Involvement of yeast HSP90 isoforms in response to stress and cell death induced by acetic acid

Acetic acid-induced apoptosis in yeast is accompanied by an impairment of the general protein synthesis machinery, yet paradoxically also by the up-regulation of the two isoforms of the heat shock protein 90 (HSP90) chaperone family, Hsc82p and Hsp82p. Herein, we show that impairment of cap-dependent translation initiation induced by acetic acid is caused by the phosphorylation and inactivation of eIF2 alpha by Gcn2p kinase. A microarray analysis of polysome-associated mRNAs engaged in translation in acetic acid challenged cells further revealed that HSP90 mRNAs are over-represented in this polysome fraction suggesting preferential translation of HSP90 upon acetic acid treatment. The relevance of HSP90 isoform translation during programmed cell death (PCD) was unveiled using genetic and pharmacological abrogation of HSP90, which suggests opposing roles for HSP90 isoforms in cell survival and death. Hsc82p appears to promote survival and its deletion leads to necrotic cell death, while Hsp82p is a pro-death molecule involved in acetic acid-induced apoptosis. Therefore, HSP90 isoforms have distinct roles in the control of cell fate during PCD and their selective translation regulates cellular response to acetic acid stress.This work was supported by Fundacao para a Ciencia e Tecnologia and COMPETE/QREN/EU (PTDC/BIA-MIC/114116/2009), and by the Canadian Institute for Health Research (MOP 89737 to MH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

REAL-WORLD ITALIAN EXPERIENCE OF POMALIDOMIDE IN RELAPSED-REFRACTORY MYELOMA: RETROSPECTIVE MULTICENTER STUDY BY THE RETE EMATOLOGICA PUGLIESE AND BASILICATA

Background: The POM+LoDEX combination was approved for patients with RRMM who have received at least two prior therapies including lenalidomide and bortezomib. Aims: We report here retrospective analysis of 94 patients with RRMM treated with POM+LoDEX as salvage therapy at 12 hematological centers in the Puglia and Basilicata Network to describe the outcomes and toxicities in a daily practice setting outside clinical trials. Methods: From January 2016 to September 2018, 94 patients (60 F and 34 M) were treated in our haematogical Institutions. Sixty-three patients of them (67%) had relapsed MM and 31 patients (33%) MM refractory to two or more previous treatment lines. The median age was 73 years (range 42–86). Twenty-four patients (23,3%) had EMD. Patients received a median 3 previous lines of therapy. The last treatment received was bortezomib-based regimens in 29% of patients, lenalidomide-based regimens in 50% of patients, and bendamustine containing regimen in 18% of patients. Results: The median number of cycles administered was 5 (range 1–27). The ORR was 51%. Higher ORR was recorded in the patient group with relapsed MM compared to those with refractory disease (p &lt; 0.05). There were no statistically significant differences in terms of response between patients who had received two or more previous lines of therapy (p NS) and between patients aged over or under 70 years (p 0.25). After median follow-up of 9.5 months, median TTP and median OS in the ITT population were respectively, 10 months (range 7–17) and 16 months (range 11–24). The median TTP was significantly longer in patients who achieved the haematological response (p &lt; 0.001) and in patients aged &gt;70 years (p 0.03). The median OS was significantly longer for fit patients (p 0.03). The “disease status’’, the “prior exposure to lenalidomide-based strategies’’, the “number of previous lines of therapy’’ did not influence the TTP and the OS. Multivariate analysis of median TTP identified the “high LDH levels’’ as negative variable (p &lt; 0.001) and the “age &gt;70 years’’ as positive prognostic factor (p &lt; 0.001). Multivariate analysis of median OS identified the “frailty score’’ and confirmed “high LDH levels’’ as statistically significant variables (p &lt; 0.001). Median TTNT was 30 months (range 18–30). Neutropenia was the most common hematologic adverse event and occurred in 32% of patients. The most frequent grade 3–4 non-haematologic toxicities were fatigue (6%) and infections (4%). Summary/Conclusion: POM+LoDEX resulted in a longer OS and TTP compared to data reported from clinical trials. This advantage was observed mainly in elderly patients and in those with haematologic response and the outcome benefit remained consistent regardless of number of prior and last therapy received. The good toxicity profile and the all-oral administration of POM+LoDEX make this combination a recommended therapeutic opportunity also in older patients and should be recommended mainly in patients living far from the hospital

