Cellular and Molecular Life Sciences

Helicobacter pylori infection and gastrointestinal tract cancer biology: considering a double-edged sword reflection

Adult stem cells at work: regenerating skeletal muscle Abstract Skeletal muscle regeneration is a finely tuned process involving the activation of various cellular and molecular processes. Satellite cells, the stem cells of skeletal muscle, are indispensable for skeletal muscle regeneration. Their functionality is critically modulated by intrinsic signaling pathways as well as by interactions with the stem cell niche. Here, we discuss the properties of satellite cells, including heterogeneity regarding gene expression and/or their phenotypic traits and the contribution of satellite cells to skeletal muscle regeneration. We also summarize the process of regeneration with a specific emphasis on signaling pathways, cytoskeletal rearrangements, the importance of miRNAs, and the contribution of non-satellite cells such as immune cells, fibro-adipogenic progenitor cells, and PW1-positive/Pax7-negative interstitial cells.

Progress on chicken T cell immunity to viruses Abstract Avian virus infection remains one of the most important threats to the poultry industry. Pathogens such as avian influenza virus (AIV), avian infectious bronchitis virus (IBV), and infectious bursal disease virus (IBDV) are normally controlled by antibodies specific for surface proteins and cellular immune responses. However, standard vaccines aimed at inducing neutralizing antibodies must be administered annually and can be rendered ineffective because immune-selective pressure results in the continuous mutation of viral surface proteins of different strains circulating from year to year. Chicken T cells have been shown to play a crucial role in fighting virus infection, offering lasting and cross-strain protection, and offer the potential for developing universal vaccines. This review provides an overview of our current knowledge of chicken T cell immunity to viruses. More importantly, we point out the limitations and barriers of current research and a potential direction for future studies.

Characterization of functional subgroups among genetically identified cholinergic neurons in the pedunculopontine nucleus Abstract The pedunculopontine nucleus (PPN) is a part of the reticular activating system which is composed of cholinergic, glutamatergic and GABAergic neurons. Early electrophysiological studies characterized and grouped PPN neurons based on certain functional properties (i.e., the presence or absence of the A-current, spike latency, and low threshold spikes). Although other electrophysiological characteristics of these neurons were also described (as high threshold membrane potential oscillations, great differences in spontaneous firing rate and the presence or absence of the M-current), systematic assessment of these properties and correlation of them with morphological markers are still missing. In this work, we conducted electrophysiological experiments on brain slices of genetically identified cholinergic neurons in the PPN. Electrophysiological properties were compared with rostrocaudal location of the neuronal soma and selected morphometric features obtained with post hoc reconstruction. We found that functional subgroups had different proportions in the rostral and caudal subregions of the nucleus. Neurons with A-current can be divided to early-firing and late-firing neurons, where the latter type was found exclusively in the caudal subregion. Similar to this, different parameters of high threshold membrane potential oscillations also showed characteristic rostrocaudal distribution. Furthermore, based on our data, we propose that high threshold oscillations rather emerge from neuronal somata and not from the proximal dendrites. In summary, we demonstrated the existence and spatial distribution of functional subgroups of genetically identified PPN cholinergic neurons, which are in accordance with differences found in projection and in vivo functional findings of the subregions. Being aware of functional differences of PPN subregions will help the design and analysis of experiments using genetically encoded opto- and chemogenetic markers for in vivo experiments.

Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword Abstract Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.

A role for polycystin-1 and polycystin-2 in neural progenitor cell differentiation Abstract Polycystin-1 (PC1) and polycystin-2 (PC2) are transmembrane proteins encoded by the Pkd1 and Pkd2 genes, respectively. Mutations in these genes are causative for the development of autosomal-dominant polycystic kidney disease. A prominent feature of this disease is an unbalanced cell proliferation. PC1 and PC2 physically interact to form a complex, which localizes to the primary cilia of renal epithelial cells. Recently, PC1 and PC2 have also been described to be present in primary cilia of radial glial cells (RGCs) and to contribute to the planar cell polarity of late RGCs and E1 ependymal cells. As neural progenitor cells (NPCs), early RGCs have to balance proliferation for expansion, or for self-renewal and differentiation to generate neurons. It is not known whether the polycystins play a role in this process. Here, we show that PC1 and PC2 are expressed in RGCs of the developing mouse cerebral cortex during neurogenesis. Loss-of-function analysis and cell-based assays reveal that a reduction of PC1 or PC2 expression leads to increased NPC proliferation, while the differentiation to neurons becomes impaired. The increased NPC proliferation is preceded by enhanced Notch signaling and accompanied by a rise in the number of symmetric cell divisions. The transcription factor STAT3 seems to be mechanistically important for polycystin signaling in NPCs as either STAT3 knockdown or inhibition of STAT3 function abrogates the increased proliferation driven by reduced polycystin expression. Our findings indicate that PC1 and PC2 are critical for maintaining a balance between proliferation and differentiation of NPCs.

Advances in targeted degradation of endogenous proteins Abstract Protein silencing is often employed as a means to aid investigations in protein function and is increasingly desired as a therapeutic approach. Several types of protein silencing methodologies have been developed, including targeting the encoding genes, transcripts, the process of translation or the protein directly. Despite these advances, most silencing systems suffer from limitations. Silencing protein expression through genetic ablation, for example by CRISPR/Cas9 genome editing, is irreversible, time consuming and not always feasible. Similarly, RNA interference approaches warrant prolonged treatments, can lead to incomplete protein depletion and are often associated with off-target effects. Targeted proteolysis has the potential to overcome some of these limitations. The field of targeted proteolysis has witnessed the emergence of many methodologies aimed at targeting specific proteins for degradation in a spatio-temporal manner. In this review, we provide an appraisal of the different targeted proteolytic systems and discuss their applications in understanding protein function, as well as their potential in therapeutics.

The role of ASXL1 in hematopoiesis and myeloid malignancies Abstract Recent high-throughput genome-wide sequencing studies have identified recurrent somatic mutations in myeloid neoplasms. An epigenetic regulator, Additional sex combs-like 1 (ASXL1), is one of the most frequently mutated genes in all subtypes of myeloid malignancies. ASXL1 mutations are also frequently detected in clonal hematopoiesis, which is associated with an increased risk of mortality. Therefore, it is important to understand how ASXL1 mutations contribute to clonal expansion and myeloid transformation in hematopoietic cells. Studies using ASXL1-depleted human hematopoietic cells and Asxl1 knockout mice have shown that deletion of wild-type ASXL1 protein leads to impaired hematopoiesis and accelerates myeloid malignancies via loss of interaction with polycomb repressive complex 2 proteins. On the other hand, ASXL1 mutations in myeloid neoplasms typically occur near the last exon and result in the expression of C-terminally truncated mutant ASXL1 protein. Biological studies and biochemical analyses of this variant have shed light on its dominant-negative and gain-of-function features in myeloid transformation via a variety of epigenetic changes. Based on these results, it would be possible to establish novel promising therapeutic strategies for myeloid malignancies harboring ASXL1mutations by blocking interactions between ASXL1 and associating epigenetic regulators. Here, we summarize the clinical implications of ASXL1 mutations, the role of wild-type ASXL1 in normal hematopoiesis, and oncogenic functions of mutant ASXL1 in myeloid neoplasms.

