Distinct spatial landscapes in clear-cell renal cell carcinoma as revealed by whole transcriptome analysis.

Background: Clear-cell renal cell carcinoma (ccRCC) is the most common and aggressive form of renal cancer and a paradigm of inter- and intratumor heterogeneity. We carried out an exploratory digital spatial profiling of the tumor interior and periphery of two ccRCC tumor specimens and mapped spatially the molecular and cellular composition of their tumor microenvironment and ecosystem. Materials and methods: Digital spatial profiling of the whole transcriptome of 19 regions of interest (ROIs) was carried out from two selected highly immunogenic stage pT3a/grade 3 (G3) and stage pT3a/grade 4 (G4) ccRCC. A total of 9-10 ROIs were selected from distinct areas from each tumor, including tumor interior and tumor periphery, and differences in gene expression were analyzed by RNA sequencing, pathway enrichment analysis, and cell deconvolution. Results: The distinct areas from the two locally advanced tumors displayed unique gene expression spatial patterns defining distinct biological pathways. Dimensional reduction analysis showed that the G3 ccRCC, compared to the G4 ccRCC, correlated with more variability between regions from the tumor interior and tumor periphery. Cell deconvolution analysis illustrated higher abundance of immune cells, including macrophages, myeloid dendritic cells, and CD4 T cells, and lower abundance of regulatory T cells in the tumor periphery compared to the tumor interior. Conclusions: Transcriptome spatial profiling revealed high inter- and intratumor heterogeneity in the analyzed tumors and provided information with potential clinical utility. This included the finding of less intratumor heterogeneity and more tumor-infiltrated T cells in the ccRCC tumor specimen with a higher grade.

Note: cryogenic microstripline-on-Kapton microwave interconnects.

Simple broadband microwave interconnects are needed for increasing the size of focal plane heterodyne radiometer arrays. We have measured loss and crosstalk for arrays of microstrip transmission lines in flex circuit technology at 297 and 77 K, finding good performance to at least 20 GHz. The dielectric constant of Kapton substrates changes very little from 297 to 77 K, and the electrical loss drops. The small cross-sectional area of metal in a printed circuit structure yields overall thermal conductivities similar to stainless steel coaxial cable. Operationally, the main performance tradeoffs are between crosstalk and thermal conductivity. We tested a patterned ground plane to reduce heat flux.

Bioavailability of metals in stream food webs and hazards to brook trout (Salvelinus fontinalis) in the upper Animas River watershed, Colorado.

The water quality, habitats, and biota of streams in the upper Animas River watershed of Colorado, USA, are affected by metal contamination associated with acid drainage. We determined metal concentrations in components of the food web of the Animas River and its tributaries-periphyton (aufwuchs), benthic invertebrates, and livers of brook trout (Salvelinus fontinalis)-and evaluated pathways of metal exposure and hazards of metal toxicity to stream biota. Concentrations of the toxic metals cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) in periphyton, benthic invertebrates, and trout livers from one or more sites in the upper Animas River were significantly greater than those from reference sites. Periphyton from sites downstream from mixing zones of acid and neutral waters had elevated concentrations of aluminum (Al) and iron (Fe) reflecting deposition of colloidal Fe and Al oxides, and reduced algal biomass. Metal concentrations in benthic invertebrates reflected differences in feeding habits and body size among taxa, with greatest concentrations of Zn, Cu, and Cd in the small mayfly Rhithrogena, which feeds on periphyton, and greatest concentrations of Pb in the small stonefly Zapada, a detritivore. Concentrations of Zn and Pb decreased across each trophic linkage, whereas concentrations of Cu and Cd were similar across several trophic levels, suggesting that Cu and Cd were more efficiently transferred via dietary exposure. Concentrations of Cu in invertebrates and trout livers were more closely associated with impacts on trout populations and invertebrate communities than were concentrations of Zn, Cd, or Pb. Copper concentrations in livers of brook trout from the upper Animas River were substantially greater than background concentrations and approached levels associated with reduced brook trout populations in field studies and with toxic effects on other salmonids in laboratory studies. These results indicate that bioaccumulation and transfer of metals in stream food webs are significant components of metal exposure for stream biota of the upper Animas River watershed and suggest that chronic toxicity of Cu is an important factor limiting the distribution and abundance of brook trout populations in the watershed.

