Genistein-Aspirin Combination Exerts Cytotoxic and Anti-Migratory Effects in Human Colorectal Cancer Cells.

Colorectal cancer (CRC) is a heterogenous pathology with high incidence and mortality rates globally, but it is also preventable so finding the most promising candidates (natural compounds or repurposed drugs) to be chemopreventive alternatives has become a topic of interest in recent years. The present work aims to elucidate the potential effects of a combination between genistein (GEN), an isoflavone of natural origin, and aspirin (ASA) in CRC prevention/treatment by performing an in vitro evaluation in human colorectal cancer cells (HCT-116) and an in ovo analysis using the chick embryo chorioallantoic membrane (CAM) model. Cell viability was verified by an MTT (migratory potential by scratch) assay, and the expressions of MMP-2 and MMP-9 were analyzed using RT-qPCR. Our results indicated a dose-dependent cytotoxic effect of ASA (2.5 mM) + GEN (10-75 µM) combination characterized by reduced cell viability and morphological changes (actin skeleton reorganization and nuclei deterioration), an inhibition of HCT-116 cells' migratory potential by down-regulating MMP-2 and MMP-9 mRNA expressions, and an antiangiogenic effect by modifying the vascular network. These promising results raise the possibility of future in-depth investigations regarding the chemopreventive/therapeutical potential of ASA+GEN combination.

Significance of the Galectin-8 Immunohistochemical Profile in Ovarian Cancer.

Ovarian cancer (OC) still registers a high prevalence in female gynecological pathology. Given the aggressiveness of the tumor and the lack of response to conventional therapies, a current research interest is the identification of new prognostic markers. Gal-8, a member of the galectin family of molecules, involved in tumorigenesis, disease progression, and metastasis, has been assigned as a valuable tumor prognostic factor, and its inhibition may open new perspectives in cancer therapeutic management. Few studies have been carried out so far to evaluate OCs' galectin profiles. Our study aimed to characterize the Gal-8 profile in different types of ovarian neoplasia and to demonstrate its prognostic value. Our study group comprised 46 cases of OCs that were histologically and immunohistochemically investigated, introduced to Gal-8 immunoreactivity, qualitatively and semi-quantitatively evaluated, and correlated with clinicopathological characteristics. Gal-8 immunoexpression was identified in tumor epithelial cells, showing a dominant nuclear labeling, followed by cytoplasmic and mixed, nuclear, and cytoplasmic labeling. Significant differences between tumor histotypes were found in the statistical analysis between low and high Gal-8 immunoscore levels and clinicopathological features: HGSC (eng.= high-grade serous carcinoma) vs. LGSC (eng. = low-grade serous carcinoma), pathogenic types (type I vs. type II), and tumor grades. Our results reflect Gal-8 expression variability depending on the histological type and subtype, the progression stages, and the degree of differentiation of ovarian tumors, supporting its value as a prognostic factor. Our findings open perspectives for larger studies to validate our results, along with a potential Gal-8 transformation into a future therapeutic target.

Galectin-8 Immunohistochemical Profile in Pancreatic Ductal Adenocarcinoma: Emerging Evidence for Its Prognostic Role.

Pancreatic ductal adenocarcinoma (PDAC) represents the most frequent pancreatic malignancy, with stromal and epithelial heterogeneity reflected in outcome variability. Therefore, a molecular classification is promoted based on the validation of new diagnostic and prognostic markers. Galectin-8 (Gal8) has been pointed out as a prognostic factor for survival in several types of tumors. Due to limited existing data on PDAC, our study aimed to evaluate the Gal8 profile in PDAC alongside its prognostic status. A total of 87 cases of PDAC were immunohistochemically investigated, and Gal8 immunoexpression was qualitatively and semi-quantitatively assessed and correlated with classical clinicopathological parameters and survival. Gal8 immunoexpression was identified to be mostly nuclear and cytoplasmic, followed by exclusively cytoplasmic and exclusively nuclear. A statistical analysis between Gal8 profiles defined by negative, low, or high scores and clinicopathological characteristics showed significant differences in tumor size, pN stage, and lympho-vascular invasion. Although a Cox regression analysis did not support the prognostic status of Gal8, and we did not confirm its relationship with OS, our results show that exclusively nuclear labeling was associated with an increased mean OS compared with cytoplasmic and nuclear labeling (29.37 vs. 17.93 months). To the best of our knowledge, this is the first study to report a detailed pattern of Gal8 immunostaining in PDAC and to correlate this pattern with clinicopathological characteristics and survival. Our results show that Gal8 immunoexpression is associated with a more aggressive phenotype, thus opening perspectives for larger studies to validate Gal8 as a prognostic factor.

