OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

Malnutrition modifies the response to multimodal prehabilitation: a pooled analysis of prehabilitation trials.

Patients with colorectal cancer are at risk of malnutrition before surgery. Multimodal prehabilitation (nutrition, exercise, stress reduction) readies patients physically and mentally for their operation. However, it is unclear whether extent of malnutrition influences prehabilitation outcomes. We conducted a pooled analysis from five 4-week multimodal prehabilitation trials in colorectal cancer surgery (prehabilitation: n = 195; control: n = 71). Each patient's nutritional status was evaluated at baseline using the Patient-Generated Subjective Global Assessment (PG-SGA; higher score, greater need for treatment of malnutrition). Functional walking capacity was measured with the 6-minute walk test distance (6MWD) at baseline and before surgery. A multivariable mixed effects logistic regression model evaluated the potential modifying effect of PG-SGA on a clinically meaningful change of ≥19 m in 6MWD before surgery. Multimodal prehabilitation increased the odds by 3.4 times that colorectal cancer patients improved their 6MWD before surgery as compared with control (95% confidence interval (CI): 1.6 to 7.3; P = 0.001, n = 220). Nutritional status significantly modified this outcome (P = 0.007): Neither those patients with PG-SGA ≥9 (adjusted odds ratio: 1.3; 95% CI: 0.23 to 7.2, P = 0.771, n = 39) nor PG-SGA <4 (adjusted odds ratio: 1.3; 95% CI: 0.5 to 3.8, P = 0.574, n = 87) improved in 6MWD with prehabilitation. In conclusion, baseline nutritional status modifies prehabilitation effectiveness before colorectal cancer surgery. Patients with a PG-SGA score 4-8 appear to benefit most (physically) from 4 weeks of multimodal prehabilitation. Novelty: Nutritional status is an effect modifier of prehabilitation physical function outcomes. Patients with a PG-SGA score 4-8 benefited physically from 4 weeks of multimodal prehabilitation.

The Genomics, Epigenomics, and Transcriptomics of HPV-Associated Oropharyngeal Cancer--Understanding the Basis of a Rapidly Evolving Disease.

Human papillomavirus (HPV) has been shown to represent a major independent risk factor for head and neck squamous cell cancer, in particular for oropharyngeal carcinoma. This type of cancer is rapidly evolving in the Western world, with rising trends particularly in the young, and represents a distinct epidemiological, clinical, and molecular entity. It is the aim of this review to give a detailed description of genomic, epigenomic, transcriptomic, and posttranscriptional changes that underlie the phenotype of this deadly disease. The review will also link these changes and examine what is known about the interactions between the host genome and viral genome, and investigate changes specific for the viral genome. These data are then integrated into an updated model of HPV-induced head and neck carcinogenesis.

Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo.

The 70kDa ribosomal protein S6 kinases (S6K1 and S6K2) play important roles in the regulation of protein synthesis, cell growth and survival. S6Ks are activated in response to mitogen stimulation and nutrient sufficiency by the phosphorylation of conserved serine and threonine residues. Here we show for the first time, that in addition to phosphorylation, S6Ks are also targeted by lysine acetylation. Following mitogen stimulation, S6Ks interact with the p300 and p300/CBP-associated factor (PCAF) acetyltransferases. S6Ks can be acetylated by p300 and PCAF in vitro and S6K acetylation is detected in cells expressing p300. Furthermore, it appears that the acetylation sites targeted by p300 lie within the divergent C-terminal regulatory domains of both S6K1 and S6K2. Acetylation of S6K1 and 2 is increased upon the inhibition of class I/II histone deacetylases (HDACs) by trichostatin-A, while the enhancement of S6K1 acetylation by nicotinamide suggests the additional involvement of sirtuin deacetylases in S6K deacetylation. Both expression of p300 and HDAC inhibition cause increases in S6K protein levels, and we have shown that S6K2 is stabilized in cells treated with HDAC inhibitors. The finding that S6Ks are targeted by histone acetyltransferases uncovers a novel mode of crosstalk between mitogenic signalling pathways and the transcriptional machinery and reveals additional complexity in the regulation of S6K function.

Using the LMS method to calculate z-scores for the Fenton preterm infant growth chart.

