Infrared Photodissociation Spectroscopy of Water-Tagged Ions with a Widely Tunable Quantum Cascade Laser for Planetary Science Applications.

This work presents a benchtop method for collecting the room temperature gas phase infrared (IR) action spectra of protonated amino acids and their isomers. The adopted setup uses a minimally modified commercial electrospray ionization linear ion trap mass spectrometer (ESI-LIT-MS) coupled to a broadband continuous wave (cw) quantum cascade laser (QCL) source. This approach leverages messenger assisted action spectroscopic techniques using water-tagged molecular ions with complex formation, irradiation, and subsequent analysis, all taking place within a single linear ion trap stage. This configuration thus circumvents the use of multiple mass selection and analysis stages, cryogenic buffer cells, and complex high-power laser systems typically called upon to execute these techniques. The benchtop action spectrometer is used to collect the 935-1600 cm-1 (6.2-10.7 µm) IR action spectrum of a collection of amino acids and a dipeptide with results cross referenced against literature examples obtained with a free electron laser source. Recorded IR spectra are used for the analysis of binary mixture samples composed of constitutional isomers α-alanine and ß-alanine with ratios determined to ∼4% measurement uncertainty without the aid of a front-end separation stage. This turn-key QCL-based approach is a major step in showing the viability of tag-based action spectroscopic techniques for use in future in situ planetary science sensors and general analytical applications.

Dual hydrogen-bonding motifs in complexes formed between tropolone and formic acid.

The near-ultraviolet π*←π absorption system of weakly bound complexes formed between tropolone (TrOH) and formic acid (FA) under cryogenic free-jet expansion conditions has been interrogated by exploiting a variety of fluorescence-based laser-spectroscopic probes, with synergistic quantum-chemical calculations built upon diverse model chemistries being enlisted to unravel the structural and dynamical properties of the pertinent ground [X̃1A'] and excited [Ã1A'π*π] electronic states. For binary TrOH ⋅ FA adducts, the presence of dual hydrogen-bond linkages gives rise to three low-lying isomers designated (in relative energy order) as INT, EXT1, and EXT2 depending on whether docking of the FA ligand to the TrOH substrate takes place internal or external to the five-membered reaction cleft of tropolone. While the symmetric double-minimum topography predicted for the INT potential surface mediates an intermolecular double proton-transfer event, the EXT1 and EXT2 structures are interconverted by an asymmetric single proton-transfer process that is TrOH-centric in nature. The Ã-X̃ origin of TrOH ⋅ FA at ν̃00=27 484.45cm-1 is displaced by δν̃00=+466.76cm-1 with respect to the analogous feature for bare tropolone and displays a hybrid type - a/b rotational contour that reflects the configuration of binding. A comprehensive analysis of vibrational landscapes supported by the optically connected X̃1A' and Ã1A'π*π manifolds, including the characteristic isotopic shifts incurred by partial deuteration of the labile TrOH and FA protons, has been performed leading to the uniform assignment of numerous intermolecular (viz., modulating hydrogen-bond linkages) and intramolecular (viz., localized on monomer subunits) degrees of freedom. The holistic interpretation of all experimental and computational findings affords compelling evidence that an external-binding motif (attributed to EXT1), rather than the thermodynamically more stable cleft-bound (INT) form, was the carrier of fluorescence signals observed during the present work.

Prebiotic Oligosaccharides: Comparative Evaluation Using In Vitro Cultures of Infants' Fecal Microbiomes.