Periostin in ovarian carcinoma: from heterogeneity to prognostic value.

INTRODUCTION: Periostin (POSTN), an extracellular matrix protein, is involved in tumor-associated extracellular matrix (ECM) remodeling. However, its potential value as a prognostic and/or predictive factor has not yet been confirmed. The present study aims to assess POSTN expression separately in tumor cells and stroma of different ovarian carcinoma (OC) histological types, and its relationship with clinicopathological features. MATERIAL AND METHODS: 102 cases of different histological OC subtypes were immunohistochemically investigated, for POSTN expression assessment in both epithelial tumor cells and tumor stroma. Statistical analysis was performed to correlate POSTN profile with clinicopathological characteristics, therapeutic response, and survival. RESULTS: POSTN expression in epithelial tumor cells was significantly correlated with POSTN expression in tumor stroma. The expression of POSTN in tumor cells was associated with histological type, tumor type (type I and II), tumor recurrence, progression-free survival (PFS), and overall survival (OS), whereas stromal POSTN expression was significantly correlated with age, histological type, tumor type, grade, and stage, residual disease, tumor recurrence, response to chemotherapy, and OS. Survival analysis revealed significant differences of PFS and OS in patients with high POSTN expression in tumor cells and negative stromal POSTN expression compared to patients with low POSTN expression in tumor cells and positive stromal POSTN expression (PFS: hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.33-3.37, P = 0.002; OS: HR = 1.78, 95% CI: 1.09-2.89, P = 0.019). CONCLUSIONS: The comparative assessment of POSTN immunoexpression in two tumor compartments: in tumor cells and stroma, by use of different scoring systems revealed that higher stromal POSTN levels are evidently correlated with unfavorable clinical features and poorer prognosis, while POSTN expression in tumor cells seems to be associated with a better patient outcome.

The Impact of Medical Nutrition Intervention on the Management of Hyperphosphatemia in Hemodialysis Patients with Stage 5 Chronic Kidney Disease: A Case Series.

The treatment and interdisciplinary management of patients with chronic kidney disease (CKD) continue to improve long-term outcomes. The medical nutrition intervention's role is to establish a healthy diet plan for kidney protection, reach blood pressure and blood glucose goals, and prevent or delay health problems caused by kidney disease. Our study aims to report the effects of medical nutrition therapy-substituting foods rich in phosphorus-containing additives with ones low in phosphates content on phosphatemia and phosphate binders drug prescription in stage 5 CKD patients with hemodialysis. Thus, 18 adults with high phosphatemia levels (over 5.5 mg/dL) were monitored at a single center. Everyone received standard personalized diets to replace processed foods with phosphorus additives according to their comorbidities and treatment with prosphate binder drugs. Clinical laboratory data, including dialysis protocol, calcemia, and phosphatemia, were evaluated at the beginning of the study, after 30 and 60 days. A food survey was assessed at baseline and after 60 days. The results did not show significant differences between serum phosphate levels between the first and second measurements; thus, the phosphate binders' initial doses did not change. After 2 months, phosphate levels decreased considerably (from 7.322 mg/dL to 5.368 mg/dL); therefore, phosphate binder doses were diminished. In conclusion, medical nutrition intervention in patients with hemodialysis significantly reduced serum phosphate concentrations after 60 days. Restricting the intake of processed foods containing phosphorus additives-in particularized diets adapted to each patient's comorbidities-and receiving phosphate binders represented substantial steps to decrease phosphatemia levels. The best results were significantly associated with life expectancy; at the same time, they showed a negative correlation with the dialysis period and participants' age.