OBJECTIVES: The use of exact percentiles and z-scores permit optimal assessment of infants' growth. In addition, z-scores allow the precise description of size outside of the 3rd and 97th percentiles of a growth reference. To calculate percentiles and z-scores, health professionals require the LMS parameters (Lambda for the skew, Mu for the median, and Sigma for the generalized coefficient of variation; Cole, 1990). The objective of this study was to calculate the LMS parameters for the Fenton preterm growth chart (2003). DESIGN: Secondary data analysis of the Fenton preterm growth chart data. METHODS: The Cole methods were used to produce the LMS parameters and to smooth the L parameter. New percentiles were generated from the smooth LMS parameters, which were then compared with the original growth chart percentiles. RESULTS: The maximum differences between the original percentile curves and the percentile curves generated from the LMS parameters were: for weight; a difference of 66 g (2.9%) at 32 weeks along the 90th percentile; for head circumference; some differences of 0.3 cm (0.6-1.0%); and for length; a difference of 0.5 cm (1.6%) at 22 weeks on the 97th percentile. CONCLUSION: The percentile curves generated from the smoothed LMS parameters for the Fenton growth chart are similar to the original curves. These LMS parameters for the Fenton preterm growth chart facilitate the calculation of z-scores, which will permit the more precise assessment of growth of infants who are born preterm.

Higher versus lower protein intake in formula-fed low birth weight infants.

BACKGROUND: The ideal quantity of dietary protein for formula-fed low birth weight infants < 2.5 kilograms is still a matter of controversy and debate. In premature infants, the protein intake must be sufficient to achieve normal growth without negative effects such as acidosis, uremia, and elevated levels of circulating amino acids (e.g. phenylalanine levels). This systematic review evaluates the benefits and risks of higher (>= 3.0 g/kg/day) versus lower (< 3.0 g/kg/day) protein intakes during the initial hospital stay of formula-fed preterm infants < 2.5 kilograms. OBJECTIVES: To determine whether higher (>= 3.0 g/kg/day) versus lower (< 3.0 g/kg/day) protein intakes during the initial hospital stay of formula-fed preterm infants < 2.5 kilograms result in improved growth and neurodevelopmental outcomes without evidence of short and long-term morbidity. SEARCH STRATEGY: Two review authors searched MEDLINE (1966 - May 2005), CINAHL (1982 - May 2005), PubMed (1966 - May 2005), EMBASE (1980 - May 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005), abstracts, conferences and symposia proceedings from Society of Pediatric Research, and American Academy of Pediatrics. Cross references were reviewed independently for additional relevant titles and abstracts for articles up to fifty years old. SELECTION CRITERIA: Randomized controlled trials contrasting levels of formula protein intakes as low (< 3.0 g/kg/day), high (=> 3.0 g/kg/day but < 4.0 g/kg/day), or very high protein intake (=> 4.0 g/kg/day) during hospitalization of neonates less than 2.5 kilograms at birth who were formula-fed. Studies were not included if infants received partial parenteral nutrition during the study period or were fed formula as a supplement to human milk. Given the small number of studies that met all inclusion criteria, studies in which nutrients other than protein also varied (> 10% relative difference) were added in a post-facto analysis. DATA COLLECTION AND ANALYSIS: Two review authors used standard methods of the Cochrane Collaboration and of the Cochrane Neonatal Review Group to independently assess trial eligibility and quality, and extracted data. In a 3-arm trial where two groups fell within the same predesignated protein intake group, weighted means and pooled standard deviations were calculated. MAIN RESULTS: The literature search identified 37 studies, of which five met all the inclusion criteria. All five studies compared low (< 3.0 g/kg/day) to high protein intakes (=> 3.0 g/kg/day but < 4.0 g/kg/day). The overall analysis revealed an improved weight gain (WMD 2.36 g/kg/day, 95% CI 1.31, 3.40) and higher nitrogen accretion (WMD 143.7 mg/kg/day, 95% CI 128.7, 158.8) in infants receiving formula with higher protein content while other nutrients were kept constant. None of the studies reported IQ or Bayley scores at 18 months or later. No significant differences were seen in rates of necrotizing enterocolitis, sepsis or diarrhea. Of three studies included in the post-facto analysis, only one could be included in the meta-analysis. The post-facto analysis revealed further improvement in all growth parameters in infants receiving formula with higher protein content (weight gain: WMD 2.53 g/kg/day, 95% CI 1.62, 3.45, linear growth: WMD 0.16 cm/week, 95% CI 0.03, 0.30, and head growth: WMD 0.23, 95% CI 0.12, 0.35). There was no significant difference (WMD 0.25, 95% CI -0.20, 0.70) in the concentration of plasma phenylalanine between the high and low protein intake groups. One study (Goldman 1969) in the post-facto analysis documented a significantly increased incidence of low IQ scores, below 90, in infants of birth weight less than 1300 grams who received a very high protein intake (6 to 7.2 g/kg/day). AUTHORS' CONCLUSIONS: This systematic review suggests that higher protein intake (=> 3.0 g/kg/day but < 4.0 g/kg/day) from formula accelerates weight gain. Based on increased nitrogen accretion rates, this most likely indicates an increase in lean body mass. Although accelerated weight gain is considered to be a positive effect, increase in other outcome measures examined may represent a negative or ambivalent effect. These include elevated blood urea nitrogen levels and increased metabolic acidosis. Limited information was available regarding the impact of higher formula protein intakes on long term outcomes such as neurodevelopmental abnormalities. As determined in this review, existing research literature on this topic is not adequate to make specific recommendations regarding the provision of very high protein intake (> 4.0 g/kg/day) from formula.