E2F1 mediates the downregulation of POLD1 in replicative senescence Abstract POLD1, the catalytic subunit of DNA Pol δ, plays an important role in DNA synthesis and DNA damage repair, and POLD1 is downregulated in replicative senescence and mediates cell aging. However, the mechanisms of age-related downregulation of POLD1 expression have not been elucidated. In this study, four potential CpG islands in the POLD1 promoter were found, and the methylation levels of the POLD1 promoter were increased in aging 2BS cells, WI-38 cells and peripheral blood lymphocytes, especially at a single site, CpG 36, in CpG island 3. Then, the transcription factor E2F1 was observed to bind to these sites. The binding affinity of E2F1 for the POLD1 promoter was found to show age-related attenuation and was confirmed to be positively regulated by the E2F1 level and negatively regulated by POLD1 promoter methylation. Moreover, cell senescence characteristics were observed in the cells transfected with shRNA-E2F1 and could contribute to the downregulation of POLD1 induced by the E2F1 decline. Collectively, these results indicated that the attenuation of the binding affinity of E2F1 for the POLD1 promoter, mediated by an age-related decline in E2F1 and increased methylation of CpG island 3, downregulates POLD1 expression in aging.

Multiple roles of CTDK-I throughout the cell Abstract The heterotrimeric carboxy-terminal domain kinase I (CTDK-I) in yeast is a cyclin-dependent kinase complex that is evolutionally conserved throughout eukaryotes and phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II (RNApII) on the second-position serine (Ser2) residue of YSPTSPS heptapeptide repeats. CTDK-I plays indispensable roles in transcription elongation and transcription-coupled processing, such as the 3′-end processing of nascent mRNA transcripts. However, recent studies have revealed additional roles of CTDK-I beyond its primary effect on transcription by RNApII. Here, we describe recent advances in the regulation of genomic stability and rDNA integrity by CTDK-I and highlight the previously underappreciated cellular roles of CTDK-I in rRNA synthesis by RNA polymerase I and translational initiation and elongation. These multiple roles of CTDK-I throughout the cell expand our understanding of how this complex functions to coordinate diverse cellular processes through gene expression and how the human orthologue exerts its roles in diseased states such as tumorigenesis.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Surgery

Predictive value of the Ki67 index for lymph node metastasis of small non-functioning pancreatic neuroendocrine neoplasms Abstract Background We evaluated the clinicopathological factors associated with lymph node metastasis in patients with non-functioning pancreatic neuroendocrine neoplasms (PanNENs), focusing on the risk factors and range of lymph node metastasis for tumors ≤ 2 cm in diameter. Methods The subjects of this study were patients with PanNENs consecutively diagnosed at our hospital between January, 2000 and June, 2018. We analyzed 69 patients who underwent R0 resection of a non-functioning sporadic PanNEN with no distant metastasis, as well as 43 patients with tumors ≤ 20 mm in radiological diameter. Results Nineteen patients (27.5%), including 7 (16.3%) with a small PanNEN, had lymph node metastasis. A large radiological diameter, a high Ki67 index, and cyst formation correlated significantly with positive lymph node metastasis. In patients with tumors ≤ 20 mm in diameter, a high Ki67 index correlated significantly with lymph node metastasis. When we set the cut-off Ki67 index as 3.3%, 2 of 43 patients had lymph node metastasis. Tumors in the uncinate process readily metastasized to the region around the superior mesenteric artery. Conclusions These findings suggest that a high Ki67 index indicates a risk of lymph node metastasis for tumors ≤ 20 mm in diameter and that lymphadenectomy should be performed in the region spatially adjacent to the primary tumor.

Robotic versus laparoscopic surgery for rectal cancer: an overview of systematic reviews with quality assessment of current evidence Abstract Purpose The clinical benefits of robotic surgery for patients with rectal cancer have been reported and many systematic reviews have been published. However, they have investigated a variety of outcomes and differ remarkably in quality. In this overview, we summarize the findings of these reviews and evaluate their quality. Methods The PubMed, Scopus, and Cochrane Central Register of Controlled Trials databases were comprehensively searched to identify systematic reviews and meta-analyses that compared robotic and laparoscopic surgery. We assessed the quality of the reviews using the AMSTAR-2 tool. Results The literature search identified 17 eligible reviews, all of which reported that the incidence of conversion to open surgery was lower for robotic surgery than for laparoscopic surgery. Most of the reviews reported no difference in the other outcomes between robotic surgery and laparoscopic surgery. However, the quality of the reviews was judged to be low or critically low. Conclusions Critically low quality evidence suggests that robotic surgery for rectal cancer decreases the likelihood of conversion to open surgery, but other clinical benefits remain unclear. High-quality systematic reviews in which selection of high-quality studies is combined with adequate methodology are needed to clarify the true efficacy of robotic surgery for rectal cancer.

No inflammatory benefit obtained by single-incision laparoscopic surgery for right hemicolectomy compared with conventional laparoscopy Abstract Purpose We evaluated the perioperative inflammatory mediators in a right hemicolectomy performed with single-incision laparoscopic surgery (SILS) and traditional multi-port laparoscopic surgery (MLS) to compare the postoperative inflammatory response and feasibility of SILS with that of MLS. Methods In this retrospective study, we enrolled 56 consecutive colorectal cancer patients who underwent right hemicolectomy prospectively. Twenty patients underwent SILS, and 36 underwent MLS. The preoperative and postoperative levels of plasma vascular endothelial growth factor (VEGF), serum interleukin-6 (IL-6), and C-reactive protein (CRP) as well as the number of platelet cells were measured in all patients. The operation duration, number of harvested lymph nodes, length of the resected bowel, blood loss, and duration of hospital stay were also compared between the two groups. Results Neither SILS nor MLS had any conversion cases. The operation duration was longer for MLS than for SILS. Blood loss tended to be lower among patients who underwent SILS than among those who underwent MLS. However, the number of harvested LNs was significantly lower with SILS than with MLS. In both pre- and postoperative blood examinations, there was no marked difference in inflammatory mediators between MLS and SILS. Conclusion There was no systemic inflammatory advantage associated with SILS compared with MLS.

Lung-diffusing capacity for carbon monoxide predicts early complications after cardiac surgery Abstract Purpose Preoperative pulmonary dysfunction has been associated with increased operative mortality and morbidity after cardiac surgery. This study aimed to determine whether values for the diffusing capacity of the lung for carbon monoxide (DLCO) could predict postoperative complications after cardiac surgery. Methods This study included 408 consecutive patients who underwent cardiac surgery between June 2008 and December 2015. DLCO was routinely determined in all patients. A reduced DLCO was clinically defined as %DLCO < 70%. %DLCO was calculated as DLCO divided by the predicted DLCO. The association between %DLCO and in-hospital mortality was assessed, and independent predictors of complications were identified by a logistic regression analysis. Results Among the 408 patients, 338 and 70 had %DLCO values of ≥ 70% and < 70%, respectively. Complications were associated with in-hospital mortality (P < 0.001), but not %DLCO (P = 0.275). A multivariate logistic regression analysis with propensity score matching identified reduced DLCO as an independent predictor of complications (OR, 3.270; 95%CI, 1.356–7.882; P = 0.008). Conclusions %DLCO is a powerful predictor of postoperative complications. The preoperative DLCO values might provide information that can be used to accurately predict the prognosis after cardiac surgery. Clinical trial registration number UMIN000029985.