The objective of this study was to systematically assess the bifidogenic effect of three commonly used prebiotic products using in vitro cultures of infant fecal samples. Fresh stool samples collected from six term infants, each exclusively fed human milk (n = 3) or infant formula (n = 3), at 28 days of age were used as inocula. The following prebiotic products were added at concentrations applicable to infant formula: Vivinal GOS 15 (containing 28.5% galacto-oligosaccharide [GOS]) at 7.2 g/liter, Beneo HP (99.5% long-chain inulin [IN]) at 0.8 g/liter, Beneo Synergy 1 (enriched oligofructose and inulin [OF-IN]) at 4 g/liter, and a combination of Vivinal GOS 15 (7.2 g/liter) and Beneo HP (0.8 g/liter) (GOS-IN). The growth of total bacteria, Bifidobacterium, Bacteroides, Bifidobacterium longum, and Escherichia coli was quantified using specific quantitative PCR (qPCR). Bifidobacterium was also enumerated on selective Beerens agar plates, with representative colonies identified by sequencing of their 16S rRNA genes. Volatile fatty acids (VFA) and pH in the cultures were also determined. Irrespective of the feeding methods, the GOS product, either alone or in combination with Beneo HP, resulted in substantially higher growth of total bifidobacteria, and much of this growth was attributed to growth of B. longum. Beneo Synergy 1 also increased the abundance of total bifidobacteria and B. longum. Corresponding to the increases in these two bacterial groups, acetic acid concentrations were higher, while there was a trend of lower E. coli levels and pH. The lower pH and higher acetic acid concentration might be directly responsible for the lower E. coli population. At the concentrations studied, the GOS product was more bifidogenic and potent in inhibiting E. coli than the other products tested. These results suggest that supplementation of infant formula with GOS may increase intestinal bifidobacteria and benefit infant health.

Missing in action: A bibliometric analysis of military research in the medical literature since 1950.

BACKGROUND: Top-tier general and specialty scientific journals serve as a bellwether for national research priorities. We hypothesize that military-relevant publications are underrepresented in the scientific literature and that such publications decrease significantly during peacetime. METHODS: We identified high impact journals in the fields of Medicine, Surgery and Critical Care and developed Boolean searches for military-focused topics using National Library of Medicine Subject Headings terms. A PubMed search from 1950 to 2020 returned the number of research publications in relevant journals and the rate of military-focused publications by year. Rates of military publications were compared between peacetime and wartime. Publication rate trends were modeled with a quadratic function controlling for the start of active conflict and total casualty numbers. Baseline proportions of military physicians relative to the civilian sector served to estimate expected publication rates. Comparisons were performed using Pearson's χ 2 and Mann-Whitney U test, with p < 0.05 considered a significant difference. RESULTS: From 1950 to 2020, a total of 716,340 manuscripts were published in the journals queried. Of these, military-relevant manuscripts totaled 4,052 (0.57%). We found a significant difference in the rate of publication during times of peace and times of war (0.40% vs. 0.69%, p < 0.001). Subgroup analysis found significantly reduced rates of publication in medical and critical care journals during peacetime. For each conflict, the percentage of military-focused publications peaked during periods of war but then receded below baseline levels within a median of 2.5 years (interquartile range, 1.5-3.8 years) during peacetime. The proportion of military-focused publications never reached the current proportion of military physicians in the workforce. CONCLUSION: There is marked reduction in rates of publication for military-focused articles in high impact journals during peacetime. Military-focused articles are underrepresented in high-impact journals. Investigators of military-relevant topics and editors of high-impact journals should seek to close this gap.

Suspected tick-borne flavivirus meningoencephalomyelitis in dogs from the UK: six cases (2021).

OBJECTIVES: Tick-borne encephalitis virus and louping ill virus are neurotropic flaviviruses transmitted by ticks. Epidemiologically, tick-borne encephalitis is endemic in Europe whereas louping ill's predominant geographical distribution is the UK. Rarely, these flaviviruses affect dogs causing neurological signs. This case series aimed to describe the clinical, clinicopathological, and imaging findings, as well as the outcomes in six dogs with meningoencephalitis and/or meningomyelitis caused by a flavivirus in the UK in 2021. MATERIALS AND METHODS: Observational retrospective case-series study. Clinical data were retrieved from medical records of dogs with positive serological or immunohistochemical results from three different institutions from spring to winter 2021. RESULTS: Six dogs were included in the study. All dogs presented an initial phase of pyrexia and/or lethargy followed by progressive signs of spinal cord and/or intracranial disease. Magnetic resonance imaging showed bilateral and symmetrical lesions affecting the grey matter of the thalamus, pons, medulla oblongata, and thoracic or lumbar intumescences with none or mild parenchymal and meningeal contrast enhancement. Serology for tick-borne encephalitis virus was positive in five dogs with the presence of seroconversion in two dogs. The viral distinction between flaviviruses was not achieved. One dog with negative serology presented positive immunohistochemistry at post-mortem examination. Three dogs survived but presented neurological sequelae. Three dogs were euthanased due to the rapid progression of the clinical signs or static neurological signs. CLINICAL SIGNIFICANCE: These cases raise awareness of the presence of tick-borne encephalitis as an emergent disease or the increased prevalence of louping ill virus affecting dogs in the UK.