Breast milk supplementation for preterm infants: parental preferences and postdischarge lactation duration.

Breast milk supplementation is frequently used to improve preterm infant growth and to achieve satisfactory intakes of minerals and vitamins. In the North American market there are commercial preparations: two powders and a liquid. The nutritional data available suggest these products are similar and their utilization is based on healthcare team choice. Parental perception about supplementation has not been previously evaluated although parental attitudes are known to impact on lactation success. The objectives of this paper are to determine parental preference and breastfeeding duration for very-low-birth-weight infants given commercial breast milk enrichment products. The study design is a randomized clinical trial with parental interviews. Sixty-three families with 71 infants were enrolled. Parents expressed their preference for the addition of a powder over a liquid preparation (p<0.01). Those mothers whose infants received the liquid enrichment had a shorter lactation relative to their goal, compared with the mothers of the infants who received the powder (p = 0.017). Parents prefer a powder product for breast milk supplementation and this choice positively impacts on the duration of breastfeeding for very-low-birth-weight infants.

Serum triglycerides of breast milk-fed very-low-birth-weight infants.

Normative triglyceride levels were obtained from eighty-five infants weighing < 1500 g. At least 80% of their nutritional intake was their own mother's breast milk. Triglyceride levels did not correlate with birth weight, gestational age, volume of milk fed, age in days, or use of milk fortifier. The 95th percentile triglyceride value was 2.5 mmol/L. Assuming that breast milk-fed infants have triglyceride in the normal range, the acceptable limit of triglyceride values in very-low-birth-weight infants receiving i.v. lipids could be revised upward to 2.5 mmol/L.

Twin pregnancy: the distribution of maternal weight gain of non-smoking normal weight women.

We documented the pattern and distribution of weight gain through twin pregnancies of healthy non-smoking women with good birth outcomes. The mean birthweight was 2621 g and the mean gestational age at delivery was 37.6 weeks. As few of the women were weighed after 34 weeks, the weight gain graph was drawn to this point. The sample was separated into subgroups based on birthweights and gender of the infants. Weight gains, parity, income, first measured weight, BMI and Apgars were not different between the subgroups. The only difference between those with infants that were small for gestational age (SGA), over 3 kg, or intermediate in weight was gestational age. For the groups divided by infant gender, the only differences were maternal age and infant birthweight. The mean, median and 80% confidence limits for weight gain at 34 weeks were 14.1, 13.6, and between 8.5 and 19.4 kg, respectively. There was a wide range of weight gained by these women carrying twin pregnancies.

Assessment of artificial neural networks in health futures research.