Clinical outcome of patients with recurrent non-small cell lung cancer after trimodality therapy Abstract Purposes The purpose of this study was to review the clinical course of patients with recurrence after induction chemoradiotherapy followed by surgery (trimodality therapy) for locally advanced non-small cell lung cancer (LA-NSCLC) and to identify the factors associated with favorable clinical outcome after recurrence. Methods We analyzed the records of 140 patients with LA-NSCLC who were treated with trimodality therapy between 1999 and 2014. Results Recurrence developed after trimodality therapy in 48 patients. A yp-N positive status was associated with a high risk of recurrence (HR, 2.05; P = 0.048). Of the 45 of these patients able to be assessed retrospectively, 18 had oligometastatic recurrence and 20 underwent local treatment with curative intent. Local treatment was most frequently given to patients with oligometastatic recurrence (P < 0.001). The median post-recurrence survival (PRS) was 41.4 months, and the 2-year PRS rate was 62%. Patients who received local treatment showed better PRS (P = 0.009). The presence of liver metastasis (P = 0.008), bone metastasis (P = 0.041), or dissemination (P < 0.0001) were associated with worse PRS. Conclusion The survival of patients who received aggressive local treatment for postoperative recurrence after trimodality therapy for LA-NSCLC was better than that of patients who did not.

The overall survival of breast cancer patients without adjuvant therapy Abstract Purpose There are little data regarding the overall survival (OS) of patients without adjuvant systemic therapy, because most patients have been subject to standardized systemic therapies. We evaluated the baseline risk to facilitate making decisions about adjuvant therapy. Patients and methods A total of 1835 breast cancer patients who did not receive adjuvant systemic therapy between 1964 and 1992 were retrospectively evaluated. We investigated the 10-year disease-free survival (DFS) and OS according to the number of metastatic lymph nodes, pathological T classification, stage, and estrogen receptor (ER) status. Results Survival curves showed that as the number of metastatic lymph nodes, pathological T classification, and staging increased, the 10-year OS and DFS decreased. In univariate and multivariable analyses, the number of metastatic lymph nodes was significantly associated with the DFS and OS, while in a univariate analysis, the pathological T classification and stage were significantly associated with the DFS and OS. ER positivity was a good prognostic factor for the 5-year DFS. However, between 6 and 7 years after surgery, ER negativity was a better prognostic factor than ER positivity. Conclusion We showed survival rates of patients without adjuvant therapy according to TNM classification and ER status. This information can aid in treatment selection for doctors and patients through a shared decision-making approach.

Cancer-induced spiculation on computed tomography: a significant preoperative prognostic factor for colorectal cancer Abstract Purpose Cancer-induced spiculation (CIS) on computed tomography, which is reticular or linear opacification of the pericolorectal fat tissues around the cancer site, is generally regarded as cancer infiltration into T3 or T4, but its clinicopathological significance is unknown. This study examines the correlation between CIS and clinicopathological findings to establish its prognostic value. Methods The subjects of this retrospective study were 335 patients with colorectal cancer (CRC), who underwent curative surgery between January, 2010 and December, 2011, at the National Defense Medical College Hospital in Saitama Prefecture, Japan. Results The level of interobserver agreement in the evaluation of CIS was substantial (83%; kappa value, 0.65). The presence of CIS was specific for T3/T4 disease (positive predictive value, 88.3%), and was significantly associated with tumor size and venous invasion. The 5-year relapse-free survival rate was significantly lower in patients with CIS than in those without CIS (68.6% and 84.0%, respectively, p = 0.001). Subgroup analysis revealed remarkable prognostic differences in patients with stage III and T3 disease. Multivariate analysis revealed that CIS was a significant independent prognostic factor. Conclusions CIS was a significant preoperative prognostic factor and could be useful in the selection of preoperative therapy for patients with CRC.

A novel dual-covering method in video-assisted thoracic surgery for pediatric primary spontaneous pneumothorax Abstract Background Primary spontaneous pneumothorax (PSP) generally occurs in young adults, whereas pediatric PSP is uncommon. It is difficult to source reliable data on pediatric PSP, the management of which is based on guidelines for adult PSP; however, the rate of recurrence after video-assisted thoracoscopic surgery (VATS) for pediatric PSP is reported to be higher. Methods We reviewed retrospectively a collective total of 66 surgical cases of a first pneumothorax episode in 46 children under 16 years of age, who were treated at our hospital between February, 2005 and November, 2017. Results The surgical cases were divided into two groups, depending on how the treated lesions were covered. In the dual-covering (DC) group, the PSP was covered by oxidized regenerated cellulose and polyglycolic acid (8 patients; 13 cases) and in the single-covering (SC) group, the PSP was covered by oxidized regenerated cellulose (38 patients; 53 cases). There was no incidence of recurrence after surgery in the DC group, but 17 cases (32.1%) of recurrence after surgery in the SC group. This difference was significant. Conclusion The DC method prevented the recurrence of PSP more effectively than the SC method after VATS in pediatric patients. Long-term follow-up after VATS for pediatric PSP is also important because of the risk of delayed recurrence.

Keys to successful induction chemoradiotherapy followed by surgery for stage III/N2 non-small cell lung cancer Abstract Surgical intervention after induction chemoradiation is designed as curative treatment for resectable stage III/N2 non-small cell lung cancer. However, there is no definitive evidence to support this approach, possibly because successful treatment requires certain "arts", such as proper patient selection, an appropriate induction regimen, and choice of the best surgical procedure. We review the previous reports and discuss our own experience to explore the appropriate strategy for patients with resectable stage III/N2 disease, and to identify the factors associated with successful surgical intervention. Among the studies reviewed, the complete resection rate among intention-to-treat cases was correlated well with the 5-year survival rate, whereas the pneumonectomy rate was correlated inversely with the 5-year survival rate. The clinical response rate and downstaging after induction treatment were not associated with survival. Based on these findings, we conclude that complete resection with the avoidance of pneumonectomy is important when selecting candidates for multimodal treatment including radical surgery.

Additional effects of duodenojejunal bypass on glucose metabolism in a rat model of sleeve gastrectomy Abstract Purpose Sleeve gastrectomy with duodenojejunal bypass (SG-DJB) is expected to become a popular procedure in East Asia. The aim of this study was to evaluate the effects of duodenojejunal bypass on glucose metabolism in a rat model of sleeve gastrectomy (SG). Methods Twenty-four Sprague–Dawley rats were divided into two groups: SG-DJB and SG alone. 6 weeks after surgery, body weight, feed intake, and metabolic parameters were measured, and oral glucose tolerance tests (OGTT) were performed. The mRNA expression of factors related to gluconeogenesis and glucose transport was evaluated using jejunal samples. Protein expression of factors with significantly different mRNA expression levels was evaluated using immunohistochemistry. Results Body weight and metabolic parameters did not significantly differ between the two groups. During the OGTT, the SG-DJB group showed an early increase in serum insulin followed by an early decrease in blood glucose compared with the SG group. Expression levels of glucose transporter 1 (GLUT1) and sodium-glucose cotransporter 1 (SGLT1) mRNA and protein in the alimentary limb (AL) were greater in the SG-DJB group than in the SG group. Conclusions The additional effects of duodenojejunal bypass on glucose metabolism after SG may be related to increased expression of GLUT1 and SGLT1 in the AL.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Food Research and Technology

