term uteroplacental insufficiency was defined: placental infarct, fibrosis of chorionic villi, thickening of blood vessels and poor vascularity of the chorionic villi.Macroscopic placental findings were available for 1,104 singleton FGR neonates; of these, 395 placentas had microscopic examinations. A significant greater proportion of preterm FGR cases had pathology findings associated with uteroplacental insufficiency as compared to term FGR (29.4 vs. 36.7%; OR = 1.4 95%, CI = 1.05-1.9; P = 0.019). The same pattern was seen while comparing placentas of FGR neonates who were born before and after 34 weeks (32.4 vs. 39.4%; OR = 1.4, 95% CI 1.02-1.8; P = 0.028). Syncytial knots were significantly more common in placentas from neonates who were delivered before 34 weeks of pregnancy (15.2 vs. 6.3%; OR = 2.6, 95% CI 1.3-5.6; P = 0.005). This trend was not statistically significant while comparing FGR before and after 37 weeks gestation (10.9 vs. 4.6%; OR = 2.4, 95% CI 0.99-7.7; P = 0.052). Meconial impregnation was more common among term versus preterm FGR neonates37 weeks (22.4% vs. 7.2% OR = 3.7, 95% CI 2.3-5.9; P 0.001), as well as among neonates who were born before and after 34 weeks of gestation (14.5 vs. 5.9%; OR = 0.4, 95% CI 0.2-0.6; P 0.001).Placentas of preterm FGR neonates (either37 weeks or34 weeks gestation) reveal numerous pathologies reflecting uteroplacental insufficiency and abnormal blood supply. The presence of increased syncytial knots in preterm FGR neonates is probably due to exposure to hypoxia and reactive oxygen agents.

To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine fetal death (IUFD).A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was made between placentas from term and preterm (37 weeks' gestation) pregnancies complicated by IUFD. A second analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks' gestation. Uteroplacental insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor vascularity of the chorionic villi, intravascular thrombi and vascular occlusion.During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were noted. When comparing gross and microscopic findings in term and preterm (37 weeks) IUFD placentas, higher rates of calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks' gestation, higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks. Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third of both term and preterm placentas demonstrated histological chorioamionitis.A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.

Splenic metastasis from endometrial carcinoma is a rare clinical event, with only 11 cases documented previously in the literature. A 58-year-old woman had surgery and radiotherapy for stage IIB endometrial carcinoma. Eighteen months later, PET scan discovered a hypermetabolic splenic mass and two hypermetabolic lung nodules. Spleen biopsy showed metastasis from endometrial carcinoma. Chemotherapy with six cycles of cyclophosphamide, adriamycin and cisplatin effected a partial response of the splenic and lung metastasis. After few months, however, splenectomy was performed because of substantial growth of the spelnic metastasis and it confirmed that the splenic metastasis was of endometrial origin and solitary in the peritoneal cavity. After splenectomy, the patient received chemotherapy with six cycles of paclitaxel. To date, 6 months after splenectomy, she is alive with no intraperitoneal disease and with few stable lung metastases. This is the 12th reported case of splenic metastasis from endometrial carcinoma. Splenic metastasis from endometrial carcinoma is usually solitary splenic metastasis limited to the splenic parenchyma. Splenectomy is an appropriate treatment to avoid splenic rupture, splenic vein thrombosis and painful splenomegaly, to circumvent the splenic metastasis being a source of secondary metastatic disease, and to provide the potential for cure or extended survival. Since patients with splenic metastasis may be asymptomatic and the interval between the diagnoses of endometrial carcinoma and splenic metastasis may be prolonged, careful and extended follow-up after primary treatment of endometrial carcinoma is warranted.

Microfibrillar collagen hemostat (MCH; trade name Avitene) is a partially water-insoluble acid salt of purified bovine corium collagen. This agent has been widely used to control hemorrhage at surgery, and especially during pediatric neurosurgeries at the authors' institution. Despite its effectiveness, rare case reports detailing adverse inflammatory reactions to MCH have been documented. Based primarily on MR imaging, postoperative reactions have most commonly elicited clinical differential diagnoses of tumor recurrence or abscess. According to the literature, MCH induces a very characteristic mixed inflammatory response that is rich in eosinophils; in light of these observations, many authors have suggested an allergy-based pathogenesis.The authors retrospectively reviewed 3 pediatric neurosurgical cases treated at their institution, wherein a common histomorphological inflammatory reaction to MCH was elicited at the site of prior craniotomy.Case 1 is that of a 10-year-old girl whose diagnosis was a right temporal lobe ganglioglioma, classified as WHO Grade I. Case 2 is that of a 9-year-old boy whose diagnosis was a left parietal lobe anaplastic ependymoma, classified as WHO Grade III. Finally, Case 3 is that of a 15-year-old girl whose diagnosis was focal cortical dysplasia Type IIA affecting the left occipital lobe. Each patient presented with new or recurrent seizures 5–6 weeks after the initial resection. The postsurgical reactions incited by MCH mimicked the radiological appearance of either an abscess (Cases 2 and 3) or recurrent tumor (Case 1). Histologically, the mixed inflammatory infiltrate was typified by the presence of MCH-centric necrotizing granulomas that were surrounded by a palisade of macrophages and often several eosinophils.The findings are in keeping with previous case reports describing the clinicopathological features of adverse reactions occurring due to MCH. Based on the authors' observations, the possibility of an idiopathic inflammatory reaction to MCH should be considered when either seizures, a typical radiological appearance (that is, consistent with tumor recurrence or abscess formation), or both arise shortly after initial surgery. A conservative treatment approach to this type of inflammatory lesion appears to be the most appropriate management strategy.

A 72-year-old woman, who had total hysterectomy and left adnexectomy for a fibroid uterus 20 years ago, presented with a pelvic mass. Computerised tomography showed a 10 cm right pelvic semisolid m...

To compare the placental pathologies and perinatal outcomes in fetal growth restriction (FGR) pregnancies with and without oligohydramnios.A retrospective cohort study, comparing placental findings in all singleton deliveries with FGR.Macroscopic placental findings were available for 1,104 singleton FGR pregnancies. A total of 397 placentas were microscopically examined; of which 89 placentas were of FGR neonates who had oligohydramnios. No significant differences in placental vascular mal-perfusion were found between pregnancies with and without oligohydramnios (69.3 vs. 74.3%; P = 0.357). Likewise, no significant differences were noted between the groups regarding diffuse villous fibrosis (10.1 vs. 4.9%; P = 0.573), and amnion cell metaplasia (65.9 vs. 64.3%; P = 0.779). Cases of FGR complicated with oligohydramnios had significantly higher rates of perinatal mortality (9.9 vs. 5.9%; P = 0.028), preterm deliveries (34.9 +/- 3.4 vs. 35.4 +/- 3.1 weeks of pregnancy; P = 0.041), and lower birth weight (1,737 +/- 542 vs. 1,845 +/- 467 g; P = 0.002) compared to FGR without oligohydramnios.Oligohydramnios is a significant risk factor for adverse perinatal outcome in FGR pregnancies; nevertheless, no significant differences in placental pathologies were noted.