Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma

10.1038/bjc.2011.333British Journal of Cancer1057945-952BJCA

Polymorphic residues in rice NLRs expand binding and response to effectors of the blast pathogen

Accelerated adaptive evolution is a hallmark of plant-pathogen interactions. Plant intracellular immune receptors (NLRs) often occur as allelic series with differential pathogen specificities. The determinants of this specificity remain largely unknown. Here, we unravelled the biophysical and structural basis of expanded specificity in the allelic rice NLR Pik, which responds to the effector AVR-Pik from the rice blast pathogen Magnaporthe oryzae. Rice plants expressing the Pikm allele resist infection by blast strains expressing any of three AVR-Pik effector variants, whereas those expressing Pikp only respond to one. Unlike Pikp, the integrated heavy metal-associated (HMA) domain of Pikm binds with high affinity to each of the three recognized effector variants, and variation at binding interfaces between effectors and Pikp-HMA or Pikm-HMA domains encodes specificity. By understanding how co-evolution has shaped the response profile of an allelic NLR, we highlight how natural selection drove the emergence of new receptor specificities. This work has implications for the engineering of NLRs with improved utility in agriculture

Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the colon cancer family registry cohort

Objectives: Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression. Design: This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification). Results: Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression. Conclusions: A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.Christophe Rosty, Mark Clendenning, Michael D Walsh, Stine V Eriksen … Nicola Poplawski … Joanne Young … et al

Modulating RNA structure and catalysis: lessons from small cleaving ribozymes

RNA is a key molecule in life, and comprehending its structure/function relationships is a crucial step towards a more complete understanding of molecular biology. Even though most of the information required for their correct folding is contained in their primary sequences, we are as yet unable to accurately predict both the folding pathways and active tertiary structures of RNA species. Ribozymes are interesting molecules to study when addressing these questions because any modifications in their structures are often reflected in their catalytic properties. The recent progress in the study of the structures, the folding pathways and the modulation of the small ribozymes derived from natural, self-cleaving, RNA motifs have significantly contributed to today’s knowledge in the field

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Avaliação da função pulmonar e da qualidade de vida em pacientes submetidos à ressecção pulmonar por neoplasia Assessment of pulmonary function and quality of life in patients submitted to pulmonary resection for cancer

OBJETIVO: Avaliar as repercussões da ressecção pulmonar sobre a função pulmonar e a qualidade de vida (QV) de pacientes com câncer de pulmão primário ou metastático. MÉTODOS: Estudo de coorte prospectivo que incluiu todos os pacientes que realizaram ressecção pulmonar por neoplasia no Hospital A. C. Camargo entre setembro de 2006 e março de 2007. Os pacientes foram avaliados no pré-operatório e após seis meses do procedimento cirúrgico através de espirometria. Após seis meses de pós-operatório, os pacientes responderam a um questionário de QV geral (Medical Outcomes Study 36-item Short-form Health Survey) e um específico para sintomas respiratórios (Saint George's Respiratory Questionnaire). Os valores de QV obtidos foram comparados a valores de uma população geral e aos de uma população de portadores de DPOC. RESULTADOS: Foram incluídos 33 pacientes (14 homens e 19 mulheres), com idade entre 39 e 79 anos. Todos os pacientes, tabagistas ou não, apresentaram piora significativa da função pulmonar. Observamos uma redução de aproximadamente 5% na média dos escores do questionário de QV geral em comparação àquela da população geral. Houve uma redução de 50-60% nos vários domínios do questionário específico para sintomas, quando comparado aos resultados da população geral, e um aumento de aproximadamente 20%, quando comparado aos resultados da população com DPOC. CONCLUSÕES: Existe impacto direto da ressecção pulmonar na deterioração da função pulmonar e na QV com ênfase nos aspectos diretamente ligados à função pulmonar. Cabe ressaltar a importância da avaliação da função pulmonar destes pacientes no pré-operatório para se estimar sua evolução pós-cirúrgica.<br>OBJECTIVE: To evaluate the effects that pulmonary resection has on pulmonary function and quality of life (QoL) in patients with primary or metastatic lung cancer. METHODS: This was a prospective cohort study involving all patients submitted to pulmonary resection for cancer between September of 2006 and March of 2007 at the A. C. Camargo Hospital in São Paulo, Brazil. Patients underwent spirometry in the preoperative period and at six months after the surgical procedure. After a postoperative period of six months, the patients completed an overall QoL questionnaire (the Medical Outcomes Study 36-item Short-form Health Survey) and another one, specific for respiratory symptoms (the Saint George's Respiratory Questionnaire). The scores obtained in our study were compared with those previously obtained for a general population and for a population of patients with COPD. RESULTS: We included 33 patients (14 males and 19 females), ranging in age from 39 to 79 years. All of the patients, smokers and nonsmokers alike, presented significant worsening of pulmonary function. The mean scores on the overall QoL questionnaire were approximately 5% lower than those obtained for the general population. The scores of various domains of the symptom-specific QoL questionnaire were 50-60% lower than those obtained for the general population and approximately 20% higher than those obtained for the population with COPD. CONCLUSIONS: Pulmonary resection has a direct negative impact on pulmonary function and QoL, especially on the QoL related to aspects directly linked to pulmonary function. We highlight the importance of preoperative assessment of pulmonary function in patients undergoing pulmonary resection, in order to predict their postoperative evolution