Triticum aestivum ssp. vulgare and ssp. spelta cultivars: 2. Bread-making optimisation Abstract In this study, we analysed the bread quality parameters of five bread-making flour from single cultivars, namely two spelt wheats ('Espelta Álava' and 'Espelta Navarra') and three bread wheats ('Bonpain', 'Craklin' and 'Sensas'). The grain from the five cultivars, all grown in an organic system, had been milled using the same procedure. Given that bread-making value of flour is closely linked to the dough rheological properties, the use of flour types other than bread wheat requires us to consider modifying the bread-making process. Therefore, the first step of this study was to optimise the bread-making process seeking to maximise the quality of the five breads. Subsequently, it was found that despite the poorer rheological properties and higher gli/glu ratio, the breads made with the spelt flours had better bread quality parameters: larger loaf volume, higher crumb resilience and lower crumb density and firmness. Principal component analysis separated the two spelt wheats from the other samples. We speculate that the bread-making process itself may be a major factor in the quality found in these breads.

Possibilities of reducing amounts of vicine and convicine in faba bean suspensions and sourdoughs Abstract Vicine and convicine may be removed from faba bean by hydrolysis to the corresponding aglycones, divicine and isouramil. For total elimination of their toxicity, further degradation of the aglycones should be shown. The aim of the study was to investigate hydrolysis of vicine and convicine using the enzymatic activity in faba bean in flour suspensions and selected lactic acid bacteria used as starters for faba bean fermentation. In addition, the effect of acidity on the stability of vicine and convicine was investigated. Sourdoughs were used in a baking process to obtain breads as final products. Vicine, convicine, and their aglycones were analyzed using reversed phase high pressure liquid chromatography with UV detection (RP-HPLC-UV). Incubation of the suspensions showed rather small vicine and convicine losses. Acidity itself did not cause losses under the conditions studied, apart from that of convicine at low pH. In sourdough fermentation with strains of Lactobacillus plantarum and Pediococcus pentosaceus, losses of vicine and convicine were dependent on the fermentation temperature and the β-glucosidase activity of the starter. Compared to fermentation at 20 °C, more intense acidification at 25 °C resulted in decrease of vicine up to 85% and convicine up to 47%. Levels of vicine and convicine in breads were comparable to levels in sourdoughs. Furthermore, the aglycones were not detected from breads.

Prophylactic properties of Bacillus subtilis in a bovine β-lactoglobulin sensitized mice model Abstract Probiotics have gained considerable attention in recent years due to their biotechnological and immunomodulatory properties. The proteolytic activity and the protective effect of Bacillus subtilis isolated from Algerian goat milk preventing the development of allergic reactions were determined. On the base of SDS–PAGE analysis and the increase of detectable α-NH2 groups, it can be concluded that the isolated isolate has high proteolytic activity. Oral administration of studied Bacillus subtilis DAF442 resulted in significantly lower titers of anti β-lactoglobulin IgG and IgE. This was correlated with a significant decrease in the anaphylactic response ex vivo as measured by reduced short circuit current (Isc) and epithelial conductance (G) and in vivo in mice. Bacillus subtilis DAF442 pretreatment promoted an important protection against changes in intestinal morphology induced by β-lactoglobulin. Hence it can be concluded that studied Bacillus subtilis strain with high proteolytic activity can modulate effectively the immune response and prevent allergic reactions against β-lactoglobulin.

Microbiological status based on 454-pyrosequencing and volatilome analysis of gilthead seabream ( Sparus aurata ) fed on diets with hydrolyzed feather meal and poultry by-product meal as fishmeal replacers Abstract The effect of two experimental diets with different animal protein sources on sensory, microbiological and chemical attributes of Sparus aurata flesh stored at chilling temperatures were explored through sensory evaluation, tag-pyrosequencing of the 16S rRNA gene (V3–V4 region) and SPME–GC/MS. respectively. The 50% replacement of fishmeal by either hydrolyzed feather meal (HFM) or poultry by-product meal (PBM), did not affect the initial microbial composition of seabream. Differences were observed on spoiled fish indicating that the diet with non-ruminant processed animal protein (PAPs) in combination with the applied storage conditions affect the selection of spoilage microbiota. Minor differences were also detected in volatile compounds profile of PAP-fed seabream showing no strong effect on flesh quality of fish. This research constitutes the baseline for further investigation on the use of non-ruminant PAPs in fish diets in order for aquaculture to produce a high quality of farmed fish for the consumer.

High temperature and heating effect on the oxidative stability of dietary cholesterol in different real food systems arising from eggs Abstract Cholesterol, a monounsaturated sterol present in food of animal origin, can be oxidized during food processing and storage, thus generating a series of oxidation products, collectively called oxysterols. These compounds are increasingly considered of potential interest in the onset and development of vascular disease due to their ability to trigger irreversible damage of vascular cells with consequent activation of phagocytes, up-regulation of the expression and synthesis of adhesion molecules and inflammatory cytokines. The understanding of the conditions, in the presence of which the cholesterol oxidation occurs in foods, could certainly help to prevent the accumulation of oxysterols, allowing to avoid harmful effects on human health. The aim of this work was to verify the presence of 7-ketocholesterol, the most representative of oxysterols family, in eggs and derivative obtained through different procedures of cooking. In the light of our results, we confirmed that the temperature and the lipid nature of the food matrix are closely related to the oxidative stability of cholesterol in foodstuffs. In particular, we tested 7-ketocholesterol formation in the presence of palm oil, rich in saturated fatty acids, or soybean oil, rich in polyunsaturated compounds.

Effect of drying processes in the chemical, physico-chemical, techno-functional and antioxidant properties of flours obtained from house cricket ( Acheta domesticus ) Abstract The aims of this study were determine (1) the chemical composition (2) the physico-chemical properties (3) the fatty acid profile (4) the techno-functional and (5) the antioxidant properties of flours obtained from house cricket (Acheta domesticus) using two different methods of drying. In thermal drying cricket flour (TDCF) and lyophilized cricket flour (LCF) high content of protein (62.68–67.48%, respectively) and fat (24.91–19.32% respectively) was found. This content was higher than found in several cereal or pseudocereal flours such as wheat, oat or quinoa. Both types of flours showed good techno-functional properties (water and oil holding capacity, Swelling capacity, emulsion and foam capacity and stability) with higher values in LCF than TDCF. The values obtained for techno-functional properties were similar to those found for several flours obtained from cereal or pseudocereal of fruits coproducts. In LCF and TDFC the main fatty acid detected were linoleic, oleic and palmitic acids. LCF showed stronger radical scavenging (7.18–2.82 mg Trolox equivalent/g, respectively), reducing (0.24–0.15 Trolox equivalent/g, respectively) and chelating capacity (43.78–32.23 µg EDTA/g, respectively) than TDCF. Due to the protein and fat content, the good techno-functional and antioxidant properties the flours obtained from house cricket could be used as food ingredient in the development of novel foods.

