Robust Evaluation of Ultraviolet-C Sensitivity for SARS-CoV-2 and Surrogate Coronaviruses.

UV light, more specifically UV-C light at a wavelength of 254 nm, is often used to disinfect surfaces, air, and liquids. In early 2020, at the cusp of the COVID-19 pandemic, UV light was identified as an efficient means of eliminating coronaviruses; however, the variability in published sensitivity data is evidence of the need for experimental rigor to accurately quantify the effectiveness of this technique. In the current study, reliable and reproducible UV techniques have been adopted, including accurate measurement of light intensity, consideration of fluid UV absorbance, and confirmation of uniform dose delivery, including dose verification using an established biological target (T1UV bacteriophage) and a resistant recombinant virus (baculovirus). The experimental results establish the UV sensitivity of SARS-CoV-2, HCoV-229E, HCoV-OC43, and mouse hepatitis virus (MHV) and highlight the potential for surrogate viruses for disinfection studies. All four coronaviruses were found to be easily inactivated by 254 nm irradiation, with UV sensitivities of 1.7, 1.8, 1.7, and 1.2 mJ/cm2/log10 reduction for SARS-CoV-2, HCoV-229E, HCoV-OC43, and MHV, respectively. Similar UV sensitivities for these species demonstrate the capacity for HCoV-OC43, HCoV-229E, and MHV to be considered surrogates for SARS-CoV-2 in UV-inactivation studies, greatly reducing hazards and simplifying procedures for future experimental studies. IMPORTANCE Disinfection of SARS-CoV-2 is of particular importance due to the global COVID-19 pandemic. UV-C irradiation is a compelling disinfection technique because it can be applied to surfaces, air, and water and is commonly used in drinking water and wastewater treatment facilities. UV inactivation depends on the dose received by an organism, regardless of the intensity of the light source or the optical properties of the medium in which it is suspended. The 254 nm irradiation sensitivity was accurately determined using benchmark methodology and a collimated beam apparatus for four coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-OC43, and MHV), a surrogate indicator organism (T1UV), and a resistant recombinant virus (baculovirus vector). Considering the light distribution across the sample surface, the attenuation of light intensity with fluid depth, the optical absorbance of the fluid, and the sample uniformity due to mixing enable accurate measurement of the fundamental inactivation kinetics and UV sensitivity.

A comprehensive scoring system to evaluate patient-centred risk factors regarding lower extremity amputation.

Care of the patient with a presumed life- or limb-threatening lower extremity wound poses many challenges. The mindset regarding potential outcomes of such conditions is mostly driven by the experiences and expertise of those providing the care. This mindset generally appears as two primary actions presented to the afflicted patient: attempted resolution of the problem via medical, surgical or combination treatment, with the hope of low recurrence risk, or exacerbation and amputation-amputations at a level sufficient to, at least in the mind of the surgeon, eliminate the problem. Achieving the former outcome is dependent on a number of factors associated with both patient and caregiver. If healing is achieved, the secondary goal of prevention of recurrence may be no less arduous, with failure most likely resulting in amputation. Clearly, these considerations appear to be based more on the health professionals perception, of the patient's physical and medical status rather than on patient-centred considerations. This article will review considerations and recommendations for lower extremity amputation, and the short- and long-term implications. Based on our research, there is clear need for a set of criteria against which to weigh not just the medical issues, but also definitive patient-centred issues when considering a lower extremity amputation. We offer a set of patient-centred, easily verified and recognised criteria that we believe addresses this need. The goal of the Miller-Newgent Amputation Scale (MENACE) is to provide a decision base from which to consider and evaluate all factors in determining the need for a lower extremity amputation. This involves identification of patient-centred issues, which are likely to produce satisfactory short- and long-term physical and quality-of-life outcomes if the amputation does proceed.

Subduction-driven recycling of continental margin lithosphere.