Paediatric referrals in rural Tanzania: the Kilombero District Study – a case series

BACKGROUND: Referral is a critical part of appropriate primary care and of the Integrated Management of Childhood Illness (IMCI) strategy. We set out to study referrals from the aspect both of primary level facilities and the referral hospital in Kilombero District, southern Tanzania. Through record review and a separate prospective study we estimate referral rates, report on delays in reaching referral care and summarise the appropriateness of pediatric referral cases in terms of admission to the pediatric ward at a district hospital METHODS: A sample of patient records from primary level government health facilities throughout 1993 were summarised by age, diagnosis, whether a new case or a reattendance, and whether or not they were referred. From August 1994 to July 1995, mothers or carers of all sick children less than five years old attending the Maternal and Child Health (MCH) clinic or outpatient department (OPD) of SFDDH were interviewed using a standard questionnaire recording age, sex, diagnosis, place of residence, whether the child was admitted to the paediatric ward, and whether the child was referred. RESULTS: From record review, only 0.6% of children from primary level government facilities were referred to a higher level of care. At the referral hospital, 7.8 cases per thousand under five catchment population had been referred annually. The hospital MCH clinic and OPD were generally used by children who lived nearby: 91% (n = 7,166) of sick children and 75% (n = 607) of admissions came from within 10 km. Of 235 referred children, the majority (62%) had come from dispensaries. Almost half of the referrals (48%) took 2 or more days to arrive at the hospital. Severe malaria and anaemia were the leading diagnoses in referred children, together accounting for a total of 70% of all the referrals. Most referred children (167/235, 71%) were admitted to the hospital paediatric ward. CONCLUSIONS: The high admission rate among referrals suggests that the decision to refer is generally appropriate, but the low referral rate suggests that too few children are referred. Our findings suggest that the IMCI strategy may need to be adapted in sparsely-populated areas with limited transport, so that more children may be managed at peripheral level and fewer children need referral

Haematological and Biochemical Reference Values for Healthy Adults in the Middle Belt of Ghana

BACKGROUND: Reference values are very important in clinical management of patients, screening participants for enrollment into clinical trials and for monitoring the onset of adverse events during these trials. The aim of this was to establish gender-specific haematological and biochemical reference values for healthy adults in the central part of Ghana. METHODS: A total of 691 adults between 18 and 59 years resident in the Kintampo North Municipality and South District in the central part of Ghana were randomly selected using the Kintampo Health and Demographic Surveillance System and enrolled in this cross-sectional survey. Out of these, 625 adults made up of 316 males and 309 females were assessed by a clinician to be healthy. Median values and nonparametric 95% reference values for 16 haematology and 22 biochemistry parameters were determined for this population based on the Clinical Laboratory and Standards Institute guidelines. Values established in this study were compared with the Caucasian values being used currently by our laboratory as reference values and also with data from other African and western countries. RESULTS: REFERENCE VALUES ESTABLISHED INCLUDE: haemoglobin 113-164 g/L for males and 88-144 g/L for females; total white blood cell count 3.4-9.2 × 10(9)/L; platelet count 88-352 × 10(9)/L for males and 89-403 × 10(9)/L for females; alanine aminotransferase 8-54 U/L for males and 6-51 U/L for females; creatinine 56-119 µmol/L for males and 53-106 µmol/L for females. Using the haematological reference values based on the package inserts would have screened out up to 53% of potential trial participants and up to 25% of the population using the biochemical parameters. CONCLUSION: We have established a panel of locally relevant reference parameters for commonly used haematological and biochemical tests. This is important as it will help in the interpretation of laboratory results both for clinical management of patients and safety monitoring during a trial