Spruce galactoglucomannan-stabilized emulsions as essential fatty acid delivery systems for functionalized drinkable yogurt and oat-based beverage Abstract The food industry has a considerable demand for functional foods, such as emulsions as delivery system for omega-6 and omega-3 fatty acids. Such delivery systems must be stabilized, ideally with a compound that fulfills the criteria for both functionality and sustainability. Spruce galactoglucomannans (GGM) are novel, wood-derived, natural, value-added, versatile, multi-purpose emulsifiers that can physically stabilize oil-in-water emulsions while simultaneously protecting the oil phase against oxidation. In this study, we present for the first time the use of GGM-stabilized emulsions as complex multicomponent delivery systems for omega-6 and omega-3 fatty acids, i.e., (1) cod liver oil in drinkable yogurt and (2) oat oil in a gluten-free vegan beverage. The emulsions and the resulting functionalized beverages were characterized in terms of their physical stabilities. In addition, functionalized, drinkable yogurt was characterized in terms of the oxidative stability of the oil. Results highlighted that oil droplets stabilized with GGM were stable during storage, against thermal treatment, upon addition into the beverages, and GGM protected cod liver oil against oxidation in drinkable yogurt. The results reported here highlight the vast potential for the use of wood lignocellulose-derived, multi-functional hydrocolloids in modern foods.

Gluten-free bread: effect of soy and corn co-products on the quality parameters Abstract Bread is one of the most consumed products in the world and the most studied among the gluten-free foods. Agroindustry co-products are rich sources of functional ingredients, and their chemical composition suggests great potential as a raw material for the food industry. The objective of this study was to evaluate the effect of the addition of 10–30% of okara flour (OF), and 15–45% of corn bran (CB) on the physical and chemical characteristics, sensory profile and consumer preference of gluten-free breads. The addition of higher concentrations of OF resulted in products with decreased technological properties (lower specific volumes, lower slice height, higher firmness, darkening and discoloration of the yellow color). The addition of CB contributed to the maintenance of the yellow color in the crust and crumb and to the increase in the corn flavor intensity. The formulation with 20% OF and 40% CB would be the most interesting, because of the chemical composition (30 µmol of isoflavones aglycones/g of sample and 12.87 g of dietary fiber/100 g of sample and lower content of carbohydrates and caloric value) and similar consumer preference to the other formulations. This formulation had lower discoloration of the yellow color and showed sensory properties suited to consumer preference, such as firmness, porosity, compaction (appearance), corn flavor and moisture (texture). The okara flour and corn bran, soy and corn co-products, respectively, can be used as ingredients in the preparation of gluten-free breads with adequate physical, chemical, technological and sensorial characteristics.

Effect of aroma potential of Saccharomyces cerevisiae fermentation on the volatile profile of raw cocoa and sensory attributes of chocolate produced thereof Abstract This research describes on-farm-inoculated cocoa bean fermentation with two selected strains of high aroma-producing Saccharomyces cerevisiae isolated from wine fermentation and their effects on volatile profile of resulted raw cocoa material and sensory characteristics of chocolates produced. Both strains produced suitably flavour-active esters, aldehydes, ketones and pyrazines in raw cocoa. Inoculation of S. cerevisiae at 0.5 g kg−1 significantly improved the volatile profile of raw cocoa beans and enabled production of chocolate with enhanced intense fresh fruits and floral notes. Chocolate produced thereof presented better overall quality attributed whatever the fermentation time in comparison to the chocolate issued from spontaneous fermentation. Our results suggested the ways of using selected enhanced yeasts as S. cerevisiae for on-farm implementation of bean fermentation as promising alternative possibilities to improve the cocoa fermentation process, desirable flavourful raw cocoa material and high-aroma-quality chocolates produced.

Characterization of polyphenolic constituents from Sanguisorba officinalis L. and its antibacterial activity Abstract Sanguisorba officinalis L., one kind of perennial plants, has been widely distributed in southern Europe, northern Africa and China. The objective of the present work was to evaluate the antibacterial captivities of polyphenolic extract (PE) of S. officinalis L. on five pathogenic bacteria, including Gram-negative bacteria (Escherichia coli and Salmonella typhimurium) and Gram-positive bacteria (Staphylococcus aureus, Listeria monocytogenes and Bacillus subtilis). The antibacterial activities were determined by the diameter of inhibition zone, minimum inhibitory concentration and minimum bactericidal concentration tests. The results showed that purified PE had significantly better performance in inhibiting bacteria than crude PE (P < 0.05), and PE had better inhibition effect on Gram-positive bacteria than Gram-negative bacteria. Using LC–ESI–QTOF–MS/MS technology, a total of 44 polyphenolic compounds were tentatively identified, 26 of which have been discussed for the first time in S. officinalis L. Gallic acid, ellagic acid, catechin and their derivatives, which have been identified as antibacterial bioactivities previously, were the major constituents with the amounts of 10, 8 and 11, respectively. Besides, compared with potassium sorbate and sodium benzoate, purified PE with a low concentration had significantly stronger antibacterial ability against all the tested bacteria (P < 0.05), suggesting that purified PE of S. officinalis L. could be a promising source of food preservatives.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Neurology

Livedo racemosa generalisata: an anthological vision through Vladímir Lébedev painting

Obituary for Prof. Dr. Dr. h.c. Dipl. Ing. Frank Lehmann-Horn

High-intensity training in patients with spinal and bulbar muscular atrophy Abstract Objective Long duration, moderate-intensity exercise is not well tolerated in patients with spinal and bulbar muscular atrophy (SBMA). This study investigated whether patients with SBMA can benefit from high-intensity training (HIT). Methods Ten patients with SBMA were randomized to 8 weeks of supervised HIT [n = 5; age = 50 (25–63) years] followed by 8 weeks of self-training or 8 weeks of no training followed by 8 weeks of non-supervised HIT [n = 5; age = 50 (26–54) years]. Training consisted of 2 × 5-min exercise periods with 1-min cyclic blocks of intermittent maximal intensity exercise on an ergometer bike. Maximal oxygen capacity (VO2max) and workload (Wmax) were measured before and after training by incremental exercise tests. Plasma creatine kinase levels, self-rated muscle pain, muscle fatigue, and activity level were monitored throughout the training period. Results Eight patients completed training. One patient dropped out after 5 weeks of training for private reasons. Another patient was excluded after 4 weeks due to lack of compliance. Eight weeks of training increased both VO2max(1.9 ± 2.3 ml min−1 kg−1; p = 0.04) and Wmax (15.6 ± 17.9 W; p = 0.03) in the 8 patients who completed training. There were no changes in plasma creatine kinase levels, self-reported muscle pain or muscle fatigue activity level after training. Conclusion This pilot study suggests that high-intensity training is safe and improves fitness in patients with SBMA. Unlike low- and moderate-intensity training, HIT is efficacious and favored over other training forms by the patients.

Anticholinergic drug usage and cognitive impairment: findings from three large European cohort studies

James Crichton-Browne (1840–1938)

"Can't seem to keep my mind to it": did Arthur Miller's Salesman have dementia with Lewy bodies? Abstract We present evidence that Willy Loman, the protagonist of Arthur Miller's play "Death of a Salesman", meets current diagnostic criteria for probable dementia with Lewy bodies. In particular, he presents with attentional deficits and executive dysfunction (with additional subtle visuoperceptual deficits) in addition to dramatic fluctuations in attention and vivid visual hallucinations. Dementia with Lewy bodies is the second most common neurodegenerative dementia. However, it is frequently misdiagnosed or underdiagnosed, even—we contest—in one of the most well-known characters in modern literature.