The Impact of the COVID-19 Pandemic on Quality Education of the Medical Young Generation.

(1) Generating the need to impose social distancing to reduce the spread of the virus, the COVID-19 pandemic altered the ways in which the teaching process normally happens. The aim of our study was to determine the impact of online teaching on medical students during this period. (2) Our study included 2059 medical, dental and pharmacy students from the University of Medicine and Pharmacy "Grigore T. Popa", Iasi, Romania. We used a modified metacognition questionnaire after translation into Romanian and validation. Our questionnaire included 38 items, and it was divided into four parts. Academic results and preferences regarding the on-site or online courses, information regarding practical training, self-awareness in terms of one's feelings such as anger, boredom and anxiety and also substance use linked to online teaching, and contextualization of the relationship with colleagues, teachers, friends and family were among the most important points evaluated. A comparison was made between preclinical and clinical students. A five-item Linkert-like scale was used for rating the answers in the last three parts that evaluated the impact of the SARS-CoV-2 pandemic on the educational process. (3) Preclinical medical students, compared to preclinical dental students, obtained statistically significant improvements in their evaluation results, with fewer failed exams (p < 0.001) and with similar results being obtained by comparing dental with pharmacy students. All students obtained statistically significant improvements in their academic results during the online evaluation. A statistically significant increase in anxiety and depression with a p-value of <0.001 was registered among our students. (4) The majority found it difficult to cope with this intense period. Both teachers and students found it difficult to adjust on such short notice to the challenges posed by the new concept of online teaching and learning.

Comparative Quality Assessment of Five Bread Wheat and Five Barley Cultivars Grown in Romania.

Cereals whole grains contain vitamins, phytochemicals, antioxidants, resistant starch, and minerals with potential benefits to human health. The consumption of whole grains is correlated with a lowered risk of the most important chronic diseases, including type II diabetes, cardiovascular diseases, and some cancers. This study aimed to characterize and evaluate the content of five cultivars of wheat (Triticum aestivum L.) and five cultivars of barley (Hordeum vulgare L.) obtained by conventional plant breeding using crossing and selection methods. The novelty and the purpose of this research was to quantitatively and qualitatively analyze these ten cultivars from Romania and to show the importance of, and the changes produced by, crossing and selection methods when these are aimed at the physiological or morphological development of the cultivars. Studies based on gluten dosing; spectrophotometry using Bradford, fructan and protein dosing; Kjeldahl protein dosing; GC-MS/MS-protein and amino acid dosing; and identification of protein fractions using polyacrylamide gel electrophoretic method were conducted. This study demonstrates the possibility of developing future cultivars using conventional methods of improvement to modify the content and composition of nutrients to increase their health benefits.

HOXB13 and TFF3 can contribute to the prognostic stratification of prostate adenocarcinoma.

Homeobox B13 (HOXB13) and trefoil factor 3 (TFF3) are novel candidates for the classification of prostate cancer (PC) in molecular subtypes that could predict the clinical evolution of patients. The aim of our study was to analyze the possible associations between HOXB13 and TFF3 immunohistochemical (IHC) expression in sporadic prostate adenocarcinoma (PAC), the potential prognostic value in relation to the classical clinico-pathological parameters, as well as their role in defining distinct molecular subtypes of this malignancy. The study group comprised 105 patients diagnosed with PAC who underwent radical prostatectomy. IHC exam was performed using anti-HOXB13 and anti-TFF3 antibodies and a scoring system that permit the separation of the cases into two subgroups, with low and high immunoexpression, respectively. The statistical analysis evaluated the relationship between the two immunomarkers and clinico-pathological parameters. The Kaplan-Meier curves and log-rank Mantel-Cox test were used for assessing the prostate-specific antigen (PSA)-progression free survival. Four subgroups of PAC were defined based on the IHC overexpression and low immunoexpression of HOXB13 and TFF3. High HOXB13 and TFF3 immunoexpression was commonly identified in cases characterized by a Gleason score over 7, a G4 or G5 dominant pattern, a grade group of 3 or 4 and a preoperatory PSA serum level over 20 ng/mL. HOXB13 overexpression was also associated with pathological tumor-node-metastasis (pTNM) stage. The subgroup with both low HOXB13 and TFF3 immunoexpression had the highest PSA-progression free interval, whereas the subgroup with high HOXB13 immunoexpression and low TFF3 immunoexpression presented the lowest rate, but no statistically significant differences were registered. Our results sustain the role of HOXB13 and TFF3 in the stratification of PAC. Further investigations in larger cohorts are imposed to validate the clinical significance of these subgroups in the diagnostic and prognostic of PAC.

