The biomechanical difference between running with traditional and 3D printed orthoses.

Running-related injuries have been associated with excessive foot pronation and high vertical loading rates. Traditional plaster-molded (TPM) foot orthoses are commonly prescribed to minimize these atypical biomechanical patterns. Recently, 3D printed (3DP) orthoses have become popular, yet the functional difference between these two types of orthoses remains unknown. Therefore, this study compared running biomechanics and perceived comfort during treadmill running in three orthotic conditions: 3DP orthoses, TPM orthoses, and a no-orthoses control condition (CON). Thirteen female asymptomatic runners with excessive foot pronation were recruited. Rearfoot eversion angle and velocity (at initial contact and peak) during stance, vertical loading rates, and perceived comfort were compared. Results showed lower peak rearfoot eversion angles during running with TPM (p=0.001, d=0.38) or 3DP orthoses (p=0.002, d=0.24) than CON. No differences were observed in other biomechanical parameters among the three conditions (p>0.05). Running with TPM (p≤0.001, d=1.74-1.82) and 3DP orthoses (p<0.003, d=1.06-1.34) resulted in better perceived comfort in "medial-lateral control" and "heel cushioning" than CON. There were no statistical differences in all parameters between TPM and 3DP orthoses. The present findings indicate improved comfort during running with TPM or 3DP orthoses, which hinted 3DP orthoses could be a viable alternative to TPM orthoses for clinical practice.

Long-Term Survival After Surgery and Radiotherapy for Recurrent or Persistent Ovarian and Tubal Cancer.

OBJECTIVE: This study examines the factors associated with long-term disease-specific survival (DSS) and complications after radiotherapy (RT) for recurrent or persistent ovarian and tubal cancer. METHODS/MATERIALS: Between 1980 and 2015, 65 women with ovarian (57), tubal (3), or co-existent ovarian/endometrial carcinoma (5) received RT (>45 Gy) with curative intent for recurrent (45) or persistent cancer (20) found at second-look surgery. Surgery to debulk (± restage) was integrated into the management of all but 7 cases. RESULTS: Twenty-two women had no evidence of disease at last contact after a median of 15.6 years (range = 1.0-35.8 years). Of the 53 patients treated more than 10 years ago, 18 (34%) are in this long-term no evidence of disease group. Univariate analysis showed that the following factors were significantly associated with longer DSS (P < 0.05): initial stage I, II (vs III, IV); endometrioid histology (vs serous and other); no or 1 previous chemotherapy (vs ≥2); no macroscopic tumor before RT (vs macroscopic); localized tumor encompassed by a limited-volume RT field (vs more widespread tumor), and chemotherapy and RT (vs RT only). Multivariate analysis showed that endometrioid (vs other histology HR = 4.37, P = 0.017) and localized tumor (vs more widespread tumor, HR = 2.43, P = 0.017) were significantly associated with longer DSS.After RT to the pelvis and/or abdomen, 13 (21.7%) of 60 patients developed G3 or 4 bowel complications requiring surgery. In 10, these occurred in the presence of tumor, RT changes, and adhesions, and in 3, there was no sign of cancer. Six patients (9.2%) developed a subsequent malignancy. CONCLUSIONS: We conclude that there is a role for the use of RT in selected cases of localized recurrent or persistent ovarian cancer and may confer long-term survival. Surgery is useful to debulk and define the extent of tumor to be irradiated but may confer an increased risk of severe bowel complications.

The K-INBRE symposium: a 10-institution collaboration to improve undergraduate education.

The Kansas-IDeA Network of Biomedical Research Excellence (K-INBRE) is an infrastructure-building program funded by the National Institute of General Medical Sciences. Undergraduate education, through undergraduate research, is a key component of the program. The K-INBRE network includes 10 higher education institutions in Kansas and northern Oklahoma, with over 1,000 student participants in 16 yr. Since 2003, the K-INBRE has held an annual state-wide research symposium that includes national and regional speakers and provides a forum for undergraduates to give platform and poster presentations. The symposium is well attended by K-INBRE participants and has grown to a size of over 300 participants per year from all 10 K-INBRE schools. Two surveys were distributed to students and mentors to assess the impact of the symposium on student learning. Surveys (153) were distributed to students who participated in K-INBRE from 2013 through 2015 with a 51% response rate. Mentors were surveyed with a response of 111 surveys out of 161. Survey results indicate that students and mentors alike find the symposium to be beneficial and enriching of the student experience. Almost 80% of student respondents indicated that their participation in the symposium fostered appreciation of research. In short, the K-INBRE symposium provides a unique opportunity for students to gain experience in collecting, preparing, and communicating research in a professional environment. The collaborative experience of the annual K-INBRE symposium, the impact it has on student learning, and how it has influenced the research culture at our 10 institutions will be described.