Anti-natalizumab antibodies during 8 years of natalizumab treatment: effect on natalizumab concentration and α4-integrin receptor saturation

Seizures and epilepsy in multiple sclerosis: epidemiology and prognosis in a large tertiary referral center Abstract Background Seizures and epilepsy may substantially add to the burden of disease in multiple sclerosis (MS), whereas the exact prevalence and prognosis of seizures and epilepsy in patients with MS remains largely unknown. Objectives We aimed to investigate the epidemiology and prognosis of seizures and epilepsy in MS. Methods We retrospectively analyzed a cohort of 4078 MS patients from a single tertiary referral clinic. Results After excluding 37 patients with unconfirmed MS and alternative seizure etiologies, we found seizures attributable to MS in 1.5% and epilepsy in 0.9% of patients. 40.4% of patients with a follow-up of at least twelve months experienced only a single seizure and 59.6% had recurring seizures. 39% of patients with recurrent seizures were considered drug-resistant, with 9.7% experiencing status epilepticus. Seizure recurrence after a first seizure depended significantly on the MS subtype and was seen more often if the first seizure occurred simultaneously with a MS relapse than in the absence of a relapse. Conclusion Our study shows a lower number of seizures and epilepsy in MS than previously reported. While a single seizure in MS usually has a good prognosis, relapse-associated seizures and established epilepsy in MS may not be as benign as previously assumed.

Occurrence of cerebral small vessel disease at diagnosis of MPO-ANCA-associated vasculitis Abstract Background Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often causes peripheral nervous system impairments. However, little is known about subclinical involvements of the central nervous system in AAV. We investigated the frequency and progression of cerebral small vessel disease (SVD) in patients with AAV. Methods This single-center, case–control study comprised 56 patients with myeloperoxidase (MPO)-ANCA-positive AAV. Cerebral SVD presenting periventricular and deep white matter hyperintensities was assessed using brain magnetic resonance imaging (MRI). Seventy-five patients with non-stroke-associated neurological diseases were employed as controls. Results At clinical diagnosis of MPO-ANCA-positive AAV, the frequency of periventricular hyperintensities in the AAV group was significantly higher than that in the control group (P = 0.014). Shinohara and Fazekas grades of periventricular hyperintensities in the AAV group were significantly higher than those in the control group (P = 0.019 and 0.020, respectively). In the AAV group, atherosclerosis-related factors, such as age and hypertension, were not associated with the Shinohara grades of periventricular hyperintensities, whereas serum CRP levels were significantly associated (odds ratio = 6.000, 95% confidence interval 1.648–21.840, P = 0.004). MRI changes were followed in 23 patients with AAV until 2 years after 6 months of diagnosis. Six of these patients worsened the grades of periventricular hyperintensities, while two of 27 in the control group worsened the grades (P = 0.013). Conclusion Inflammatory events are associated with the occurrence of cerebral SVD before clinical diagnosis of MPO-ANCA-positive AAV. The patients may be continuously exposed to the risk of cerebral SVD after immunosuppressive therapy.

In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients Abstract Fatigue is among the most disabling symptoms in patients with multiple sclerosis (PwMS). The common distinction between cognitive and motor fatigue is typically incorporated in self-rating instruments, such as the Chalder Fatigue Questionnaire (CFQ), the Fatigue Scale for Motor and Cognitive Functions (FSMC) or the Modified Fatigue Impact Scale (MFIS). The present study investigated the factor structure of the CFQ, the FSMC and the MFIS utilizing exploratory (EFA) and confirmatory factor analysis (CFA) as well as exploratory structural equation modeling (ESEM). Data of 1.403 PwMS were analyzed, utilizing four samples. The first sample (N = 605) was assessed online and split into two stratified halves to perform EFA, CFA, and ESEM on the CFQ and FSMC. The second sample (N = 293) was another online sample. It served to calculate CFA and ESEM on the CFQ and FSMC. The third sample was gathered in a clinical setting (N = 196) and analyzed by applying CFA and ESEM to the FSMC. The fourth sample (N = 309) was assessed in a clinical setting and allowed to run a CFA and ESEM on the MFIS. Proposed factor structures of all questionnaires were largely confirmed in EFA. However, none of the calculated CFAs and ESEMs could verify the proposed factor structures of the three measures, even with oblique rotation techniques. The findings might have implications for future research into the pathophysiological basis of MS-related fatigue and could affect the suitability of such measures as outcomes for treatment trials, presumably targeting specific sub-components of fatigue.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Microbiology

Correction to: The Isolation and Characterization of Kronos, a Novel Caulobacter Rhizosphere Phage that is Similar to Lambdoid Phages The original version of this article unfortunately contained mistakes in Table 1 values. Some of the values in "TAY-ASD who received services" were incorrect. The corrected Table 1 is given below.

Correction to: Common findings of bla CTX-M-55 -encoding 104–139 kbp plasmids harbored by extended-spectrum β-lactamase-producing Escherichia coli in pork meat, wholesale market workers, and patients with urinary tract infection in Vietnam The original version of this article unfortunately contained a mistake. The legends of Tables 2 and 3, Fig. 1 are incorrect. The corrected legends are given below,

Correction to: Coraliitalea coralii gen. nov., sp. nov., a Marine Bacterium of the Family Flavobacteriaceae Isolated from the Hard Coral Galaxea fascicularis In the original version of this paper, the Chemotaxonomic Characteristics in the Results and Discussion section and legend of Table 2 given in the above paper are incorrect. These errors are corrected with this erratum.

Effect of Host Human Products on Natural Transformation in Acinetobacter baumannii Abstract Our previous data show that serum albumin can trigger natural transformation in Acinetobacter baumannii. However, extracellular matrix/basal membrane components, norepinephrine, and mucin did not have a significant effect on this process. Therefore, the effect of human products appears to be albumin specific, as both BSA and HSA have been shown to increase of natural transformation.

Genome Analysis of Carbaryl-Degrading Strain Pseudomonas putida XWY-1 Abstract Carbaryl was a widely used pesticide in the agriculture industry. The toxicity against non-target organisms and the environmental pollution it caused became the focus of public concern. However, the microbial mechanism of carbaryl degradation was not fully investigated. In the study, we reported the complete genome of the carbaryl-degrading Pseudomonas putida strain XWY-1, which consists of a chromosome (5.9 Mbp) and a plasmid (0.4 Mbp). The carbaryl degradation genes are located on the plasmid. The study on the genome will facilitate to further elucidate the carbaryl degradation and advance the potential biotechnological applications of P. putidastrain XWY-1.

Bla OXA-10 and PSE-1 Genes Located on Class 1 Integrons in Gallibacterium anatis

New Insights of Ustilago maydis as Yeast Model for Genetic and Biotechnological Research: A Review Abstract The basidiomycete Ustilago maydis is a biotrophic organism responsible for corn smut disease. In recent years, it has become one of the most promising models for biochemical and biotechnological research due to advantages, such as rapid growth, and easy genetic manipulation. In some aspects, this yeast is more similar to complex eukaryotes, such as humans, compared to standard laboratory yeast models. U. maydis can be employed as a tool to explore physiological processes with more versatility than other fungi. Previously, U. maydis was only considered as a phytopathogenic fungus, but different studies have shown its potential as a research model. Therefore, numerous promising studies have focused on deepening our understanding of the natural interactions, enzyme production, and biotechnological capacity. In this review, we explore general characteristics of U. maydis, both as pathogenic and "innocuous" basidiomycete. Additionally, a comparison with other yeast models focusing on genetic, biochemical, and biotechnological research are analyzed, to emphasize the versatility, dynamism, and novelty that U. maydis has as a research model. In this review, we highlight the applications of the yeast form of the fungus; however, since the filamentous form is also of relevance, it is addressed in the present work, as well.