Whereas subduction recycling of oceanic lithosphere is one of the central themes of plate tectonics, the recycling of continental lithosphere appears to be far more complicated and less well understood. Delamination and convective downwelling are two widely recognized processes invoked to explain the removal of lithospheric mantle under or adjacent to orogenic belts. Here we relate oceanic plate subduction to removal of adjacent continental lithosphere in certain plate tectonic settings. We have developed teleseismic body wave images from dense broadband seismic experiments that show higher than expected volumes of anomalously fast mantle associated with the subducted Atlantic slab under northeastern South America and the Alboran slab beneath the Gibraltar arc region; the anomalies are under, and are aligned with, the continental margins at depths greater than 200 kilometres. Rayleigh wave analysis finds that the lithospheric mantle under the continental margins is significantly thinner than expected, and that thin lithosphere extends from the orogens adjacent to the subduction zones inland to the edges of nearby cratonic cores. Taking these data together, here we describe a process that can lead to the loss of continental lithosphere adjacent to a subduction zone. Subducting oceanic plates can viscously entrain and remove the bottom of the continental thermal boundary layer lithosphere from adjacent continental margins. This drives surface tectonics and pre-conditions the margins for further deformation by creating topography along the lithosphere-asthenosphere boundary. This can lead to development of secondary downwellings under the continental interior, probably under both South America and the Gibraltar arc, and to delamination of the entire lithospheric mantle, as around the Gibraltar arc. This process reconciles numerous, sometimes mutually exclusive, geodynamic models proposed to explain the complex oceanic-continental tectonics of these subduction zones.

Dynamics of continental accretion.

Subduction zones become congested when they try to consume buoyant, exotic crust. The accretionary mountain belts (orogens) that form at these convergent plate margins have been the principal sites of lateral continental growth through Earth's history. Modern examples of accretionary margins are the North American Cordilleras and southwest Pacific subduction zones. The geologic record contains abundant accretionary orogens, such as the Tasmanides, along the eastern margin of the supercontinent Gondwana, and the Altaïdes, which formed on the southern margin of Laurasia. In modern and ancient examples of long-lived accretionary orogens, the overriding plate is subjected to episodes of crustal extension and back-arc basin development, often related to subduction rollback and transient episodes of orogenesis and crustal shortening, coincident with accretion of exotic crust. Here we present three-dimensional dynamic models that show how accretionary margins evolve from the initial collision, through a period of plate margin instability, to re-establishment of a stable convergent margin. The models illustrate how significant curvature of the orogenic system develops, as well as the mechanism for tectonic escape of the back-arc region. The complexity of the morphology and the evolution of the system are caused by lateral rollback of a tightly arcuate trench migrating parallel to the plate boundary and orthogonally to the convergence direction. We find geological and geophysical evidence for this process in the Tasmanides of eastern Australia, and infer that this is a recurrent and global phenomenon.

A technique for murine irradiation in a controlled gas environment.

NASA’s extra-vehicular activities (EVAs) involve exposure to high energy photons while breathing 100% oxygen. Using previously verified mouse models, our laboratory is studying whether low dose irradiation under these hyperoxic conditions could lead to an increase in carcinogenic potential. To simulate the environment astronauts encounter during an EVA, enclosed chambers were constructed that allowed for mouse movement, controlled gas conditions, and uniform radiation dose delivery. Custom-built gas chambers with input/output gas valves and dividers that allowed for uniform gas flow were used to keep 6 unanesthetized mice separated while they were irradiated. The chambers were supplied with 100% oxygen or air using ball valves linked together with T-splitters. A calibrated ion chamber was used to verify the radiation dose distribution across an entire chamber. Mice were placed in the gas environments for 0.5 h, irradiated with a 10 or 18 MV photon beam from a medical linear accelerator, and left in their gas environment for 2 h post-irradiation. We irradiated 200 mice (5 different doses between 0-1000 mGy) under normoxic or 100% oxygen conditions. For the next step of this research, these mice will be euthanized 9 months post-irradiation, and lung tumors will be counted and sized to determine if hyperoxia increases the carcinogenic effect for this model.

Continuing Colorado plateau uplift by delamination-style convective lithospheric downwelling.