Isotopic dependence of excited-state proton-tunneling dynamics in tropolone probed by polarization-resolved degenerate four-wave mixing spectroscopy.

The origin band of the Ã1B2-X1A1 (π* ← π) absorption system in monodeuterated tropolone (TrOD) has been probed with near-rotational resolution by applying the frequency-domain techniques of polarization-resolved degenerate four-wave mixing (DFWM) spectroscopy under ambient, bulk-gas conditions. Judicious selection of polarization geometries for the incident and detected electromagnetic waves alleviated intrinsic spectral congestion and facilitated dissection of overlapping transitions, thereby enabling refined rotational-tunneling parameters to be extracted for the Ã1B2(π*π) manifold. A tunneling-induced bifurcation of Δ0à = 2.241(14) cm(-1) was measured for the zero-point level of electronically excited TrOD, reflecting the presence of a substantial barrier along the O-D···O ↔ O···D-O reaction coordinate and representing nearly a 10-fold decrease in magnitude over the analogous quantity in the parent (TrOH) isotopologue. Observed trends in hydron-migration rates are discussed in light of the changes in the potential-surface topology sustained from the π* ← π electron promotion and the dynamical effects incurred by selective isotopic modification of the nuclear framework, with similar considerations being applied to interpret rotational constants and inertial defects. Simultaneous analyses performed on an interloping sequence band built upon ν38(b1) gave an excited-state tunneling splitting of Δ(ν38)à = 1.217(61) cm(-1), highlighting the ability of this symmetric, out-of-plane normal mode to inhibit the unimolecular tautomerization process.

Visual pathway axonal loss in benign multiple sclerosis: a longitudinal study.

BACKGROUND: Benign multiple sclerosis (MS), traditionally defined as Expanded Disability Status Scale (EDSS) score ≤3 and ≥15-year disease duration, is thought to follow a milder clinical course. We determined the extent of visual pathway axonal loss by optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness in a benign MS cohort and examined the relation to vision and quality of life (QOL). METHODS: In this longitudinal study of vision in MS at 3 academic centers, a subset of patients with EDSS, visual function, OCT, and QOL assessments was analyzed. Low- and high-contrast letter acuity was performed to assess visual function. RNFL thickness was determined using time-domain OCT. QOL scales included the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Short Form-36 Health Survey. RESULTS: Among 68 patients (135 eyes) studied longitudinally, 13 (26 eyes) had benign MS using criteria of EDSS score ≤3 and ≥15-year disease duration. Benign MS eyes had as much RNFL thinning (-3.6 µm, P = 0.0008 vs baseline, paired t test) as typical MS eyes (-3.3 µm, P < 0.0001). Both groups had significant low-contrast acuity loss. History of optic neuritis (ON) was more frequent in benign MS (69% vs 33% of eyes). History of ON distinguished benign vs typical MS (P = 0.002) and correlated with RNFL thickness at baseline (P = 0.002) and disease duration (P = 0.03) but not EDSS (P = 0.32, logistic regression). NEI-VFQ-25 scores were also worse for benign MS, accounting for age (75 ± 21 vs 88 ± 11, P = 0.005). CONCLUSION: Patients with benign MS have RNFL axonal loss that is as marked as that of typical MS and have reduced vision and QOL. While overall neurologic impairment is mild, visual dysfunction, not well captured by the EDSS, accounts for a substantial degree of disability in benign MS.

An Ultra-Broadband High Efficiency Polarization Beam Splitter for High Spectral Resolution Polarimetric Imaging in the Near Infrared.

A broadband, high efficiency polarized beam splitter (PBS) metagrating based on integrated resonant units (IRUs) to enable simultaneous polarization analysis, spectral dispersion, and spatial imaging in the near infrared (NIR) is developed. A PBS metagrating with a diameter of 60 mm is the key technology component of the high-resolution multiple-species atmospheric profiler in the NIR (HiMAP-NIR), which is a spaceborne instrument concept crafted to be a core payload of NASA's new generation Earth System Observatory. HiMAP-NIR will enable the aerosol profiling in Earth's planetary boundary layer (from surface to2 km altitude) by simultaneously measuring four spatial-spectral-polarimetric images from 680 to 780 nm. Through detailed optimization of hybridized resonant modes in IRUs, the PBS metagrating shows a diffraction efficiency of 70% (or better) for all four linear-polarized incident light, and polarization contrasts between orthogonal states are 0.996 (or better) from 680 to 780 nm. It meets the stringent performance required by the HiMAP-NIR exploiting a new paradigm for the broad applications of metasurfaces.

Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis.

OBJECTIVE: Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON). METHODS: Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at 3 centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed. RESULTS: Among 299 patients (593 eyes) with >or=6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p < 0.001; VA: p = 0.005). RNFL thinning increased over time, with average losses of 2.9microm at 2 to 3 years and 6.1microm at 3 to 4.5 years (p < 0.001 vs 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (>or=6.6microm) increased from 11% at 0 to 1 year to 44% at 3 to 4.5 years (p < 0.001). INTERPRETATION: Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with subclinical axonal loss in the anterior visual pathway in MS, and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.

Infrared spectra of (12)CF(2)=(12)CH(2) and (12)CF(2)=(13)CH(2), quantum-chemical calculations of anharmonicity, and analyses of resonances.

Infrared spectra obtained in gas and liquid argon phases are reported for (12)CF(2) horizontal line(12)CH(2) and (12)CF(2) horizontal line(13)CH(2). These spectra firmly establish the positions of nu(3)(A(1)) and nu(6)(A(2)) for both isotopomers. Using anharmonicity constants from MP2 calculations, Fermi resonances affecting nu(1)(A(1)), nu(2)(A(1)), nu(3), and nu(8)(B(1)) are analyzed. Deperturbed fundamental frequencies from these analyses are used in conjunction with unaffected fundamentals and ab initio anharmonicity data to predict all 12 "observed" harmonic frequencies. A Darling-Dennison type resonance between 2nu(6) and nu(11) + nu(12) is diagnosed, the calculation of which from ab initio data requires modification of the existing second-order treatment of such constants, where Fermi resonance type terms are also present. Predictions are made of many overtone and combination band frequencies, aiding assignment of observed spectra. From the isolated CH stretching frequency obtained here of 3125.4 cm(-1), the C-H equilibrium bond length is predicted to be 1.0762(11) A.

A 90-102 GHz CMOS based pulsed Fourier transform spectrometer: New approaches for in situ chemical detection and millimeter-wave cavity-based molecular spectroscopy.

We present a system level description of a cavity-enhanced millimeter-wave spectrometer that is the first in its class to combine source and detection electronics constructed from architectures commonly deployed in the mobile phone industry and traditional pulsed Fourier transform techniques to realize a compact device capable of sensitive and specific in situ gas detections. The instrument, which has an operational bandwidth of 90-102 GHz, employs several unique components, including a custom-designed pair of millimeter-wave transmitter and heterodyne receiver integrated circuit chips constructed with 65 nm complementary metal-oxide semiconductor (CMOS) techniques. These elements are directly mated to a hybrid coupling structure that enables free-space interaction of the electronics with a small gas volume while also acting as a cavity end mirror. Instrument performance for sensing of volatile compounds is highlighted with experimental trials taken in bulk gas flows and seeded molecular beam environments.

Current status of spray cryotherapy for airway disease.

The use of liquid nitrogen to treat skin and mucosal lesions is well understood in the dermatologic and gastrointestinal literature. Direct spray cryotherapy (SCT) in the airway has shown promising results in the treatment of esophageal premalignant and even invasive lesions. In the airway, several studies have shown it to be a safe, effective treatment for both benign and malignant disease. It is easily administered in the outpatient setting and can be repeated several times without undue side effects. In this article, we review the current literature on the use of SCT for the treatment of endobronchial lesions and also describe our own institutional experience of the use of SCT in the airway. The use of proper technique and airway venting is important in mitigating the complications of barotrauma from massive expansion of nitrogen upon conversion from the liquid to gaseous state. We also review some of the basic science principals behind the use of the cryotherapy to treat lesions in different tissues. We feel that SCT is a potential area for further research at both clinical and basic science level.

Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are found in most families with cases of both breast and ovarian cancer or with many cases of early-onset breast cancer. However, in an outbred population, the prevalence of BRCA1 and BRCA2 mutations in patients with breast cancer who were unselected for a family history of this disease has not been determined. METHODS: Mutations in the BRCA1 and BRCA2 genes were detected in blood samples from two population-based series of young patients with breast cancer from Britain. RESULTS: Mutations were detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36 years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363 women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 years were mutation carriers, compared with 45% (five of 11) of patients with two or more affected first- or second-degree relatives. The standardized incidence ratio for breast cancer in mothers and sisters was 365 (five observed and 1.37 expected) for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587 noncarriers. If we assume recent penetrance estimates, the respective proportions of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in the general population. CONCLUSIONS: Mutations in the BRCA1 and BRCA2 genes make approximately equal contributions to early-onset breast cancer in Britain and account for a small proportion of the familial risk of breast cancer.

Causes of cervical cancer in the Philippines: a case-control study.

BACKGROUND: Among the numerous human papillomavirus (HPV) types, only types 16 and 18 have been formally classified as human carcinogens. To evaluate the associations of 33 HPV types and other risk factors with squamous cell carcinoma and adenocarcinoma of the cervix, we performed a hospital-based, case-control study in the Philippines. METHODS: The study included 356 case subjects who had histologically confirmed cervical cancer (323 incident cases of squamous cell carcinoma and 33 incident cases of adenocarcinoma/adenosquamous carcinoma) and 381 control subjects. Information on risk factors was obtained by personal interview. HPV DNA was detected in exfoliated cervical cells and biopsy specimens by use of a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 93.8% of case subjects with squamous cell carcinoma and in 90.9% of case subjects with adenocarcinoma/adenosquamous carcinoma compared with 9.2% of control subjects, giving age-adjusted odds ratios of 156 (95% confidence interval [CI] = 87-280) for squamous cell carcinoma and 111 (95% CI = 31-392) for adenocarcinoma/adenosquamous carcinoma. Fifteen different HPV types were detected in squamous cell carcinoma, and six different HPV types were detected in adenocarcinoma/adenosquamous carcinoma. Among HPV types other than types 16 and 18, the associations of HPV with risk of squamous cell carcinoma were strongest for HPV45. In addition to HPV, high parity, low socioeconomic status, and smoking were also associated with both types of cervical cancer. CONCLUSIONS: As has been shown for squamous cell carcinoma, HPV is the central cause of adenocarcinoma/adenosquamous carcinoma of the uterine cervix. The observed associations of less prevalent HPV types with cervical cancer have important implications for cervical cancer prevention strategies.

Risk factors for cervical cancer in Thailand: a case-control study.

BACKGROUND: Human papillomaviruses (HPV) types 16 and 18 are clearly involved in the etiology of cervical cancer, but the evidence for the carcinogenicity of other HPV types is limited. Cofactors involved in the progression from infection with HPV to high-grade precursors and cancer have not been clearly defined by the results of previous studies. METHODS: We conducted a hospital-based, case-control study of invasive cervical cancer to investigate risk in relation to HPV infection and its epidemiologic cofactors in Hat-Yai, Thailand. A total of 338 patients with squamous cell carcinoma, 39 patients with adenocarcinoma/adenosquamous carcinoma, and 261 control subjects were included in the study and were interviewed to obtain information with regard to cervical cancer risk factors. HPV DNA presence in cervical exfoliated cells or frozen biopsy specimens was determined by a polymerase chain reaction assay. RESULTS: HPV DNA was detected in 95% of patients with squamous cell carcinoma, 90% of those with adenocarcinoma/adenosquamous carcinoma, and 16% of control subjects. For patients with squamous cell carcinoma, the most common types of HPV found were type 16 (60% of the positives), type 18 (18%), type 58 (3%), type 52 (3%), and type 31 (2%). For patients with adenocarcinoma/adenosquamous carcinoma, the most common HPV types found were type 18 (60% of the positives), type 16 (37%), and type 45 (3%). The risk factors that remained associated with risk of both histologic types after adjustment for HPV and their mutual confounding effects were limited education, increasing number of sexual partners, history of venereal diseases, and interval since last Pap smear (i.e., cytologic) test. Among patients with squamous cell carcinoma, some association with smoking was also observed. CONCLUSION: New preventive strategies for cervical cancer will require the consideration of multiple HPV types.

Experimental pharmacokinetics of RSU-1069 and its analogues: high tumor/plasma ratios.