Complete Genome Sequence of Actinosynnema pretiosum X47, An Industrial Strain that Produces the Antibiotic Ansamitocin AP-3 Abstract Ansamitocins are extraordinarily potent antitumor agents. Ansamitocin P-3 (AP-3), which is produced by Actinosynnema pretiosum, has been developed as a cytotoxic drug for breast cancer. Despite its importance, AP-3 is of limited applicability because of the low production yield. A. pretiosum strain X47 was developed from A. pretiosum ATCC 31565 by mutation breeding and shows a relatively high AP-3 yield. Here, we analyzed the A. pretiosum X47 genome, which is ~8.13 Mb in length with 6693 coding sequences, 58 tRNA genes, and 15 rRNA genes. The DNA sequence of the ansamitocin biosynthetic gene cluster is highly similar to that of the corresponding cluster in A. pretiosum ATCC 31565, with 99.9% identity. However, RT-qPCR analysis showed that the expression levels of ansamitocin biosynthetic genes were significantly increased in X47 compared with the levels in the wild-type strain, consistent with the higher yield of AP-3 in X47. The annotated complete genome sequence of this strain will facilitate understanding the molecular mechanisms of ansamitocin biosynthesis and regulation in A. pretiosum and help further genetic engineering studies to enhance the production of AP-3.

Probiotic Bacteria: A Promising Tool in Cancer Prevention and Therapy Abstract Gut microbiota is widely considered to be one of the most important components to maintain balanced homeostasis. Looking forward, probiotic bacteria have been shown to play a significant role in immunomodulation and display antitumour properties. Bacterial strains could be responsible for detection and degradation of potential carcinogens and production of short-chain fatty acids, which affect cell death and proliferation and are known as signaling molecules in the immune system. Lactic acid bacteria present in the gut has been shown to have a role in regression of carcinogenesis due to their influence on immunomodulation, which can stand as a proof of interaction between bacterial metabolites and immune and epithelial cells. Probiotic bacteria have the ability to both increase and decrease the production of anti-inflammatory cytokines which play an important role in prevention of carcinogenesis. They are also capable of activating phagocytes in order to eliminate early-stage cancer cells. Application of heat-killed probiotic bacteria coupled with radiation had a positive influence on enhancing immunological recognition of cancer cells. In the absence of active microbiota, murine immunity to carcinogens has been decreased. There are numerous cohort studies showing the correlation between ingestion of dairy products and the risk of colon and colorectal cancer. An idea of using probiotic bacteria as vectors to administer drugs has emerged lately as several papers presenting successful results have been revealed. Within the next few years, probiotic bacteria as well as gut microbiota are likely to become an important component in cancer prevention and treatment.

Nannochloropsis sp. and Spirulina sp. as a Source of Antifungal Compounds to Mitigate Contamination by Fusarium graminearum Species Complex Abstract Phenolic (free, conjugated and bound) and carotenoid extracts from microalgae Nannochloropsis sp. and Spirulina sp. were investigated regarding their potential to mitigate contamination by Fusarium complex fungal pathogens. Free phenolic acid extracts from both microalgae were the most efficient, promoting the lowest mycelial growth rates of 0.51 cm day− 1 (Spirulina sp.) and 0.78 cm day− 1 (Nannochloropsis sp.). An experiment involving natural free phenolic acid extracts and synthetic solutions was carried out based on the natural phenolic acid profile. The results revealed that the synthetic mixtures of phenolic acids from both microalgae were less efficient than the natural extracts at inhibiting fungal growth, indicating that no purification is required. The half-maximal effective concentration (EC50) values of 49.6 μg mL− 1 and 33.9 μg mL− 1 were determined for the Nannochloropsis and Spirulina phenolic acid extracts, respectively. The use of phenolic extracts represents a new perspective regarding the application of compounds produced by marine biotechnology to prevent Fusariumspecies contamination.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Breast Research and Treatment

HER2+ and triple-negative phenotypes in invasive lobular carcinoma might have different specific biological features

Correction to: Breast cancer risk in relation to plasma metabolites among Hispanic and African American women In the original publication of the article, the sixth author name Krita A. Zanetti was mistakenly included as co-author. The corrected author group is given in the correction article. The original article has been corrected.

Microinvasion: could it be sufficient diagnostic criteria for the optimal treatment decision?

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis Abstract Purpose Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA's in patients with bone metastases from breast cancer. Methods We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014–March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI). Results From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88–1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15–1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation. Conclusions These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.

Effects of tea consumption and the interactions with lipids on breast cancer survival Abstract Purpose The effect of tea consumption on breast cancer survival remained to be explored. Meanwhile, green tea favorably facilitates lipid metabolisms in breast cancer survivors. This study aimed to examine the effect of tea consumption and the interactions with lipids on breast cancer survival. Methods A total of 1551 breast cancer patients were recruited between April 2008 and March 2012 and followed up until 31 December 2017 in Guangzhou. The endpoint was progression-free survival (PFS). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariate Cox proportional to estimate the associations. Results PFS was better among women who regularly drank all teas (mainly green tea) except oolong after cancer diagnosis compared with non-tea drinkers (HR 0.52; 95% CI 0.29 ~ 0.91). This association was more evident among women with normal (HR 0.38; 95% CI 0.18 ~ 0.82) than higher (HR 1.22; 95% CI 0.13 ~ 11.82) total cholesterol, though the interaction was not significant. Moreover, the more they drank (≥ 7 times/week), the better prognosis was (HR 0.30; 95% CI 0.11 ~ 0.84). In contrast, oolong tea was observed to have a potential impaired effect on PFS. Conclusions Our findings suggested that regularly drinking all teas (mainly green tea) except oolong after diagnosis was beneficial to breast cancer survival, particularly for women with normal lipids, while oolong tea may have an impaired effect.