The Colorado plateau is a large, tectonically intact, physiographic province in the southwestern North American Cordillera that stands at ∼1,800-2,000 m elevation and has long been thought to be in isostatic equilibrium. The origin of these high elevations is unclear because unlike the surrounding provinces, which have undergone significant Cretaceous-Palaeogene compressional deformation followed by Neogene extensional deformation, the Colorado plateau is largely internally undeformed. Here we combine new seismic tomography and receiver function images to resolve a vertical high-seismic-velocity anomaly beneath the west-central plateau that extends more than 200 km in depth. The upper surface of this anomaly is seismically defined by a dipping interface extending from the lower crust to depths of 70-90 km. The base of the continental crust above the anomaly has a similar shape, with an elevated Moho. We interpret these seismic structures as a continuing regional, delamination-style foundering of lower crust and continental lithosphere. This implies that Pliocene (2.6-5.3 Myr ago) uplift of the plateau and the magmatism on its margins are intimately tied to continuing deep lithospheric processes. Petrologic and geochemical observations indicate that late Cretaceous-Palaeogene (∼90-40 Myr ago) low-angle subduction hydrated and probably weakened much of the Proterozoic tectospheric mantle beneath the Colorado plateau. We suggest that mid-Cenozoic (∼35-25 Myr ago) to Recent magmatic infiltration subsequently imparted negative compositional buoyancy to the base and sides of the Colorado plateau upper mantle, triggering downwelling. The patterns of magmatic activity suggest that previous such events have progressively removed the Colorado plateau lithosphere inward from its margins, and have driven uplift. Using Grand Canyon incision rates and Pliocene basaltic volcanism patterns, we suggest that this particular event has been active over the past ∼6 Myr.

Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates.

Narcolepsy-cataplexy, a disorder of excessive sleepiness and abnormalities of rapid eye movement (REM) sleep, results from deficiency of the hypothalamic orexin (hypocretin) neuropeptides. Modafinil, an atypical wakefulness-promoting agent with an unknown mechanism of action, is used to treat hypersomnolence in these patients. Fos protein immunohistochemistry has previously demonstrated that orexin neurons are activated after modafinil administration, and it has been hypothesized that the wakefulness-promoting properties of modafinil might therefore be mediated by the neuropeptide. Here we tested this hypothesis by immunohistochemical, electroencephalographic, and behavioral methods using modafinil at doses of 0, 10, 30 and 100 mg/kg i.p. in orexin-/- mice and their wild-type littermates. We found that modafinil produced similar patterns of neuronal activation, as indicated by Fos immunohistochemistry, in both genotypes. Surprisingly, modafinil more effectively increased wakefulness time in orexin-/- mice than in the wild-type mice. This may reflect compensatory facilitation of components of central arousal in the absence of orexin in the null mice. In contrast, the compound did not suppress direct transitions from wakefulness to REM sleep, a sign of narcolepsy-cataplexy in mice. Spectral analysis of the electroencephalogram in awake orexin-/- mice under baseline conditions revealed reduced power in the theta; band frequencies (8-9 Hz), an index of alertness or attention during wakefulness in the rodent. Modafinil administration only partly compensated for this attention deficit in the orexin null mice. We conclude that the presence of orexin is not required for the wakefulness-prolonging action of modafinil, but orexin may mediate some of the alerting effects of the compound.

Noninvasive fluorescent imaging reliably estimates biomass in vivo.

Whole-body optical imaging of small animals has emerged as a powerful, user friendly, and high-throughput tool for assaying molecular and cellular processes as they occur in vivo. As with any imaging method, the utility of such technology relies on its ability to provide quantitative, biologically meaningful information about the physiologic or pathologic process of interest. Here we used an animal tumor model to evaluate the extent of correlation between noninvasively measured fluorescence and more traditional measurements of biomass (tumor volume and tumor weight). C57/BL6 mice were injected subcutaneously with murine colon adenocarcinoma cells that were engineered to express GFP. Serial measurements of fluorescence intensities were performed with a macroscopic in vivo fluorescence system. The progressive increases in intensity correlated strongly with growth in tumor volume, as determined by caliper measurements (R2 = 0.99). A more stringent correlation was found between fluorescence intensity and tumor weight (R2 = 0.97) than between volume and weight (R2 = 0.89). In a treatment experiment using tumor necrosis factor-alpha, fluorescence intensity (but not tumor volume) was able to differentiate between treated and control groups on day 1 post-treatment. These results validate the ability of noninvasive fluorescent imaging to quantify the number of viable, fluorescent cells in vivo.

Symposium overview: genetic polymorphisms in DNA repair and cancer risk.