Although brief, the overview of literature indicates that the application of artificial neural networks (ANN) in futures research is still very much in the exploration phase, and less common than might be expected based upon theoretical concepts. Results of studies are for the most part encouraging, but it remains to determine real, sustainable value since well controlled and repeated studies have not been completed. More time appears to be required for the application to mature. One is forced to characterize the ANN field, as it relates to futures research, as "emerging with significant promise". The use of ANN as a tool in futures research has therefore at least 2 practical issues to face: (i) a lack of handbook guidance from the literature for the uninitiated; and (ii) prospects of significant effort and uncertain return on investment. Concerning guidance, the problems in which ANN perform well tend to be very nonlinear, but such situations are also least likely to comply with any generalized prescription. ANN might be considered as complex solutions to complex problems. Based upon these factors, it may be argued that the preconditions for practical use of ANN in futures research should be: (i) availability of team-based research (access to existing ANN expertise); and (ii) that the research should include other more conventional methods to duplicate estimates.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutrition and growth analysis of very low birth weight infants.

The growth and nutrition of 220 very low birth weight infants were reviewed after comprehensive data on all infants in the hospital were entered into the Neonatal Intensive Care Unit Audit Data Base for 2 years prospectively. Fluid and energy (parenteral and oral) intakes were compared in four birth weight categories (1, less than or equal to 750 g; 2, 751 to 1000 g; 3, 1001 to 1250 g; 4, 1251 to 1500 g). Parenteral nutrition was the major source of first nutrition for the small infants, but seldom did it alone provide adequate nutrition for very low birth weight infants. The age of the first nutrition (parenteral and/or oral nutrition other than dextrose) decreased with increasing birth weight. The age of the first oral feedings was later for the infants of the lower birth weights but enteral feeding became the major nutrition for all weight categories by the second week of life. During the first 50 days the infants accumulated a deficit of 3780 to 5460 kJ relative to their estimated need of 504 kJ/kg per day, with the smaller infants accumulating a significantly larger deficit. The growth of infants appropriate for gestational age and of infants small for gestational age differed from each other and from the commonly used graph of Dancis et al (J Pediatr. 1948;33:570-572).

Development of colonic sodium transport in early childhood and its regulation by aldosterone.

Aldosterone is important in the regulation of sodium conservation by both kidney and colon. In the very preterm neonate marked urinary salt wasting occurs because of immature renal tubular function, but little is known of the ontogeny of colonic transport processes. Using an in vivo rectal dialysis technique, we have shown that in the human infant the colon has well developed salt conserving mechanisms from early in the last trimester of gestation and that aldosterone is an important regulatory hormone. Sodium transport mechanisms in the colon appear to develop before those in the kidney and it is possible that the colon is the major organ of sodium conservation in the preterm neonate.

Maternal insecurity and failure to thrive in Asian children.

Four Asian babies were investigated because they failed to thrive. In all four cases the failure to thrive was a result of the mother's social isolation and inability to communicate, and to the father's refusal to accept that there was a problem in the family.

Air embolism in ventilated very low birthweight infants.

Five cases of air embolism in ventilated very low birthweight infants are reported. In all cases the outcome was fatal with the babies dying at about 15 hours of age.

Stress analysis of vasoconstriction at arterial branch sites.

The object of the research was to estimate wall stresses caused by vasoconstriction at arterial branches. The basic procedure was a combination of experimental strain measurement and analytical stress analysis. Segments of canine renal arteries were perfused and stimulated to constrict with dopamine hydrochloride and norepinephrine. Surface wall deformation was measured with a stereo-photographic technique. A plane stress finite element analysis was used to calculate wall stresses based on the experimentally derived deformations. The major result of the study was to demonstrate tensile stresses, and in some cases biaxial tension, in contracting vessels. Peak stresses in the apex of the acute angle of the branches were approximately three times unpenetrated hoop stress in the parent vessels. The results imply that constriction at a branch site may be capable of generating sufficient wall tension to tear arterial tissue, and that smooth muscle reactivity is important with respect to the etiology of cerebral aneurysms and the clinical management of acute branch site pathology.

Defective jejunal brush-border Na+/H+ exchange: a cause of congenital secretory diarrhoea.

In a child with congenital secretory diarrhoea, jejunal perfusion studies showed net water and electrolyte secretion and suggested a defect in sodium/proton exchange. A technique was developed for investigation of such exchange in brush-border membrane vesicles from jejunal biopsy specimens. Vesicles from control specimens displayed proton-gradient-dependent sodium uptake, whereas those from the patient did not. These findings, as well as pointing to a cause of congenital secretory diarrhoea, confirm the existence and importance of jejunal sodium/proton exchange in man.