The Aspergillus nidulans pyruvate dehydrogenase kinases are essential to integrate carbon source metabolism

The pyruvate dehydrogenase complex (PDH), that converts pyruvate to acetyl-coA, is regulated by pyruvate dehydrogenase kinases (PDHK) and phosphatases (PDHP) that have been shown to be important for morphology, pathogenicity and carbon source utilization in different fungal species. The aim of this study was to investigate the role played by the three PDHKs PkpA, PkpB and PkpC in carbon source utilization in the reference filamentous fungus Aspergillus nidulans, in order to unravel regulatory mechanisms which could prove useful for fungal biotechnological and biomedical applications. PkpA and PkpB were shown to be mitochondrial whereas PkpC localized to the mitochondria in a carbon source-dependent manner. Only PkpA was shown to regulate PDH activity. In the presence of glucose, deletion of pkpA and pkpC resulted in reduced glucose utilization, which affected carbon catabolite repression (CCR) and hydrolytic enzyme secretion, due to de-regulated glycolysis and TCA cycle enzyme activities. Furthermore, PkpC was shown to be required for the correct metabolic utilization of cellulose and acetate. PkpC negatively regulated the activity of the glyoxylate cycle enzyme isocitrate lyase (ICL), required for acetate metabolism. In summary, this study identified PDHKs important for the regulation of central carbon metabolism in the presence of different carbon sources, with effects on the secretion of biotechnologically important enzymes and carbon source-related growth. This work demonstrates how central carbon metabolism can affect a variety of fungal traits and lays a basis for further investigation into these characteristics with potential interest for different applications.We would like to thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant numbers 2016/07870-9 for GHG and 2014/00789-6 for LJA), the Science Foundation Ireland (SCI, grant number 13/CDA/2142 for OB) for providing financial support.info:eu-repo/semantics/publishedVersio

Metabolite Profiles of Sugarcane Culm Reveal the Relationship Among Metabolism and Axillary Bud Outgrowth in Genetically Related Sugarcane Commercial Cultivars

Metabolic composition is known to exert influence on several important agronomic traits, and metabolomics, which represents the chemical composition in a cell, has long been recognized as a powerful tool for bridging phenotype–genotype interactions. In this work, sixteen truly representative sugarcane Brazilian varieties were selected to explore the metabolic networks in buds and culms, the tissues involved in the vegetative propagation of this species. Due to the fact that bud sprouting is a key trait determining crop establishment in the field, the sprouting potential among the genotypes was evaluated. The use of partial least square discriminant analysis indicated only mild differences on bud outgrowth potential under controlled environmental conditions. However, primary metabolite profiling provided information on the variability of metabolic features even under a narrow genetic background, typical for modern sugarcane cultivars. Metabolite–metabolite correlations within and between tissues revealed more complex patterns for culms in relation to buds, and enabled the recognition of key metabolites (e.g., sucrose, putrescine, glutamate, serine, and myo-inositol) affecting sprouting ability. Finally, those results were associated with the genetic background of each cultivar, showing that metabolites can be potentially used as indicators for the genetic background

Breast cancer and neoadjuvant chemotherapy: indications for and limits of breast-conserving surgery

AIM: The aim of our study was to determine how many and what subtypes of breast cancer could be treated with breast-conserving surgery after NACT. Another outcome was to determine the applicability of MD Anderson Cancer Center nomogram to predict it. MATERIAL OF STUDY: We reviewed the histological examinations of 86 performed mastectomies according to the indications to BCS after NACT. For 73 cases, collected all the necessary data, we could use the nomogram available on the MDACC website to calculate the probability of BCS and pCR. RESULTS: In our experience the BCS rate would increase by 34,1%, from 3,7% to 3.,8%. Patients with Triple Negative and HER2+, ER- more than ER+, show higher rates of pCR and BCS. The MDACC nomogram predicts accurately the probability of pCR and BCS after NACT in HER2 negative cancers but not in HER2 positive ones treated with Trastuzumab. This suggests that a specific nomogram for HER2 positive carcinomas has to be developed. CONCLUSION: BCS after NACT is feasible and safe in terms of LRR, DFS and OS, if patients are properly studied and selected. Indication to BCS after NACT needs of a multidisciplinary assessment considering clinical staging, biological characteristics, the radiological response pattern and the expected concordance between imaging and histology

Effects of maternal anemia on computerized cardiotocography and fetal biophysical profile

