A predictive model for calculating the likelihood of recurrent uterine fibroids after surgical intervention

Aim. To develop a predictive model for calculating the likelihood of recurrent uterine fibroids after myomectomy.Materials and Methods. We consecutively recruited 149 women aged 19 to 45 years who underwent myomectomy. Prediction of uterine fibroids was carried out using multivariate analysis including a classification tree (IBM SPSS Statistics). To construct a classification tree for predicting recurrent uterine fibroids, the following patient-related parameters were used as the input features: age, family history, nulliparity, past medical history of myomectomy, obesity, rapid fibroid growth, multiple fibroids at myomectomy, BCL-2, Ki-67, and VEGF expression.Results. When analyzing the resulting classification tree, we can conclude that the most significant factors defining the recurrence of uterine fibroids are low parity, multiple fibroids at myomectomy, intensive VEGF expression, and weak expression of BCL-2.Conclusion. Our original model allows the identification of the most significant predictors of recurrent uterine fibroids and might be proposed as a useful tool for clinical practice.

Correlation Between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates

Background: In current years, the incidence and mortality of colorectal cancer (CRC) are increasing, and the 5-year survival rate of advanced metastatic CRC is poor. The Small mothers against decapentaplegic (SMAD) superfamily is an intracellular signal transduction protein associated with the development and prognosis of a variety of tumors. At present, no study has systematically analyzed the relationship between SMADs and CRC.Methods: Here, R3.6.3 was used to analyze the expression of SMADs in pan-cancer and CRC. Protein expression of SMADs were analyzed by HPA. GEPIA was used to evaluate the correlation between SMADs and tumor stage in CRC. The effect of R language and GEPIA on prognosis was analyzed. Mutation rates of SMADs in CRC were determined by c-BioPortal and potentially related genes were predicted using GeneMANIA. R analysis was used for correlation with immune cell infiltration in CRC.Results: Both SMAD1 and SMAD2 were found to be weak expression in CRC and correlated with immune invasion level. SMAD1 was correlated with patient prognosis, and SMAD2 was correlated with tumor stage. SMAD3, SMAD4 and SMAD7 were all low expressed in CRC and associated with a variety of immune cells. SMAD3 and SMAD4 proteins were also low expressed, and SMAD4 had the highest mutation rate. SMAD5 and SMAD6 were overexpressed in CRC, and SMAD6 was also associated with patient OS and CD8+ T cells, macrophages and neutrophils. Conclusions: Our results reveal innovative and strong evidence that SMADs can be used as biomarkers for the treatment and prognosis of CRC.

Human transcriptional gene regulatory network compiled from 14 data resources

Transcriptional regulatory network (TRN) orchestrates spatio-temporal expression of genes to generate cellular responses for survival. The transcription factors (TF) regulating expression of their target genes (TG) are the fundamental units of TRN. Several databases have been developed to catalogue human TRN based on low- and high-throughput experimental and computational studies considering their importance in understanding cellular physiology. However, literature lacks comparative assessment on the strength and weakness of each database. In this study, we compared over 2.2 million regulatory pairs between 1,379 TF and 22,518 TG assembled from 14 data resources. Our study reveals that the TF and TG were common across data resources but not their regulatory pairs. We observed that the TF and TG of the regulatory pairs showed weak expression correlation, significant gene ontology overlap, co-citations in PubMed and low numbers of TF-TG pairs representing transcriptional repression relationships. Furthermore, each TF-TG regulatory pair assigned a combined confidence score reflecting its reliability based on its presence in multiple databases and co-expression. The TRN containing 2,246,598 TF-TG pairs, of which, 44,284 with the information on TF′s activating or repressing effects on their TG is available upon request. This study brings the information about transcriptional regulation scattered over the literature and databases at one place in the form of one of the most comprehensive and complete human TRNs assembled to date, which will be a valuable resource for benchmarking TRN prediction tools, and to the scientific community working in functional genomics, gene expression and gene regulation analysis.

Prognostic significance of the aberrant expression of neuroendocrine markers in melanomas

Background Melanoma is a highly malignant tumor with diverse histopathological morphology and frequent aberrant expression of immunohistochemical markers. An occasionally reported phenomenon is the abnormal expression of neuroendocrine markers. Awareness of this situation is essential because such tumors need to be differentiated from neuroendocrine tumors because of their significant therapeutic and prognostic implications. Methods We retrospectively analyzed the expression of chromogranin A (CgA), synaptophysin (Syn) and CD56 as neuroendocrine markers in 308 cases with melanomas. Kaplan-Meier curves and Cox regression analyses were used for overall survival (OS) and progression-free survival (PFS) evaluation and comparison between neuroendocrine markers expression status in all melanoma cases or stage I–II cases. Results The expression of neuroendocrine markers in melanomas is not uncommon. CgA was positive in 6/304 (2.0%) cases, Syn in 26/304 (8.6%), and CD56 in 56/189 (29.6%). None of the cases co-expressed all the three markers. Focal or weak expression of at least one neuroendocrine marker was identified in 70/188 (37.2%) cases. The expression of CgA was correlated with age (p = 0.019), while the positive expression of Syn and CD56 showed borderline significance (p = 0.078 and 0.083, respectively), but not for any neuroendocrine marker expression. The expression of any neuroendocrine marker showed borderline significance with staging (p = 0.066). The expression of CgA, Syn, CD56, or any neuroendocrine marker did not correlate with clinicopathological features including sex, specimen type, origin, location, and histology subtype. Survival analyses revealed that the expression of neuroendocrine markers was not associated with OS or PFS. Conclusions Our study confirms that neuroendocrine marker expression is a common phenomenon in melanomas, but it has no prognostic significance. Nevertheless, awareness can avoid misdiagnosis in cases of melanomas with unusual morphology and immunophenotypes.