Perirenal Adipose Tissue-Current Knowledge and Future Opportunities.

The perirenal adipose tissue (PRAT), a component of visceral adipose tissue, has been recently recognized as an important factor that contributes to the maintenance of the cardiovascular system and kidney homeostasis. PRAT is a complex microenvironment consisting of a mixture of white adipocytes and dormant and active brown adipocytes, associated with predipocytes, sympathetic nerve endings, vascular structures, and different types of inflammatory cells. In this review, we summarize the current knowledge about PRAT and discuss its role as a major contributing factor in the pathogenesis of hypertension, obesity, chronic renal diseases, and involvement in tumor progression. The new perspectives of PRAT as an endocrine organ and recent knowledge regarding the possible activation of dormant brown adipocytes are nowadays considered as new areas of research in obesity, in close correlation with renal and cardiovascular pathology. Supplementary PRAT complex intervention in tumor progression may reveal new pathways involved in carcinogenesis and, implicitly, may identify additional targets for tailored cancer therapy.

An mHealth intervention to prevent postnatal smoking relapse: The RESPREMO study protocol.

Up to 70% of women who quit smoking relapse after birth, usually within 3 months postpartum. The wide adoption of mobile technologies, especially smartphones, in recent years in low- and middle-income countries (LMICs) offers the possibility of low-cost, novel, and innovative mobile phone-based interventions for smoking relapse prevention. This study presents the protocol of the RESPREMO clinical trial for postnatal smoking relapse prevention for enrolled women, who recently gave birth and quit tobacco smoking before or during pregnancy, and their life partners. This work relies on data collected in two of the largest government-owned obstetrics and gynecology clinics in Cluj-Napoca, Romania. Seventy-five couples were randomized into one of three groups: a) 24 couples were allocated to the first intervention group and asked to install and use the xSmoker app; b) 26 couples were randomized to the second intervention group, who, in addition to the use of the xSmoker app, received text messages with content focused on motivation, problem solving, and dyadic efficacy; and c) 25 couples were randomized into a control group. Several measures of engagement with the xSmoker app were assessed, including duration of app use, the frequency of utilizing the tool to calculate savings from quitting, number of app-delivered challenges accepted by users, and number of app-delivered cessation and abstinence tips. If effective, RESPREMO is expected to have a sustainable impact on the prevention of postnatal relapse tobacco smoking with positive effects for both the mother and the newborn. The implications are beyond tobacco control, and relevant to the design and implementation of other mHealth behavioral interventions focused on the pregnancy and reproductive years in general.

Macrophage Activation in COVID-19 Patients in Intensive Care Unit.

We report six cases of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, admitted to intensive care unit (ICU), for whom bone marrow aspirate revealed hemophagocytosis. We compared their clinical presentation and laboratory findings to those that can be encountered during a hemophagocytic lymphohistiocytosis. These observations might evoke a macrophage activation mechanism different from the one encountered in the hemophagocytic lymphohistiocytosis (HLH).

Osteopontin and osteoprotegerin in atherosclerotic plaque - are they significant markers of plaque vulnerability?