Residential Proximity to a Major Roadway Is Associated with Features of Asthma Control in Children

BACKGROUND: While several studies suggest that traffic-related air pollutants are detrimental for respiratory health, few studies have examined relationships between residential proximity to a major roadway and asthma control in children. Furthermore, a major limitation of existing research is reliance on self-reported outcomes. We therefore determined the spatial relationship between the distance from a major roadway and clinical, physiologic and inflammatory features of asthma in a highly characterized sample of asthmatic children 6-17 years of age across a wide range of severities. We hypothesized that a closer residential proximity to a major roadway would be associated with increased respiratory symptoms, altered pulmonary function and a greater magnitude of airway and systemic inflammation. METHODOLOGY/PRINCIPAL FINDINGS: 224 children 6-17 years with confirmed asthma completed questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, exhaled breath condensate collection and venipuncture. Residential distance from a major roadway was determined by mapping the geographic coordinates of the residential address in Geographic Information System software. The distance between the home address and the nearest major roadway was calculated according to the shortest distance between the two points (i.e., "as the crow flies"). Asthmatic children living in closer proximity to a major roadway had an increased frequency of wheezing associated with increased medication requirements and more hospitalizations even after controlling for potential confounders. These children also had increased airway resistance, increased airway inflammation reflected by a lower breath condensate pH, and higher plasma EGF concentrations. CONCLUSIONS/SIGNIFICANCE: These findings suggest that closer residential proximity to a major roadway is associated with poorer asthma control in school-age children. Assessment of residential proximity to major roadways may be useful in the clinical evaluation of asthma in children

Endothelial Cells in Co-culture Enhance Embryonic Stem Cell Differentiation to Pancreatic Progenitors and Insulin-Producing Cells through BMP Signaling

Endothelial cells (ECs) represent the major component of the embryonic pancreatic niche and play a key role in the differentiation of insulin-producing β cells in vivo. However, it is unknown if ECs promote such differentiation in vitro. We investigated whether interaction of ECs with mouse embryoid bodies (EBs) in culture promotes differentiation of pancreatic progenitors and insulin-producing cells and the mechanisms involved. We developed a co-culture system of mouse EBs and human microvascular ECs (HMECs). An increase in the expression of the pancreatic markers PDX-1, Ngn3, Nkx6.1, proinsulin, GLUT-2, and Ptf1a was observed at the interface between EBs and ECs (EB-EC). No expression of these markers was found at the periphery of EBs cultured without ECs or those co-cultured with mouse embryonic fibroblasts (MEFs). At EB-EC interface, proinsulin and Nkx6.1 positive cells co-expressed phospho-Smad1/5/8 (pSmad1/5/8). Therefore, EBs were treated with HMEC conditioned media (HMEC-CM) suspecting soluble factors involved in bone morphogenetic protein (BMP) pathway activation. Upregulation of PDX-1, Ngn3, Nkx6.1, insulin-1, insulin-2, amylin, SUR1, GKS, and amylase as well as down-regulation of SST were detected in treated EBs. In addition, higher expression of BMP-2/-4 and their receptor (BMPR1A) were also found in these EBs. Recombinant human BMP-2 (rhBMP-2) mimicked the effects of the HMEC-CM on EBs. Noggin (NOG), a BMP antagonist, partially inhibited these effects. These results indicate that the differentiation of EBs to pancreatic progenitors and insulin-producing cells can be enhanced by ECs in vitro and that BMP pathway activation is central to this process

A generalization on the solvability of integral geometry problems along plane curves

This paper is concerned with a general condition for the solvability of integral geometry problems along the plane curves of given curvatures. As two important results, the solvabilities of integral geometry problems along the family of circles with fixed radius and along the family of circles of varying radius centered on a fixed circle are given. By using some extension of the class of unknown functions, the proofs are based on the solvabilities of equivalent inverse problems for transport-like equation. MSC:35R30, 53C65, 65N30