DOG1 is commonly expressed in pancreatic adenocarcinoma but unrelated to cancer aggressiveness

Background DOG1 (ANO1; TMEM16A) is a voltage-gated calcium-activated chloride and bicarbonate channel. DOG1 is physiologically expressed in Cajal cells, where it plays an important role in regulating intestinal motility and its expression is a diagnostic hallmark of gastrointestinal stromal tumors (GIST). Data on a possible role of DOG1 in pancreatic cancer are rare and controversial. The aim of our study was to clarify the prevalence of DOG1 expression in pancreatic cancer and to study its association with parameters of cancer aggressiveness. Methods DOG1 expression was analyzed by immunohistochemistry in 599 pancreatic cancers in a tissue microarray format and in 12 cases of pancreatitis on large tissue sections. Results DOG1 expression was always absent in normal pancreas but a focal weak expression was seen in four of 12 cases of pancreatitis. DOG1 expression was, however, common in pancreatic cancer. Membranous and cytoplasmic DOG1 expression in tumor cells was highest in pancreatic ductal adenocarcinomas (61% of 444 interpretable cases), followed by cancers of the ampulla Vateri (43% of 51 interpretable cases), and absent in 6 acinus cell carcinomas. DOG1 expression in tumor associated stroma cells was seen in 76 of 444 (17%) pancreatic ductal adenocarcinomas and in seven of 51 (14%) cancers of the ampulla Vateri. Both tumoral and stromal DOG1 expression were unrelated to tumor stage, grade, lymph node and distant metastasis, mismatch repair protein deficiency and the density of CD8 positive cytotoxic T-lymphocytes in the subgroups of ductal adenocarcinomas and cancers of ampulla Vateri. Overall, the results of our study indicate that DOG1 may represent a potential biomarker for pancreatic cancer diagnosis and a putative therapeutic target in pancreatic cancer. However, DOG1 expression is unrelated to pancreatic cancer aggressiveness.

VHL Expression Level in the Pathological Tissue is Significantly Associated with Hematotoxicity of Platinum-based Chemotherapy in Non-Small Cell Lung Cancer Patients.

Objective To investigate the association between expression level of Von Hippel-Lindau(VHL) in pathological tissue and hematotoxicity of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Methods The pathological samples of NSCLC patients were obtained for immunohistochemical staining to evaluate the expression level of VHL. Furthermore, their clinical data were collected and prognosis was traced by phone. The correlation between gene expression level and the hematotoxicity was evaluated by chi-square test. The influence of VHL expression level on the risk of hematotoxicity was tested by logistic regression model. The survival curve was plotted by Kaplan-Meier method and the survival rate between the two groups was compared by log-rank test. Results A total of 110 NSCLC patients were enrolled in this study, the median follow-up time of these patients was 27.5 months. In the whole group, 31 patients had died by the last date of follow-up to get their survival information (Nov.10,2020), with a median survival time of 24.3 months. Though immunohistochemical analysis,we found that 59 patients(53.6%) had weak expression level of VHL or lack of expression in their tumor tissues,while 51 patients(46.4%) presented moderate or high expression. We found that the patients with weak expression of VHL in their carcinoma tissue or lack of expression had more opportunities to occur neutropenia after platinum-based chemotherapy(OR=0.264,95%CI=0.085-0.818,P-value=0.021).And the expression level of VHL was correlated with OS(Logrank test: P-value= 0.007，HR= 4.219,95%CI: 1.75-10.174, P-value=0.001), while not related with DFS(Logrank test：P-value=0.256，HR= 1.334,95%CI:0.642-2.769, P-value=0.440). Conclusion The expression level of VHL gene in pathological tissue is related with granulocytopenia and leukocytotoxicity after platinum-based chemotherapy in NSCLC patients. It can be used as a biomarker to predict the risk of neutropenia and the prognosis of NSCLC patients.