A symposium, Genetic Polymorphisms in DNA Repair and Cancer Risk, was presented at the 40th Annual Meeting of the Society of Toxicology, held in San Francisco, California, in March 2001. A brief report of the symposium was published (Kaiser, Science 292, 837-838, 2001). Molecular epidemiological studies have shown that polymorphic variants of genes involved in the metabolism and repair of carcinogens can act as cancer susceptibility genes. These variants of drug metabolic and DNA-repair enzymes either increase the activation of chemical carcinogens or decrease the cells' ability to detoxify/repair mutagenic damages. Although on an individual basis these variant alleles may only slightly change catalytic activity and increase cancer risk, their polymorphic frequency in the human population may contribute to a high proportion of cancer cases. Studies conducted over the past few years have identified variant alleles for a number of DNA-repair genes, some of which have been shown to change DNA-repair capacity. Identifying these genotypic alterations in DNA-repair enzymes and their association with cancer may help to elucidate the mechanisms of cancer etiology and to predict both disease risk and response to cancer therapy, since most antineoplastic treatments mediate their effects through DNA damage.

The cyclooxygenase inhibitor ibuprofen and the FLAP inhibitor MK886 inhibit pancreatic carcinogenesis induced in hamsters by transplacental exposure to ethanol and the tobacco carcinogen NNK.

PURPOSE: Pancreatic cancer is the fourth leading cause of cancer death in men and women. Smoking is a documented risk factor for pancreatic cancer, and the risk is increased in smokers who also consume alcohol. Arachidonic acid (AA)-metabolizing enzymes have been implicated in aggressive clinical behavior of pancreatic cancer while mutations in the Ki- ras gene have been associated with prolonged survival and responsiveness to therapy. Using a hamster model of exocrine pancreatic cancer induced by transplacental exposure to ethanol and the tobacco-carcinogen NNK, we have analyzed these tumors for mutations in the ras and p53 genes and tested the modulating effects of the COX inhibitor, ibuprofen, and the FLAP inhibitor, MK886, on the development of pancreatic cancer in this animal model. METHODS: Hamsters were given 10% ethanol in the drinking water from the fifth to the last day of their pregnancy and a single dose of NNK on the last day. Starting at 4 weeks of age, groups of offspring were given either the COX inhibitor ibuprofen (infant Motrin oral suspension) or the FLAP-inhibitor MK886 (dissolved in carboxymethylcellulose orally) for life while a group of offspring not receiving any treatment served as positive controls. RESULTS: None of the induced pancreatic cancers demonstrated mutations in the Ki-, N-, or H- ras or p53 genes. The development of pancreatic cancer in offspring who had been given ibuprofen or MK886 was reduced by 50% or 30%, respectively. CONCLUSION: In conjunction with the documented over-expression of COX-2 and LOX in human pancreatic cancer, our findings suggest an important role of the AA-cascade in the genesis of this cancer type and indicate that pharmacological or dietary measures that reduce AA-metabolism may be useful for the prevention and clinical management of pancreatic cancer.

Electromyographic analysis of a human powered stepper cycle during seated and standing riding.

This study examined the muscular activation patterns produced while riding the Step 'n Go, a tricycle powered by a reciprocating vertical motion and typically used by individuals with cognitive, orthopedic, and neuromuscular conditions. Seven normal, adult subjects were tested at three power levels (75, 100, and 125 W) during seated and standing riding. Eight lower extremity muscles were examined with surface electromyography. Results showed that the major power producing muscles for this device were the gluteus maximus, vastis lateralis and medialis, rectus femoris, and tibialis anterior. At the highest power level, peak and mean muscular activation in these muscles were substantially lower (17-38%) while riding standing compared to seated, and seems to reflect the benefit of body weight for power production while standing. At the lowest power level, the peak and mean muscle activation differences between positions were less remarkable, and in some cases the standing values were greater than seated. This suggests that significant muscular effort was required to maintain standing posture and balance when riding at low power levels. Individuals able to perform vastis lateralis and medialis intensive activities, such as the concentric portion of a squat or using a stepping machine (Stair Master), should be able to comfortably ride the Step 'n Go at low power levels.