A case of acute kidney injury from crystal nephropathy secondary to pomalidomide and levofloxacin use.

Pomalidomide is an analog of thalidomide with immunomodulatory, anti-angiogenic, and anti-neoplastic activity indicated for the treatment of multiple myeloma refractory to at least two prior therapies. The incidence for renal failure was <5% in a single phase II study of pomalidomide and dexamethasone in patients with multiple myeloma that failed both lenalidomide and bortezomib therapy. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury in pomalidomide and fluoroquinolone use.

Thyroid transcription factor-1 (TTF-1) immunoreactivity is an adverse prognostic factor in endometrioid adenocarcinoma of the uterine corpus.

AIMS: It is known that thyroid transcription factor-1 (TTF-1) is expressed in a small percentage of primary gynaecological adenocarcinomas. Following the observation of TTF-1 positivity in a number of endometrioid adenocarcinomas of the uterine corpus which behaved aggressively, we undertook immunohistochemical staining of a large series of endometrial adenocarcinomas of various types to investigate whether its expression is of prognostic significance. METHODS AND RESULTS: TTF-1 was performed on tissue microarrays containing 102 low-grade (grades 1 or 2) endometrioid adenocarcinomas, 101 grade 3 endometrioid adenocarcinomas, 89 serous adenocarcinomas and 29 clear cell carcinomas. All categories of endometrial adenocarcinoma exhibited TTF-1 staining in a small subset of cases (2% low-grade endometrioid, 11% grade 3 endometrioid, 9% serous, 7% clear cell). TTF-1 was less frequently expressed in low-grade endometrioid adenocarcinomas compared to other subtypes. Endometrioid adenocarcinomas which expressed TTF-1 had a statistically significant worse prognosis with poorer disease-specific survival, and this was also statistically significant in the group of low-grade endometrioid adenocarcinomas. CONCLUSIONS: Our study confirms that TTF-1 is expressed in a small, but not insignificant, proportion of endometrial adenocarcinomas. TTF-1 positivity in low-grade endometrioid adenocarcinomas is an indicator of poorer prognosis.

Cytochrome oxidase I DNA barcodes of crocodilians meat selling in Hong Kong.

The crocodilians include true crocodiles, alligators, caimans, and gharial, and the trade of crocodilian products is regulated in accordance with the Convention of Wild Fauna and Flora (CITES). Hong Kong does not have her own wild crocodilians; thus, all crocodilians meat available is presumably imported with proper license. Here, we obtained a dataset of cytochrome oxidase I (COI) gene markers of 114 crocodilian meat samples (including frozen and dried crocodilian meat products) available in the contemporary market. We have also validated these barcodes in a phylogenetic approach with other data deposited on the GenBank, and detected 112 samples belonging to four crocodile species Crocodylus siamensis, C. porosus, C. niloticus and Alligator mississippiensis, and 2 samples belonging to snake Malayopython reticulatus. The dataset generated in this study will be useful for further studies including meat inspection, illegal trading, and enhancement of international and local legislations on illegal reptile importation.

Supramolecular assembly of bent dinuclear amphiphilic alkynylplatinum(ii) terpyridine complexes: diverse nanostructures through subtle tuning of the mode of molecular stacking.

A new class of bent amphiphilic alkynylplatinum(ii) terpyridine complexes was found to adopt different modes of molecular stacking to give diverse nanostructures. In chlorinated solvents, the complexes aggregate in the presence of water droplets and assist in the formation of porous networks, while in DMSO solutions, they self-assemble to give fibrous nanostructures. The complexes would adopt a head-to-tail tetragonal stacking arrangement, as revealed by X-ray crystallographic studies, computational studies and powder X-ray diffraction (PXRD) studies. Their self-assembly follows a cooperative growth mechanism in DMSO and an isodesmic growth mechanism in DMSO-H2O mixture. The balance between hydrophobic and hydrophilic components of the complex system, in conjunction with the nuclearity and the positioning of the substituents, are found to govern the mode of molecular stacking and the fabrication of precise functional nanostructures. This class of complexes serve as versatile building blocks to construct orderly packed molecular materials and functional materials in a well-controlled manner.

Insulin-like growth factor binding protein-2 is a novel therapeutic target associated with breast cancer.