Research of the developed gel intracorneal colored implants for keratopigmentation based on various materials. Experimental study

Purpose. Evaluation of the impact of the developed intracorneal gel stained implants for keratopigmentation based on various materials on the donor human cornea during organotypic cultivation. Material and methods. Three experimental samples of intracorneal gel stained implants were investigated: sample 1 based on sodium hyaluronate with organic pigment, sample 2 based on collagen hydrolyzate with inorganic pigment, and sample 3 based on hydroxypropyl methylcellulose (HPMC) with organic pigment. To determine the toxicity of the studied implants the apoptosis of keratocytes was determined in cryostat sections of the cornea. The method of immunohistochemistry was used to study apoptosis. Scanning electron microscopy was used to visualize the corneal structures in the presence of implants. Results. During the investigation we showed that a gel implant based on a collagen hydrolyzate and a pigment with an inorganic toner (28% in the composition) causes a weak expression of the initiator proteins of apoptosis Caspasa 8 and Cytochrome C, and there is no expression of the BAX and effector proteins Caspasa 3/7. It was revealed that samples No. 1 and No. 3 undergo partial dissolution and washout from the intrastromal tunnel, sample No. 2 based on collagen hydrolyzate has a dense structure and remains in the corneal tunnel throughout the entire cultivation period, for at least 7 days, which is showed using an electron-scanning microscopy. The proposed collagen hydrolyzate gel implant can be considered compact and non-toxic. Conclusion. As a result of organotypic cultivation for 7 days showed the best results intracorneal colored implant № 2 based hydrolyzate of collagen and inorganic toner. Intracorneal colored implant based on collagen hydrolyzate has a more compact and dense structure than the accompanying experimental samples. Key words: keratopigmentation, aniridia, intracorneal colored implant.

Differential localization patterns of Claudin 10, 16 and 19 in human, mouse, and rat renal tubular epithelia

Functional properties of the paracellular pathway depend critically on the set of claudins expressed at the tight junction. Two syndromes are causally linked to loss-of-function mutations of claudins: HELIX syndrome caused by genetic variations in the CLDN10 gene, and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis caused by genetic variations in the CLDN16 or the CLDN19 gene. All three genes are expressed in the kidney, particularly in the thick ascending limb (TAL). However, localization of these claudins in humans and rodents remains to be delineated in detail. We studied the segmental and subcellular expression of CLDN10, 16 and 19 in both paraffin-embedded and frozen kidney sections from adult human, mouse and rat, using immunohistochemistry and immunofluorescence, respectively. Here CLDN10 was present in a subset of medullary and cortical TAL cells, localizing to basolateral domains and tight junction in human and rodent kidney. A weak expression was detected at the tight junction of proximal tubular cells. CLDN16 was primarily expressed in a subset of TAL cells in cortex and outer stripe of outer medulla, restricted to basolateral domains and tight junctional structures in both human and rodent kidney. CLDN19 predominantly colocalized with CLDN16 in tight junctions and basolateral domains of TAL but was also found in basolateral and junctional domains in more distal sites. CLDN10 expression at tight junction almost never overlapped with that of CLND16 and CLDN19, consistent with distinct junctional pathways with different permeation profiles in both human and rodent kidney.

The Effect Of Intrauterine Hypoxia On Testicular Reproductive Function

Goal — to assess the effect of antenatal hypoxia of various origins on the morphology and reproductive function of the testes of newborn and mature rats in experiment. Material and Methods — In experiments 15 white outbred female rats aged 4 to 10 months with a weight of 200±30 g were used. Laboratory animals were randomly divided into 2 experimental and 1 control groups, 5 females each. The first group underwent normobaric hypoxia throughout pregnancy (21 days). Hypoxia modeling was conducted in accordance with the method of N.N. Karkishchenko (2010). The second group underwent hemic hypoxia during the second and third week of pregnancy, in accordance with the method of L.M. Sosedova (2012). The third (control) group was not exposed to any effect throughout pregnancy. Results — in the testicles of newborn rats of the experimental groups, the decrease of tubule diameter was observed, the increase of stroma area and development of interstitial edema were noted. In the group of hemic hypoxia, a significant decrease in the number of Leydig cells was noted. In the tissues of the testicles of mature rats, who underwent antenatal hypoxia, a decrease of tubule diameter, a significant decrease in the spermatogenesis index and a decrease of spermatogonia number were noted. The developed damage of spermatogenic epithelium in experimental groups of newborns and mature rats was confirmed by marked expression of the apoptosis marker (Bax), weak expression of proliferation markers (Ki-67) and receptor of receptor of fibroblast growth factor (FGFR). Conclusion — in animals with chronic hypoxia of various origins, there is an inhibition of spermatogenesis and a violation of the spermatogenetic function of the testicular seminiferous tubules.

Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38−/−, Trp73+/−, and Rbm38−/−;Trp73+/− mice. We found that Rbm38−/−;Trp73+/− mice had a much shorter lifespan than that for Rbm38−/−—and to a lesser extent for Trp73+/− mice—but were less prone to spontaneous tumors than Trp73+/− or Rbm38−/− mice. We also found that Rbm38−/−;Trp73+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38−/−;Trp73+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.