Alterations at the Ink4a locus in transplacentally induced murine lung tumors.

The malignant phenotype results from multiple genetic alterations, including the activation of oncogenes and inactivation of tumor suppressor genes. Activation of the Ki-ras oncogene has been implicated as an early event in the pathogenesis of lung adenocarcinomas in humans and experimental animal models. Previous studies from this laboratory have shown that, following treatment of pregnant [D2 x B6D2F(1)]F(2) or Balb/c mice with the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC), lung tumors from the transplacentally exposed offspring exhibited a high incidence of mutations in the Ki-ras gene. The role of genetic alterations at other oncogenic or tumor suppressor loci that can mediate lung tumor initiation and/or progression have not been well characterized in either human or murine models. Using the transplacental carcinogenesis model, which results in the induction of both lung and liver tumors following in utero exposure to MC, the results of this and our previous studies show that alterations in the Ink4a locus occur in only 15 and 27% of the lung and liver tumors, respectively. Preliminary data also suggests that the type of mutation induced in the Ki-ras gene following the initial exposure to MC may influence lung tumor progression. These results imply that damage to the Ink4a gene is not a frequent pathway to malignant progression in mouse lung and liver tumors following in utero exposure to environmental carcinogens.

A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases.

BACKGROUND: Circulating inhibitors of angiogenesis have been suggested to affect the growth of distant micrometastatic disease in patients with cancer. This study was designed to evaluate circulating endostatin levels in colorectal cancer patients with liver metastases. METHODS: Plasma samples from 30 colorectal cancer patients with liver metastases were analyzed for endostatin and vascular endothelial growth factor (VEGF) by using competitive enzyme immunoassays. Samples were compared with plasma from age- and sex-matched healthy controls; values >2 SD above the control mean were considered elevated. RESULTS: Plasma endostatin levels were significantly higher in the 30 cancer patients than controls (P < .0001) and correlated with preoperative VEGF levels (P = .0008). Eighteen patients underwent surgical treatment (liver resection, n = 10; or isolated hepatic perfusion with melphalan, n = 8). Seventeen treated patients were available for follow-up. Eight of 11 patients who progressed had elevated plasma endostatin levels at the time of progression. None of six patients who remained progression free had elevated endostatin levels at last follow-up (P = .02). CONCLUSIONS: Plasma endostatin levels are elevated in colorectal cancer patients with liver metastases and correlate with VEGF levels. Elevated endostatin levels during follow-up are associated with disease progression. Understanding the role of endogenous endostatin in cancer patients may lead to novel strategies to inhibit tumor angiogenesis.

Prediction of mortality and timing of referral for lung transplantation in cystic fibrosis patients.

Lung transplantation (Tx) is an optional treatment for cystic fibrosis (CF) patients with end-stage lung disease. The decision to place a patient on the Tx waiting list is frequently complex, difficult, and controversial. This study evaluated the current criteria for lung Tx and assessed additional parameters that may identify CF patients at high risk of death. Data were extracted from the medical records of 392 CF patients. Forty of these patients had a forced expiratory volume in 1 s (FEV(1)) less than 30% predicted, and nine of these 40 patients were transplanted. A comparison was performed between the survival of those transplanted (n = 9) and those not transplanted (n = 31), by means of Kaplan-Meier survival curves. The influence on survival of age, gender, nutritional status, sputum aspergillus, diabetes mellitus, recurrent hemoptysis, oxygen use, and the decline rate of FEV(1), were investigated by means of univariate and multivariate analyses. The rate of decline of FEV(1) was evaluated employing the linear regression model. CF patients with a FEV(1)< 30% and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant (median survival 7.33 vs. 3.49 yr, 5-yr survival 73% vs. 29%). Two factors--rate of decline in FEV(1) values and age < 15 yr--were found to influence the mortality rate, while the other parameters examined did not. Our results indicate that the current criterion of FEV(1)< 30% predicted, alone is not sufficiently sensitive to predict the mortality rate in CF patients and time of referral for Tx, as many of these patients survive for long periods of time. Additional criteria to FEV(1)< 30%, should include rapidly declining FEV(1) values and age < 15 yr.

Incidence of HIV among injection drug users entering drug treatment programs in four US cities.