Transient response in doped germanium photoconductors under very low background operation.

Doped germanium photoconductors are the most sensitive detectors for astronomy in the wavelength range 40-240 µm. Under the extremely low background conditions encountered in cooled satellite instruments, these devices exhibit a number of transient effects, such as slow relaxation after a step change in illumination or bias, and spontaneous spiking at high signal levels. Such behavior can degrade the excellent instantaneous sensitivity of these detectors and create calibration uncertainties. These effects have been observed in the Ge:Be photoconductors and the stressed and unstressed Ge:Ga photoconductors in the Long Wavelength Spectrometer, one of the instruments on the Infrared Space Observatory. A systematic investigation of the transient response of the Long Wavelength Spectrometer detectors to a step change in illumination as a function of operating temperature, bias electric field, and illumination step size has been carried out to determine operating conditions that minimize the effects of this behavior. The transient effects appear to be due primarily to carrier sweep out, but they are not fully explained by existing models for transient response.

Airways obstruction and bronchiectasis: correlation with duration of symptoms and extent of bronchiectasis on computed tomography.

Many patients with bronchiectasis have diffuse airways obstruction and this may be the dominant symptom. This study was performed to assess whether the severity of airway obstruction in these patients is related to duration of bronchiectatic symptoms or to the extent of bronchiectasis demonstrated by computed tomography (CT). Twenty-six patients were studied. The severity of airflow obstruction was measured by standard physiological testing and the extent of bronchiectasis demonstrated by CT was assessed using a scoring system. Correlation was measured by Kendall's rank correlation coefficient. A highly significant correlation between FEV1 and CT score was demonstrated and a significant correlation was also observed between FEV1 and duration of symptoms. A weak correlation was present between CT score and symptom duration.

Hypertension and renal impairment as complications of acute porphyria.

Chronic hypertension with renal failure is the most common cause of death in a large family (10 children, 40 grandchildren, 109 great-grandchildren) with acute porphyria. A prospective study of 26 porphyric (19 latent) and 26 nonporphyric subjects shows a significant difference between mean systolic (141 versus 123 mmHg, P < 0.05) and diastolic (88 versus 74 mmHg, P < 0.05) blood pressures and plasma creatinines (geometric mean 99 versus 79 mmol/l, P < 0.02). Five of the 19 porphyric grandchildren have died of the complications of chronic hypertension, with renal failure in three. When the results of the retrospective and prospective studies in these 19 subjects are combined, 10 of the 16 tested (62%) had hypertension and seven of the 14 tested (50%) had renal impairment. Neither hypertension nor renal failure are known to affect the 21 grandchildren who were either not porphyric or of unknown status. This family provides a unique opportunity to study these common but little reported sequelae of acute porphyria. These complications affect subjects with latent porphyria as well as those who have experienced clinical attacks.

Is resistance to ischaemic conduction failure induced by hypoxia?

Resistance to ischaemic conduction failure is a recognised but unexplained property of diabetic peripheral nerve. We have studied matched groups of control, diabetic, and non-diabetic hypoxic subjects (hypoxia: arterial oxygen tension less than or equal to 60 mm Hg (8 kPa) on at least one occasion and secondary to chronic lung disease). Similar resistance to ischaemia was seen in the hypoxic and diabetic groups compared with control subjects (p less than 0.001). The degree of resistance correlated with arterial oxygen tension at the time of testing (r = 0.72, p less than 0.01). In all individuals with acute exacerbations of hypoxia, the resistance to ischaemia was normalised with improvement of respiratory function (p less than 0.02). These results are compatible with the hypothesis that endoneurial hypoxia may be a factor in the pathogenesis of diabetic neuropathy.