OBJETIVOS: avaliar a influência dos níveis de hemoglobina (Hb) materna nos padrões da frequência cardíaca fetal (FCF) e no perfil biofísico fetal (PBF) em gestações a termo. MÉTODOS: gestantes portadoras de anemia (Hb<11,0 g/dL) foram avaliadas prospectivamente, entre a 36ª e a 40ª semana de gestação, no período compreendido entre janeiro de 2008 e março de 2009. O Grupo Controle foi constituído por gestantes de termo, saudáveis, com valores normais de hemoglobina (Hb>11,0 g/dL). Foram excluídos casos com anomalias ou restrição do crescimento fetal. A avaliação da FCF foi realizada pela cardiotocografia computadorizada (Sistema8002-Sonicaid) e análise do traçado com 30 minutos de exame. O PBF foi realizado em todas as pacientes. Foram utilizados os testes t de Student, teste do &#967;2 e teste exato de Fisher. O nível de significância utilizado foi de 0,05. RESULTADOS: A média da Hb materna no grupo com anemia (n=18) foi de 9,4 g/dL (DP=1,4 g/dL) e no Grupo Controle 12,4 g/dL (DP=1,3 g/dL). Quanto aos parâmetros da cardiotocografia, não foi constatada diferença significativa nas médias entre os grupos com anemia e controle, respectivamente: FCF basal (131,3 bpm versus 133,7 bpm, p=0,5), acelerações da FCF > 10 bpm (7,9 versus. 8,2, p=0,866), acelerações da FCF > 15 bpm (5,2 versus 5,4, p=0,9), episódios de alta variação da FCF (17,1 versus 15,5 min, p=0,5), episódios de baixa variação da FCF (4,4 versus 3,6 min, p=0,6), e variação de curto prazo (10,5 versus 10,9 ms, p=0,5). Em ambos os grupos, todas as pacientes apresentaram PBF normal. CONCLUSÕES: este estudo sugere que a anemia materna leve ou moderada, sem outras comorbidades maternas ou fetais, não se associa a anormalidades nos parâmetros do perfil biofísico fetal e da FCF analisada pela cardiotocografia computadorizada.PURPOSES: to evaluate the influence of maternal hemoglobin (Hb) levels in the patterns of fetal heart rate (FHR) and in the fetal biophysical profile (FBP) in term gestations. METHODS: pregnant women with anemia (Hb<11.0 g/dL) were prospectively evaluated between the 36th and the 40th week of gestation, from January 2008 to March 2009. The Control Group was composed of term and healthy pregnant women, with normal values of hemoglobin (Hb>11,0 g/dL). Cases of anomalies or fetal growing restrictions were excluded. The FHR evaluation was performed by computerized cardiotocography (8002 System-Sonicaid), and by record analysis during 30 minutes of exam. The FBP was done in all the patients. Student's, &#967;2 and Fisher's exact tests were used, with 0.05 significance level. RESULTS: The average of maternal Hb in the group with anemia (n=18) was 9.4 g/dL (DP=1.4 g/dL), and in the control group, 12.4g/dL (DP=1.3 g/dL). There has been no significant mean differences between groups concerning the cardiotocography parameters, respectively: basal FHR(131.3 versus 133.7 bpm, p=0.5), FHR accelerations > 10b pm (7.9 versus 8.2, p=0.866), FHR accelerations > 15 bpm (5.2 versus. 5.4, p=0.9), episodes of high variation of the FHR (17.1 versus 15.5 min, p=0,5), episodes of variation of the FHR (4.4 versus 3.6 min, p=06), and short term variation (10.5 versus 10.9 ms, p=0.5). In both groups, all patients presented normal FBP. CONCLUSIONS: this study suggests that light or moderate maternal anemia, without other maternal or fetal comorbidity, is not associated with abnormalities in the parameters of fetal biophysical profile and of the FHR analyzed by computerized cardiotocography

Male Breast Cancer: Surgical and Genetic Features and a Multidisciplinary Management Strategy

Background: Male breast cancer (MBC) is a rare disease with a rising incidence trend. The major risk factors related to MBC are a positive family history of breast cancer (BC) and BRCA1/2 mutations, which indicate a relevant genetic role. Methods: In this retrospective series, we enrolled 69 male patients presenting with male breast cancer (MBC) between 01/01/1992 and 31/12/2018, and 26 high-risk not-affected men presenting between 01/01/2016 and 31/12/2018. Participants' electronic clinical records were reviewed. Patients' data reported age at diagnosis, tumor characteristics, therapeutic management, and BRCA1/2 status as well as a family history of breast, ovarian, or prostate cancer (PCa) in first-degree relatives. Results: We analyzed 69 MBC patients. Median age was 64 years. The majority of tumors diagnosed were of an early TNM stage. The most frequent histological subtype was invasive ductal carcinoma (76.7%). Hormone receptors were positive in &gt;90% of MBC cases. Nearly all patients underwent modified radical mastectomy or total mastectomy. Adjuvant endocrine therapy was delivered in 59.4%. Among MBC-affected patients, we recorded a high percentage of a positive family history of BC. Mutational analysis for the BRCA1/2 genes was performed in 17 MBC patients; 11.8% were carriers of BRCA2 pathogenic mutations. Among 26 healthy high-risk subjects included in this case series, 4 were BRCA1 mutation carriers and 9 were BRCA2 mutation carriers. Discussion: We evaluated the distribution of clinicopathological characteristics in MBC subjects and assessed the frequency of mutations in the BRCA genes in affected patients and healthy high-risk subjects, with the aim of proposing a surveillance program for BC and PCa