PURPOSE: Insulin-like growth factor (IGF) binding proteins (IGFBP) modulate interactions of IGF ligands with the IGF-I receptor. The role of IGFBPs, and specifically IGFBP-2, in breast cancer progression has been poorly defined. This study assesses the effect of IGFBP-2 on the behavior of human breast cancer using clinical specimens as well as in vitro and in vivo experimental systems. EXPERIMENTAL DESIGN: 4,181 primary invasive breast cancers and 120 benign breast tissue samples were identified for tumor tissue microarray construction and immunostained with IGFBP-2 antibody. Estrogen receptor-negative MDA-MB-231 cells constitutively overexpressing IGFBP-2 (MDA-MB-231BP-2) were created to assess the effect of IGFBP-2 gain-of-function. MDA-MB-468 cells, naturally expressing IGFBP-2, were used to determine the effect of IGFBP-2 loss-of-function using OGX-225, an antisense oligonucleotide drug candidate. RESULTS: IGFBP-2 expression was significantly higher in breast cancer tissue compared with benign breast tissue. MDA-MB-231BP-2 cells grew more rapidly and were more resistant to paclitaxel both in vitro and in vivo compared with parental cells. OGX-225 decreased IGFBP-2 expression and attenuated the associated aggressive phenotype of MDA-MB-231BP-2 cells both in vitro and in vivo. Furthermore, OGX-225 inhibited the in vitro and in vivo growth of MDA-MB-468 cells. CONCLUSIONS: This study provides evidence that IGFBP-2 expression is associated with breast cancer. Novel therapeutics targeting IGFBP-2, such as OGX-225, merit further evaluation.

Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases.

PURPOSE: We have previously demonstrated in a pilot study of 348 invasive breast cancers that mast cell (MC) infiltrates within primary breast cancers are associated with a good prognosis. Our aim was to verify this finding in a larger cohort of invasive breast cancer patients and examine the relationship between the presence of MCs and other clinical and pathological features. EXPERIMENTAL DESIGN: Clinically annotated tissue microarrays (TMAs) containing 4,444 cases were constructed and stained with c-Kit (CD-117) using standard immunoperoxidase techniques to identify and quantify MCs. For statistical analysis, we applied a split-sample validation technique. Breast cancer specific survival was analyzed by Kaplan-Meier [KM] method and log rank test was used to compare survival curves. RESULTS: Survival analysis by KM method showed that the presence of stromal MCs was a favourable prognostic factor in the training set (P = 0.001), and the validation set group (P = 0.006). X-tile plot generated to define the optimal number of MCs showed that the presence of any number of stromal MCs predicted good prognosis. Multivariate analysis showed that the MC effect in the training set (Hazard ratio [HR] = 0.804, 95% Confidence interval [CI], 0.653-0.991, P = 0.041) and validation set analysis (HR = 0.846, 95% CI, 0.683-1.049, P = 0.128) was independent of age, tumor grade, tumor size, lymph node, ER and Her2 status. CONCLUSIONS: This study concludes that stromal MC infiltration in invasive breast cancer is an independent good prognostic marker and reiterates the critical role of local inflammatory responses in breast cancer progression.

Large-scale DNA organization is a prognostic marker of breast cancer survival.

Breast cancer is the leading cause of cancer-related deaths among women worldwide. We investigated whether changes in large-scale DNA organization (LDO) of tumor epithelial nuclei are an indicator of the aggressiveness of the tumor. We tested our algorithm on a set of 172 duplicates TMA cores samples coming from 95 breast cancer patients. Thirty-five patients died of breast cancer, and 60 were still alive 10 years after surgery. Duplicates cores were used to create training and test set. The TMA slides were stained with Feulgen-thionin and imaged using our in-house high-resolution Imaging system. Automated segmentation of cell nuclei followed by manual selection of intact, in-focus nuclei resulted in an average of 50 cell nuclei per sample available for analysis. Using forward stepwise linear discriminant analysis, a combination of six features that combined linearly gave the best discrimination between the two groups of cells: cells collected from 'deceased' patients TMA specimens and cells collected from "survivors" patients TMA specimens. Five of these features measure the spatial organization of DNA chromatin. The resulting canonical score is named cell LDO score. A patient LDO score, percentage of cell nuclei with a cell LDO score higher than a predefined cutoff value, was processed for the specimens in the test set, and a cutoff value was defined to classify patients with a low or a high LDO score. Using this binary test, 82.1% of patients were correctly classified are "deceased" or "survivors," with a specificity of 79% and a sensitivity of 88%. The relative risk of death of an individual with a high LDO score was nine times higher than for a patient with a low LDO score. When testing the combination of LDO score, node status, histological grade, and tumor grade to predict breast cancer survival, LDO was the most significant predictor. LDO classification was also highly associated with survival for only grade 1 and 2 patients as well as for only grade 3 patients. Our result confirms the potential of LDO to measure phenotypic changes associated with more aggressive disease and could be evaluated to identify patients more likely to benefit from adjuvant therapies.

HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer.

Warburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.

Histotype-genotype correlation in 36 high-grade endometrial carcinomas.