X-ray structure study of thermotropic phases in isoacylphosphatidylcholine multibilayers.

Structures of lamellar phases in aqueous dispersions of diisoacylphosphatidylcholines (17iPC and 20iPC) were determined by x-ray diffraction methods. In agreement with previous DSC studies, subgel, gel, and liquid crystal phases were observed in each homolog. The subgel Lc(c') phases of both homologs show significant two-dimensional long range order and can be described by rectangular lattices. The dimensions of the two rectangular unit cells differ in that the side chains are canted (approximately 33 degrees) in the 20iPC homolog, while in 17iPC the side chains are normal to the bilayer plane. The gel L beta phases of 17iPC (Tgg = 17-19.5 degrees C) and 20iPC (Tgg = 44 degrees C) are similar but not identical and are consistent with a distorted, pseudohexagonal lattice for the rotationally disordered side chains. The liquid crystal phases of 17iPC (Tgl = 28 degrees C) and 20iPC (Tgl = 52 degrees C) are structurally similar and are typical of lipids with fluid side chains. Significant but different changes occur in the long spacings at Tgg and Tgl for the two homologs. This implies that interfacial states (particularly in the subgel phases) differ in the two homologs below the liquid crystal phase transition temperature.

Chester porphyria: a clinical study of a new form of acute porphyria.

Acute porphyria afflicts a large kindred in Chester that stems from a marriage in 1896 that has produced 200 descendants; this is the largest porphyric kindred to be identified in the United Kingdom. Six members aged 51 or under died from the condition over the past eight years. The diagnosis of porphyria was overlooked in some as the symptoms may mimic those of other acute illnesses, so that incomplete or incorrect death certificates have been issued. Psychosis, hypertension, and renal complications are particularly common. The porphyric members of the kindred show a previously undescribed hereditary disorder in which the characteristic enzymatic defects of acute intermittent porphyria and variegate porphyria coexist in the same subject. Acute porphyria is poorly understood by hospital and general practitioners, and this has caused anxiety in the kindred. A register of the kindred has been established, and families at risk should be offered biochemical screening, education, and genetic counselling.

Chester porphyria: biochemical studies of a new form of acute porphyria.

A previously unrecognised form of acute porphyria has been identified in a large family in Chester, UK. Patients presented with attacks of neurovisceral dysfunction and none had experienced cutaneous photosensitivity. Biochemically, the excretion pattern of haem precursors varied between individuals; some had a pattern typical of acute intermittent porphyria, others showed that of variegate porphyria, and some had an intermediate pattern. Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria. The genetic basis of this dual form of acute porphyria and its relation to the other acute porphyrias are not clear.

Structural properties of a monobrominated analog of 1, 2-dipalmitoyl-sn-glycero-3-phosphorylcholine.

Hydrated multibilayers of 1-palmitoyl-2-monobromopalmitoyl-sn-glycero-3-phosphorylcholine (BrDPPC), where the 2-chain is brominated at either the C-9 or C-10 position, have been studied by low and wide angle X-ray diffraction methods. Oriented and unoriented samples were investigated. The long spacing was observed over the temperature interval -15 degrees C to 80 degrees C. A monotonic increase from approx. 50 A to approx. 62 A (28 wt. % H2O) occurred with decreasing temperature. The BrDPPC showed no evidence of a sharp gel-to-liquid crystal phase transition. Wide angle scattering showed a diffuse peak corresponding to (4.5 A)-1. Differential scanning calorimetry measurements for hydrated liposomes (50 wt. % H2O) also showed no evidence for a phase transition (-40 less than or equal to T less than or equal to 60 degrees C). These results suggest a low temperature amorphous (glass) state for the acyl side chains of BrDPPC. Monolayer film properties of monobrominated stearic acid also reflect a chain disordering effect occurring upon midchain substitution.