Atherosclerosis (ATS) is still considered as a major, global health problem. For a deeper understanding of its pathogenesis, in the last years the research was translated from tissue visible events to molecular mechanisms. Osteopontin (OPN) and osteoprotegerin (OPG) are two molecules that have been associated with the initiation and progression of ATS lesions. The aim of our study was to assess the OPN and OPG expression in advanced stages of carotid ATS, to analyze the correlation between these markers and the ultrasonographic plaque properties, pointing out the identification of possible patterns that can predict plaque vulnerability and risks of restenosis. The study group comprised 49 consecutive patients (38 males and 11 females) diagnosed with carotid stenotic lesions by using ultrasonography. The carotid endarterectomy specimens were standardly processed for histopathological and immunohistochemical exams. The OPN and OPG expression was semi-quantitatively assessed. Our results sustained the relationship between histological American Heart Association (AHA) type and ultrasonographic classification (echogenic versus echolucent) (p<0.001). The semi-quantitative analysis showed that in most cases (31 plaques) OPG and OPN had opposite expressions, whereas in the remaining cases (18 plaques) the expression was similar. There were no correlations between low versus high expression of intra-plaque OPN and OPG (p=0.335). We found significant correlation for OPN and plaque echogenicity (p=0.011), but not for OPG (p=0.079). OPN expression (low versus high) was correlated with plaque type (stable versus unstable) (p=0.036), plaque ulceration (p=0.009) and inflammation (p<0.001). OPG expression (low versus high) did not reveal statistically significant differences with plaque type (stable versus unstable) and vulnerability plaque parameters, respectively. OPG and OPN co-exist in carotid atherosclerotic plaque demonstrating a modulatory role in inflammatory and calcification processes. OPG is strongly expressed in stable, calcified plaques, while OPN is poorly expressed in calcified plaques and in plaques without hemorrhage, ulceration, inflammation, or necrosis. Starting from the molecular mechanisms, further studies of biomarkers are important to identify new therapeutic resources meant to prevent and treat vascular calcification.

Cephalic undifferentiated carcinoma with osteoclast-like giant cells arising from the main pancreatic duct: case report and literature review.

Undifferentiated carcinoma with osteoclast-like giant cell (UCOGC) is a ductal carcinoma variant with a recently reported more protracted survival and pathognomonic histology comprising two cell populations: the mononuclear tumoral cells and nontumoral multinucleated giant cells. It usually presents as a large heterogenic tumor with mixed solid-cystic components. The tumor develops from the ductal epithelium but the sequence of epithelial changes is often not identified due to the rapid tumoral growth and associated necrotic changes. We report a case of a 76-year-old patient diagnosed with cephalic UCOGC originating in the epithelium of the main pancreatic duct with endoluminal growth and foci of other ductal neoplasms (high-grade pancreatic intraepithelial neoplasia (PanIN) and conventional ductal carcinoma). The particularity of our case consists in the identification of the columnar epithelium conversion, through high-grade PanIN, into UCOGC specific malignant features, in a large size tumor - aspect usually reported in small tumors. Alongside our case we also present a brief literature review of cephalic UCOGC case reports and case series.

DNA bending in the synaptic complex in V(D)J recombination: turning an ancestral transpososome upside down.

In all jawed vertebrates RAG (recombination activating gene) recombinase orchestrates V(D)J recombination in B and T lymphocyte precursors, assembling the V, D and J germline gene segments into continuous functional entities which encode the variable regions of their immune receptors. V(D)J recombination is the process by which most of the diversity of our specific immune receptors is acquired and is thought to have originated by domestication of a transposon in the genome of a vertebrate.  RAG acts similarly to the cut and paste transposases, by first binding two recombination signal DNA sequences (RSSs), which flank the two coding genes to be adjoined, in a process called synaptic or paired complex (PC) formation. At these RSS-coding borders, RAG first nicks one DNA strand, then creates hairpins, thus cleaving the duplex DNA at both RSSs. Although RAG reaction mechanism resembles that of insect mobile element transposases and RAG itself can inefficiently perform intramolecular and intermolecular integration into the target DNA, inside the nuclei of the developing lymphocytes transposition is extremely rare and is kept under proper surveillance. Our review may help understand how RAG synaptic complex organization prevents deleterious transposition. The phosphoryl transfer reaction mechanism of RNAseH-like fold DDE motif enzymes, including RAG, is discussed accentuating the peculiarities described for various transposases from the light of their available high resolution structures (Tn5, Mu, Mos1 and Hermes). Contrasting the structural 3D organization of DNA in these transpososomes with that of the RSSs-DNA in RAG PC allows us to propose several clues for how evolutionarily RAG may have become "specialized" in recombination versus transposition.