Endometrioid, serous, and clear cell carcinomas are the major types of endometrial carcinoma. Histologic distinction between these different tumor types can be difficult in high-grade cases, in which significant interobserver diagnostic disagreement exists. Endometrioid and clear cell carcinomas frequently harbor ARID1A and/or PTEN mutations. Serous carcinoma acquires TP53 mutations/inactivation at onset, with a significant subset harboring an additional mutation in PPP2R1A. This study examines the correlation between tumor histotype and genotype in 36 previously genotyped high-grade endometrial carcinomas. This included 23 endometrioid/clear cell genotype and 13 serous genotype tumors. Eight subspecialty pathologists reviewed representative online slides and rendered diagnoses before and after receiving p53, p16, and estrogen receptor immunostaining results. κ statistics for histotype-genotype concordance were calculated. The average κ values for histotype-genotype concordance was 0.55 (range, 0.30 to 0.67) on the basis of morphologic evaluation alone and it improved to 0.68 (range, 0.54 to 0.81) after immunophenotype consideration (P<0.001). Genotype-incompatible diagnoses were rendered by at least 2 pathologists in 12 of 36 cases (33%) (3 cases by 2/8 pathologists, 2 by 3/8, 2 by 4/8, 3 by 6/8, 1 by 7/8, and 1 case by 8/8 pathologists). Six of the 12 were endometrioid/clear cell genotype tumors, and the other 6 were serous genotype tumors. The histopathologic features associated with histotype-genotype-discordant cases were reviewed, and specific diagnostic recommendations were made to improve concordance. This study found that although the majority of morphologic diagnoses are genotype concordant, genotype-incompatible diagnoses are made in a significant subset of cases. Judicious use and interpretation of p53 immunohistochemistry in selected scenarios can improve histotype-genotype concordance.

A reinforced suture line prevents recurrence after fundoplication in patients with familial dysautonomia.

BACKGROUND/PURPOSE: Long-term follow-up of fundoplication in patients with familial dysautonomia (FD) has revealed a high rate of recurrent gastroesophageal reflux. This may be because of the unique characteristics of patients with FD which include autonomic denervation accompanied by cyclic vomiting and retching. We reviewed our results with adaptations to the Nissen fundoplication to determine which would be most effective in preventing the need for reoperation. METHODS: We reviewed the records of 108 patient with FD who underwent fundoplication by a single pediatric surgeon from November 1978 to July 1, 2004. Patients were divided into 4 groups based on the operative technique: standard Nissen fundoplication, Nissen with a posterior gastropexy, Nissen with posterior gastropexy and a superior anchoring suture, and Nissen with a reinforced suture line in addition to the previous modifications. Demographic data and surgical outcomes were abstracted. RESULTS: Patients who underwent a Nissen fundoplication with a reinforced suture line were significantly less likely to require a reoperation for recurrent reflux than any other patients (P = .05, Fisher's Exact test) despite the fact that they were younger than patients who underwent a standard Nissen alone. CONCLUSION: The addition of a reinforced suture line to the standard Nissen fundoplication decreases the failure rate for patients with gastroesophageal reflux and FD. A reinforced suture line may be an attractive modification for patients where the fundoplication may be under continued physical stress caused by autonomic perturbations, or other conditions such as uncontrolled seizures or progressive neurologic decline.

Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers.

BACKGROUND: Recent reports indicate that prostate cancers (CaP) frequently over-express the potential oncogenes, ERG or ETV1. Many cases have chromosomal rearrangements leading to the fusion of the 5' end of the androgen-regulated serine protease TMPRSS2 (21q22.2) to the 3' end of either ERG (21q22.3) or ETV1 (7p21.3). The consequence of these rearrangements is aberrant androgen receptor-driven expression of the potential oncogenes, ETV1 or ERG. AIM: To determine the frequency of rearrangements involving TMPRSS2, ERG, or ETV1 genes in CaP of varying Gleason grades through fluorescence in situ hybridisation (FISH) on CaP tissue microarrays (TMAs). METHODS: Two independent assays, a TMPRSS2 break-apart assay and a three-colour gene fusion FISH assay were applied to TMAs. FISH positive cases were confirmed by reverse transcriptase (RT) PCR and DNA sequence analysis. RESULTS: A total of 106/196 (54.1%) cases were analysed by FISH. None of the five benign prostatic hyperplasia cases analysed exhibited these gene rearrangements. TMPRSS2:ERG fusion was found more frequently in moderate to poorly differentiated tumours (35/86, 40.7%) than in well differentiated tumours (1/15, 6.7%, p = 0.017). TMPRSS2:ETV1 gene fusions were not detected in any of the cases tested. TMPRSS2:ERG fusion product was verified by RT-PCR followed by DNA sequencing in 7/7 randomly selected positive cases analysed. CONCLUSION: This study indicates that TMPRSS2:ERG gene rearrangements in CaP may be used as a diagnostic tool to identify prognostically relevant sub-classifications of these cancers.

Synthetic Studies in Phytochrome Chemistry.

An account is given of the author's several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both 2R- and 2S-phytochromobilin (4), as well as several (13)C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1.