We estimated seroincidence of human immunodeficiency virus (HIV) and prevalence of risk behaviors among injection drug users (IDUs) who accepted voluntary HIV testing on entry to drug treatment. Record-based incidence studies were conducted in 12 drug treatment programs in New York City (n = 890); Newark, New Jersey (n = 521); Seattle, Washington (n = 1,256); and Los Angeles, California (n = 733). Records of confidential HIV tests were abstracted for information on demographics, drug use, and HIV test results. More detailed data on risk behaviors were obtained by a standardized questionnaire. Although overall incidence rates were relatively low in this population (<1/100 person-years), there was a high prevalence of risk behaviors. Needle sharing was reported by more than one-third of the participants in each of the cities. HIV seroincidence rates were up to three-fold higher among younger ID Us. We found that HIV continued to be transmitted among ID Us who had received both drug treatment and HIV counseling and testing. HIV/AIDS (acquired immunodeficiency syndrome) prevention education should continue to be an important component of drug treatment.

Oncogene-dependent engraftment of human myeloid leukemia cells in immunosuppressed mice.

We have developed an in vivo model of differentiated human acute myeloid leukemia (AML) by retroviral infection of the cytokine-dependent AML cell line TF-1 with the v-Src oncogene. When injected either intravenously or intraperitoneally into 300 cGy irradiated SCID mice, animals formed multiple granulocytic sarcomas involving the adrenals, kidneys, lymph nodes and other organs. The mean survival time was 34+/-10 days (n = 40) after intravenous injection and 24+/-3 days (n = 5) after intraperitoneal injection of 20 million cells. The cells recovered from leukemic animals continued to express interleukin-3 receptors and remained sensitive to the diphtheria fusion protein DT388IL3. Further, these granulocytic sarcoma-derived cells grew again in irradiated SCID mice (n = 10). The cytogenetic abnormalities observed prior to inoculation in mice were stably present after in vivo passage. Similar to the results with v-Src transfected TF-1 cells, in vivo leukemic growth was observed with TF-1 cells transfected with the human granulocyte-macrophage colony-stimulating factor gene (n = 5) and with TF-1 cells recovered from subcutaneous tumors in nude mice (n = 5). In contrast, TF-1 cells expressing v-Ha-Ras (n = 5), BCR-ABL (n = 5), or activated Raf-1 (n = 44) did not grow in irradiated SCID mice. This is a unique, reproducible model for in vivo growth of a differentiated human acute myeloid leukemia and may be useful in the assessment of anti-leukemic therapeutics which have human-specific molecular targets such as the interleukin-3 receptor.

Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity.

Although several variants of DNA repair genes have been identified, their functional significance has not been determined. Using samples collected from 135 cancer-free women, this study evaluated whether amino acid substitution variants of DNA repair genes contribute to ionizing radiation (IR) susceptibility as measured by prolonged cell cycle G2 delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes: X-ray repair cross complementing group 1 (XRCC1, exon 6, C/T, 194 Arg/Trp and exon 10, G/A, 399 Arg/Gln), XRCC group 3 (XRCC3, exon 7, C/T, 241 Thr/Met) and apurinic/apyrimidinic endonuclease 1 (APE1, exon 5, T/G, 148 Asp/Glu). Fluorescence-activated cell sorter (FACS) analysis was used to measure cell cycle delay. APE1 (exon 5) genotype was significantly associated with mitotic delay (P = 0.01), with the Glu/Glu genotype having prolonged delay compared with the other two genotypes. The mitotic delay index (mean +/- SD) in women with the APE1 codon 148 Asp/Asp, Asp/Glu and Glu/Glu genotypes was 30.95 +/- 10.15 (n = 49), 30.65 +/- 10.4 (n = 60) and 39.56 +/- 13.12 (n = 21), respectively. There was a significant interaction between family history (FH) and APE1 (exon 5) genotype (P = 0.007) as well as FH and XRCC1 (exon 10) genotype (P = 0.005) in mitotic delay. Lastly, prolonged cell cycle delay was significantly associated with number of variant alleles when APE1 Asp148Glu and XRCC1 Arg399Gln genotypes were evaluated in a four-level model (chi(2) for linear trend = 10.9; P = 0.001). These results suggest that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity.