Hysteroscopic evaluation of menorrhagia and correlation with saline infusion sonography and histopathology of the endometrium

Background: This study aimed to evaluate and compare the diagnostic utility of hysteroscopy and saline infusion sonography in patients presenting with abnormal uterine bleeding, using the International Federation of Gynaecology and obstetrics classification system. Methods: The study included 97 women with menorrhagia attending the department of obstetrics and gynaecology, R. D. Gardi Medical College, Ujjain, from September 2011 to February 2013. All the participants underwent hysteroscopy, saline infusion sonography (SIS), and endometrial histopathology. The sensitivity, specificity, positive predictive value, and negative predictive value of each diagnostic method was calculated and compared. Results: Both hysteroscopy and SIS demonstrated high sensitivity and specificity in detecting structural lesions from the PALM group of abnormal uterine bleeding (AUB) aetiologies. For endometrial polyps, hysteroscopy had a sensitivity of 89.47% with a specificity of 87.17%, while SIS had a sensitivity of 100% and specificity of 88.46% (p<0.01). For submucous fibroids, hysteroscopy had a sensitivity of 82.35% and specificity of 91.25%, while SIS had a sensitivity of 88.23% and specificity of 88.75% (p<0.01). However, neither method was as effective for endometrial hyperplasia and the COEIN group. Hysteroscopy-guided biopsy could improve the sensitivity and specificity of hysteroscopy in detecting endometrial hyperplasia. Conclusions: Hysteroscopy and SIS are valuable tools in the diagnosis and management of AUB, with both methods demonstrating significant efficacy in detecting structural lesions, such as endometrial polyps and submucous fibroids. Further research is needed to refine these techniques and determine their optimal use in clinical practice, especially for the detection of endometrial hyperplasia and conditions within the COEIN group

Xenogeneic, extracorporeal liver perfusion in primates improves the ratio of branched-chain amino acids to aromatic amino acids (Fischer's ratio)

In fulminant hepatic failure (FHF), the development of hepatic encephalopathy is associated with grossly abnormal concentrations of plasma amino acids (PAA). Normalization of the ratio of branched-chain amino acids to aromatic amino acids (Fischer's ratio) correlates with clinical improvement. This study evaluated changes in PAA metabolism during 4 h of isolated, normothermic extracorporeal liver perfusion using a newly designed system containing human blood and a rhesus monkey liver. Bile and urea production were within the physiological range. Release of the transaminases AST, ALT and LDH were minimal. The ratio of branched (valine, leucine, isoleucine) to aromatic (tyrosine, phenylalanine) amino acids increased significantly. These results indicate that a xenogeneic extracorporeal liver perfusion system is capable of significantly increasing Fischer's ratio and may play a role in treating and bridging patients in FHF in the future

Probing the gluon Sivers function through direct photon production at RHIC

We study the production of prompt photons at the RHIC in the context of a generalized parton model framework, with a view to obtain information on the gluon Sivers function (GSF). At RHIC energy (root s = 200 GeV), the Compton process gq -> gamma q contributes significantly to the production of direct photons at midrapidity and dominates it in the negative (backward) rapidity region. We find that for direct photons, asymmetries of up to 10% are allowed by a maximal gluon Sivers function. However, the asymmetry obtained using existing fits of the GSF available in the literature is negligible. We also estimate the impact that photons produced via fragmentation can have on the signal and find that their inclusion can dilute the asymmetry by between 10% and 50% of the direct photon value. Finally, using the color-gauge invariant generalized parton model (CGI-GPM) approach, we consider the effects of initial-state and final-state interactions which can affect the universality of the Sivers functions in different processes. We find that the inclusion of these effects leads to the size of the gluon contributions being roughly halved. However, in the backward region which we are interested in, the sizes of the quark contributions are suppressed even further, leading to increased dominance of the gluon contributions

Merlin Deficiency Predicts FAK Inhibitor Sensitivity: A Synthetic Lethal Relationship

The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition lack expression of the neurofibromatosis type 2 (NF2) tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell–extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlinnegative MPM cells underlie their greater dependence on cell-ECM–induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated aldehyde dehydrogenase as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response through reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment

The extracellular matrix and focal adhesion kinase signaling regulate cancer stem cell function in pancreatic ductal adenocarcinoma

<div><p>Cancer stem cells (CSCs) play an important role in the clonogenic growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). A hallmark of PDAC is the desmoplastic reaction, but the impact of the tumor microenvironment (TME) on CSCs is unknown. In order to better understand the mechanisms, we examined the impact of extracellular matrix (ECM) proteins on PDAC CSCs. We quantified the effect of ECM proteins, β1-integrin, and focal adhesion kinase (FAK) on clonogenic PDAC growth and migration <i>in vitro</i> and tumor initiation, growth, and metastasis <i>in vivo</i> in nude mice using shRNA and overexpression constructs as well as small molecule FAK inhibitors. Type I collagen increased PDAC tumor initiating potential, self-renewal, and the frequency of CSCs through the activation of FAK. FAK overexpression increased tumor initiation, whereas a dominant negative FAK mutant or FAK kinase inhibitors reduced clonogenic PDAC growth <i>in vitro</i> and <i>in vivo</i>. Moreover, the FAK inhibitor VS-4718 extended the anti-tumor response to gemcitabine and nab-paclitaxel in patient-derived PDAC xenografts, and the loss of FAK expression limited metastatic dissemination of orthotopic xenografts. Type I collagen enhances PDAC CSCs, and both kinase-dependent and independent activities of FAK impact PDAC tumor initiation, self-renewal, and metastasis. The anti-tumor impact of FAK inhibitors in combination with standard chemotherapy support the clinical testing of this combination.</p></div