The mixed-function radiosensitizer RSU-1069 and its analogues possess both alkylating and electron-affinic properties, and have been shown to be more efficient radiosensitizers than misonidazole both in vivo and in vitro. The pharmacokinetics following intraperitoneal injection of three members of this series, RSU-1069, RSU-1164, and RSU-1172 have been studied in C57BL mice bearing B16 melanoma. Peak tumor levels of each compound, and tumor/plasma ratios (T/P) were found to be high: T/P RSU-1069 = 3.8, RSU-1164 = 3.7; RSU-1172 = 4.0. In contrast, other normal tissues including brain showed tissue/plasma ratios close to 1. The mechanisms responsible for differential tumor uptake are unknown, but may depend on the basicity of the compounds, leading to preferential uptake in areas of low pH, or alternatively they may be associated with the alkylating function. This group of compounds appear to demonstrate highly favorable tissue distributions.

A new transverse-section brain imager for single-gamma emitters.

Physical and clinical data on a new emission transverse-section scanner are given. Comparative data from an earlier tomoscanner and a rotating gamma-camera system yield the following information for the three imagers. Resolution at the center of the field is 9 mm for this tomoscanner, 18 mm for the earlier tomoscanner, and 11 mm for the rotating camera; sensitivity (cps/muCi-ml) 36K, 15.4K, 1.9K; crystal area (cm2) 3096, 619, 490, respectively. The quantification of images is discussed. Clinical emission section scans of the brain, liver, chest and skull are presented and discussed. Forty brain scans were analyzed in conjunction with x-ray transmission tomography. No false positives were found. From a total of 15 lesions seen by the CT x-ray scanner, 14 were detected by the emission tomographic scanner, 12 by standard gamma-camera imaging. One false negative case (cyst) was seen by the transmission x-ray scanner but not by the emission scanner.

The radioresponsiveness of human tumours and the initial slope of the cell survival curve.

Published data on the inherent radiosensitivity of human tumour cells has been analysed in order to reexamine the relationship between the initial slope of the cell survival curve and clinical radioresponsiveness. A clear positive correlation between these parameters is demonstrated. The surviving fraction at 2 Gy is shown to give good discrimination between resistant and sensitive tumour types.

The radiobiology of human neuroblastoma.

The radiation response of a human neuroblastoma xenograft HX138 has been studied in vitro and in vivo using single cells in suspension, multicellular spheroids, and xenografts in immune-suppressed mice. End-points used were growth delay and clonogenic cell survival. Growth delay experiments with spheroids and xenografts showed a high degree of radioresponsiveness. Cell survival curves obtained from all systems were characterised by the lack of a shoulder. An increase in Do of the cell survival curve was seen after irradiation of intact spheroids and xenografts, perhaps due to the presence of a contact effect. Cellular capacity for split-dose recovery in vitro was modest. Delayed assay experiments using spheroids and xenografts showed some potentially lethal damage (PLD) repair in vitro but not in vivo. The results show this human tumour line to be intrinsically highly radiosensitive, with a limited repair capacity.

The dose-rate effect in human tumour cells.

The radiation response of 12 cell lines derived from a variety of human tumours has been investigated over the dose-rate range from 150 to 1.6 cGy/min. As the dose rate was lowered, the amount of sparing varied widely; in 2 cell lines it was zero, in the other cell lines the dose required for 10(-2) survival ranged up to twice the value at high dose rate. Low dose-rate irradiation discriminates better than high dose rate between tumour cell lines of differing radiosensitivity. The data are equally well fitted by two mathematical models of the dose-rate effect: the LPL model of Curtis and the Incomplete Repair model of Thames. Analysis by the LPL model leads to the conclusion that the theoretical radiosensitivity in the total absence of repair was rather similar among the 7 cell lines on which this analysis was possible. What differs among these cell lines is the extent of repair and/or the probability of direct infliction of a non-repairable lesion. Recovery from radiation damage was also examined by split-dose experiments in a total of 17 human tumour cell lines. Half-time values ranged from 0.36 to 2.3 h and there was a systematic tendency for split-dose halving times to be longer than those derived from analysis of the dose-rate effect. This could imply that cellular recovery is a two-component process, low dose-rate sparing being dominated by the faster component. The extent of low dose-rate sparing shows some tendency to correlate with the magnitude of split-dose recovery; in our view the former is the more reliable measure of cellular recovery. The clinical implication of these studies is that some human tumour types may be well treated by hyperfractionation or low dose-rate irradiation, while for others these may be poor therapeutic strategies.