Efficacy of a web-based women's health survivorship care plan for young breast cancer survivors: a randomized controlled trial Abstract Purpose Breast cancer survivorship care plans (SCP) have limited content addressing women's health issues. This trial tested if young breast cancer survivors who receive a web-based, women's health SCP were more likely to improve on at least one of the four targeted issues (hot flashes, fertility-related concerns, contraception, and vaginal symptoms) compared to attention controls. Methods A randomized controlled trial recruited female survivors ages 18–45 at diagnosis, 18–50 at enrollment, completed primary cancer treatment, and had a significant women's health issue: moderate or higher fertility-related concerns; ≥ 4 hot flashes/day with ≥ 1 of moderate severity; ≥ 1 moderate vaginal atrophy symptoms; or not contracepting/using less effective methods. Survivors underwent stratified, block randomization with equal allocation to intervention and control groups. The intervention group accessed the online SCP; controls accessed curated resource lists. In intention-to-treat analysis, the primary outcome of improvement in at least one issue by 24 weeks was compared by group. Results 182 participants (86 intervention, 96 control), mean age 40.0 ± 5.9 and 4.4 ± 3.2 years since diagnosis, were randomized. 61 intervention group participants (70.9%) improved, compared to 55 controls (57.3%) (OR 1.82, 95% CI 0.99–3.4, p = 0.057). The following issue-specific improvements were observed in the intervention versus control arms: fertility-related concerns (27.9% vs. 14.6%, OR 2.3, 95% CI 1.1–4.8); hot flashes (58.5% vs. 55.8%, OR 1.1, 95% CI 0.57–2.2); vaginal symptoms (42.5% vs. 40.7%, OR 1.1, 95% CI 0.6–2.0); contraception (50% vs. 42.6%, OR 1.4, 95% CI 0.74–2.5). Conclusions In young breast cancer survivors, a novel, web-based SCP did not result in more change in the primary outcome of improvement in at least one of the four targeted women's health issues, than the attention control condition. The intervention was associated with improved infertility concerns, supporting efficacy of disseminating accessible, evidence-based women's health information to this population.

T-bet + lymphocytes infiltration as an independent better prognostic indicator for triple-negative breast cancer Abstract Purpose T-box transcription factor 21 (T-bet), which is the master regulator of effector T-cell activation, is derived by stimulation of T-cell receptors. In this study, we focused on T-bet and examined the function of activated T cells. Methods This study included 242 patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on tumor-infiltrating lymphocytes (TILs) was defined as ≥ 30 per 6.25 × 10−3 mm2. Results Of the 242 TNBC cases, CD8 was positively expressed in 127 (52.5%) tumors, and T-bet was positively expressed in 67 (27.7%) tumors. T-bet expression was significantly correlated with CD8 expression (p < 0.0001). Patients with T-bet+ tumors had longer overall survival (OS) compared with patients with T-bet− tumors (p = 0.047). The combination of CD8+ and T-bet+ was associated with a better recurrence-free survival (RFS) and OS compared to CD8+/T-bet− tumors (p = 0.037 and p = 0.024, respectively). Adjuvant chemotherapy provided significantly greater benefit to patients with T-bet+ tumors (p = 0.031 for RFS, p = 0.0003 for OS). Multivariate analysis revealed that T-bet expression on TILs was an independent and positive prognostic indicator (HR = 0.36, 95% confidence interval (CI) 0.12–0.94, p = 0.037 for RFS, HR = 0.30, 95% CI 0.07–0.95, p = 0.039 for OS). Conclusions OS was significantly improved for patients with high T-bet-expressing TILs in TNBC. Thus, T-bet may be a predictive indicator for survival and various immunotherapy strategies in TNBC.

The utility of DHL-HisZnNa, a novel antioxidant, against anticancer agent-induced alopecia in breast cancer patients: a multicenter phase II clinical trial Abstract Purpose Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of anticancer drugs; however, there are currently no mechanisms to completely prevent CIA. In this study, we performed a clinical trial to examine whether sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), an alpha-lipoic acid derivative, prevents CIA in patients with breast cancer. Methods Between July 2014 and May 2015, we performed a multi-center, single arm, clinical trial involving 103 breast cancer patients who received adjuvant chemotherapy at three medical institutions in Japan. During chemotherapy, a lotion containing 1% DHL-HisZnNa was applied daily to the patients' scalps. The primary endpoint was the incidence of grade 2 alopecia; the secondary endpoints were the duration of grade 2 alopecia, alopecia-related symptoms, and drug-related adverse events. Alopecia was evaluated by three independent reviewers using head photographs taken from four angles. Results Safety analysis was performed for 101 patients who started the protocol therapy. After excluding one patient who experienced disease progression during treatment, 100 patients who received at least two courses of chemotherapy underwent efficacy analysis. All original 101 patients developed grade 2 alopecia, the median durations of which were 119 days (112–133 days) and 203 days (196–212 days) in the groups treated with four and eight courses of chemotherapy, respectively. Mild or moderate adverse events potentially related to DHL-HisZnNa were observed in 11 patients. Alopecia-related symptoms were observed in 53 patients (52%). Conclusions The application of 1% DHL-HisZnNa to the scalp did not prevent CIA. However, this drug may promote recovery from CIA. Trial registration number: UMIN000014840.

Adult weight gain accelerates the onset of breast cancer Abstract Purpose Weight gain in adulthood is a risk factor for breast cancer; however, the impact on age of onset is unknown. The objective of this study was to investigate whether weight gain from early- to mid-adulthood influenced the timing of breast cancer onset. Methods Increase in body mass index (BMI) from lowest adult BMI to BMI at diagnosis and age at which these events occurred were calculated from breast cancer survivors enrolled in a weight loss trial (n = 660). Quartiles (Q) of the average increase in BMI were determined and associations between weight gain and age at disease onset were analyzed using analysis of covariance and spline regression models. Results A significant linear trend was observed across the quartiles of BMI change for earlier age at diagnosis [Q1 52.3 (± 0.73), Q2 51.9 (± 0.70), Q3 49.6 (± 0.66), Q4 47.3 (± 0.67), p < 0.0001] after adjusting for potential confounders. In analyses that stratified by tumor subtype and menopausal status, significant linear trends continued to be observed for earlier age at diagnosis across quartiles of BMI for ER ± , PR ± , HER2 + , as well as pre- and postmenopausal status (p-values < 0.001). Conclusions Women who gain excess weight during adulthood are not only at risk for breast cancer, but also may experience earlier onset of disease and reduced cancer-free years.

Prospective evaluation of finger two-point discrimination and carpal tunnel syndrome among women with breast cancer receiving adjuvant aromatase inhibitor therapy Abstract Purpose Aromatase inhibitors (AIs) are associated with musculoskeletal symptoms and risk of developing carpal tunnel syndrome (CTS), which can impair quality of life and prompt treatment discontinuation. The incidence of CTS and clinical utility of diagnostic tests such as 2-point discrimination (2-PD) have not been prospectively examined among women receiving AIs. Methods Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were enrolled in a randomized clinical trial investigating adjuvant AIs (Exemestane and Letrozole Pharmacogenetics, ELPh) underwent prospective evaluation of 2-PD with the Disc-criminator™ (sliding aesthesiometer) and completed a CTS questionnaire at baseline, 3, 6, and 12 months, following initiation of AI. Changes in mean 2-PD were analyzed with multivariable mixed effects modelling. A p value < 0.05 was considered statistically significant. Results Of 100 women who underwent baseline 2-PD testing, CTS was identified by questionnaire in 11% at baseline prior to AI initiation. Prevalence of CTS at any time in the first year was 26%. A significant increase in worst 2-PD score was observed from baseline to 3 months (3.7 mm to 3.9 mm, respectively, p = 0.03) when adjusted for age, prior chemotherapy, randomized treatment assignment, and diabetes. There were no significant differences in treatment discontinuation due to CTS between the arms. Conclusion For women receiving adjuvant AI, 2-PD scores were significantly worse at 3 months compared to baseline. Studies are required to assess whether change in 2-PD is an adequate objective assessment for CTS with AI therapy. Early diagnosis of CTS may expedite management, improve AI adherence, and enhance breast cancer outcomes.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com