Multidisciplinary management of CDH1 germinal mutation and prophylactic management hereditary lobular breast cancer: A case report

Introduction: Germline CDH1 mutations, classically associated with hereditary diffuse gastric cancer (HDGC), also imply an increased lifetime risk of developing lobular breast cancer (LBC) in a highly penetrant autosomal dominant manner. Presentation of case: We report a 44-year-old woman CDH1 mutation carrier with a strong family history of cancer, who previously had prophylactic total gastrectomy. We registered normal findings at the breast and axilla assessment. Mammography, ultrasonography and breast MRI scans were negative for cancer. In our Institute a bilateral prophylactic mastectomy followed by breast reconstruction was performed. Foci of atypical lobular hyperplasia(ALH) and lobular carcinoma in situ (LCIS) were histologically shown. Discussion: The current consensus guidelines for women with pathogenic CDH1 mutations recommend annual mammography, ultrasound, breast MRI scans and clinical breast examination starting at the age of 35. Due to the well-documented aggressive behavior of this particular type of cancer, bilateral mastectomy and reconstruction would be more beneficial for this kind of high-risk patients. Conclusion: Conflicting evidences and lacking data about the benefits in terms of overall survival, disease-free survival and the long-term outcomes related to prophylactic bilateral mastectomy for CDH1 mutation carriers restrict the instruction for this type of procedure to selected cases, which should always be managed by a multidisciplinary team

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Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy used as treatment of colo-rectal carcinomatosis: a multicentric study

The aim of this study is to assess the morbidity and mortality related to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colo-rectal carcinomatosis. A retrospective multi-institutional study from seven Italian Centers was performed. One hundred and seventy-two patients, submitted to cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) to treat carcinomatosis of colorectal origin, were recorded. Postoperative morbidity was evaluated in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Post-operative mortality was evaluated as patients' death within 60 days from surgical procedures. Predictors of morbidity were evaluated with univariate and multivariate analyses. Post-operative morbidity occurred in 83 patients (48.3%): grades 1-2 in 29 cases (16.9%), and grades 3-4 in 54 (31.4%). Mortality occurred in four cases (2.3%). Number of anastomoses (OR 1.45; 95% CI 1.05-2.00; p = 0.024), number of blood transfusions (OR 1.31; 95% CI 1.11-1.54; p = 0.001) and chemotherapy regimen [Oxaliplatin (OX): OR 2.87; 95% CI 1.22-6.75; p = 0.015] remained, in multivariate analysis, in a statistically significant correlation with overall morbidity. The only variable that was proven to have statistically significant correlation with 3-4 morbidity was the number of blood transfusions (OR 1.25; 95% CI 1.07-1.46; p = 0.005). Morbidity and mortality do not preclude the use of CRS plus HIPEC in the treatment of peritoneal carcinomatosis of colorectal origin

Short-term outcome of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: preliminary analysis of a multicentre study

19nononeAim: To assess the incidence of morbidity and mortality of Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy. Patients and Methods: A retrospective multicentric study was performed. Six hundred and eighty-three patients were recorded. Predictors of morbidity and mortality were evaluated with univariate and multivariate analysis. Results: In univariate analysis, older age, Eastern Cooperative Oncology Group score, a greater value of Peritoneal Cancer Index (PCI) and sub-optimal cytoreduction were correlated with higher mortality, while older age, presence of ascites, ovarian origin of carcinomatosis, closed technique, a greater value of PCI, longer operative time and sub-optimal cytoreduction were predictors of higher morbidity. In multivariate analysis, older age and a greater value of PCI were correlated with higher mortality; older age, ovarian origin of tumor, presence of ascites, closed technique and longer operative time were predictors of higher morbidity. Conclusion: Careful patient selection has to be performed to improve clinical outcomes.mixedMacrì, Antonio; Arcoraci, Vincenzo; Belgrano, Valerio; Caldana, Marina; Cioppa, Tommaso; Costantini, Barbara; Cucinotta, Eugenio; De Cian, Franco; De Iaco, Pierandrea; De Manzoni, Giovanni; Di Giorgio, Angelo; Fleres, Francesco; Muffatti, Francesca; Orsenigo, Elena; Pinna, Antonio Daniele; Roviello, Franco; Sammartino, Paolo; Scambia, Giovanni; Saladino, EdoardoMacrì, Antonio; Arcoraci, Vincenzo; Belgrano, Valerio; Caldana, Marina; Cioppa, Tommaso; Costantini, Barbara; Cucinotta, Eugenio; De Cian, Franco; De Iaco, Pierandrea; De Manzoni, Giovanni; Di Giorgio, Angelo; Fleres, Francesco; Muffatti, Francesca; Orsenigo, Elena; Pinna, Antonio Daniele; Roviello, Franco; Sammartino, Paolo; Scambia, Giovanni; Saladino, Edoard