Isotropy of Cosmic Rays beyond 10

We report an estimation of the injected mass composition of ultrahigh energy cosmic rays (UHECRs) at energies higher than 10 EeV. The composition is inferred from an energy-dependent sky distribution of UHECR events observed by the Telescope Array surface detector by comparing it to the Large Scale Structure of the local Universe. In the case of negligible extragalactic magnetic fields (EGMFs), the results are consistent with a relatively heavy injected composition at E∼10 EeV that becomes lighter up to E∼100 EeV, while the composition at E>100 EeV is very heavy. The latter is true even in the presence of highest experimentally allowed extragalactic magnetic fields, while the composition at lower energies can be light if a strong EGMF is present. The effect of the uncertainty in the galactic magnetic field on these results is subdominant.

Mutation accumulation in H. sapiens F508del CFTR countermands dN/dS type genomic analysis.

Understanding the mechanisms that underlie de novo mutations (DNMs) can be essential for interpreting human evolution, including aspects such as rapidly diverging genes, conservation of non-coding regulatory elements, and somatic DNA adaptation, among others. DNM accumulation in Homo sapiens is often limited to evaluation of human trios or quads across a single generation. Moreover, human SNPs in exons, pseudogenes, or other non-coding elements can be ancient and difficult to date, including polymorphisms attributable to founder effects and identity by descent. In this report, we describe multigenerational evolution of a human coding locus devoid of natural selection, and delineate patterns and principles by which DNMs have accumulated over the past few thousand years. We apply a data set comprising cystic fibrosis transmembrane conductance regulator (CFTR) alleles from 2,393 individuals homozygous for the F508del defect. Additional polymorphism on the F508del background diversified subsequent to a single mutational event during recent human history. Because F508del CFTR is without function, SNPs observed on this haplotype are effectively attributable to factors that govern accumulating de novo mutations. We show profound enhancement of transition, synonymous, and positionally repetitive polymorphisms, indicating appearance of DNMs in a manner evolutionarily designed to protect protein coding DNA against mutational attrition while promoting diversity.

Translation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations.

Nonsense mutations - the underlying cause of approximately 11% of all genetic diseases - prematurely terminate protein synthesis by mutating a sense codon to a premature stop or termination codon (PTC). An emerging therapeutic strategy to suppress nonsense defects is to engineer sense-codon decoding tRNAs to readthrough and restore translation at PTCs. However, the readthrough efficiency of the engineered suppressor tRNAs (sup-tRNAs) largely varies in a tissue- and sequence context-dependent manner and has not yet yielded optimal clinical efficacy for many nonsense mutations. Here, we systematically analyze the suppression efficacy at various pathogenic nonsense mutations. We discover that the translation velocity of the sequence upstream of PTCs modulates the sup-tRNA readthrough efficacy. The PTCs most refractory to suppression are embedded in a sequence context translated with an abrupt reversal of the translation speed leading to ribosomal collisions. Moreover, modeling translation velocity using Ribo-seq data can accurately predict the suppression efficacy at PTCs. These results reveal previously unknown molecular signatures contributing to genotype-phenotype relationships and treatment-response heterogeneity, and provide the framework for the development of personalized tRNA-based gene therapies.

Association of Balance Impairment with Risk of Incident Dementia among Older Adults.

BACKGROUND: A growing body of data suggests that balance impairment may be linked to the onset of dementia. OBJECTIVES: However, a large-scale epidemiologic investigation is needed to clarify its association in older adults. DESIGN: A retrospective-prospective hybrid database. SETTING: Cox proportional hazards regression model was used to assess the relationship between balance impairment and the risk of incident dementia, and the results were provided as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). All participants were tracked until the date of incident dementia, death, or 31 December 2019 whichever came first. PARTICIPANTS: We analyzed 143,788 older adults who had at least one health screening between 2009 and 2019 from the Korea National Health Insurance Service-Senior Cohort. MEASUREMENTS: A total of 3,774 cases of dementia were discovered throughout 850,425 person-years of follow-up investigation. Balance impairment was associated with a risk of dementia compared to those without balance impairment (adjusted hazard ratio [aHR] 1.83; 95% CI, 1.69-2.00; P value <0.001). RESULTS: Risks of the Alzheimer's disease (aHR, 1.80; 95% CI, 1.65-1.96; P for trend <0.001) and the vascular dementia (aHR, 2.94; 95% CI, 1.89-4.58; P for trend <0.001) showed comparable trends and findings. CONCLUSIONS: Balance impairment was found to be independently associated with an increased risk of dementia in older adults.

Intrahospital transmission and infection control of Candida auris originating from a severely infected COVID-19 patient transferred abroad.

BACKGROUND: Intrahospital spread of Candida auris, which survives tenaciously in many environments, can cause sustained colonization and infection. A large outbreak of C. auris was experienced in the intensive care units (ICUs) at the study hospital during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: The index patient with severe COVID-19, who was transferred from Vietnam in January 2022, developed C. auris candidaemia 10 days after hospitalization. From mid-June 2022 to January 2023, strengthened infection prevention and control (IPC) measures were implemented in three ICUs: (1) contact precautions and isolation (CPI) for C. auris-positive cases; (2) surveillance cultures including point-prevalence (N=718) for patients or close contacts or ICU-resident healthcare workers (HCWs); (3) intensive environmental disinfection with 10-fold diluted bleach; and (4) 2% chlorhexidine bathing for all ICU patients. Environmental cultures (ECx) on surfaces and shared objects (N=276) were conducted until early September 2022, when all ECx were negative. RESULTS: Among 53 C. auris-positive patients between February 2022 and January 2023, invasive infections resulted in seven cases of candidaemia and one case of pneumonia. C. auris was isolated from reusable tympanic thermometers (TTMs) contaminated with earwax. The isolation rate of C. auris in ECx decreased from 6.8% in June 2022 to 2.0% in August 2022, and was no longer detected in TTMs. Colonization in HCWs was remarkably rare (0.5%). The number of C. auris-positive patients peaked in July (N=10) then decreased gradually. By January 2023, no C. auris were isolated in the ICU. CONCLUSION: Aggressive IPC measures with CPI, ECx and surveillance, decontamination of TTMs, and bathing were effective in successfully controlling this C. auris outbreak.

An extremely energetic cosmic ray observed by a surface detector array.

Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.

A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.

Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection and COVID-19 disease severity.

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.

Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics.

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report that variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry multiplexed with isobaric tandem mass tags was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knockdowns sensitize P67L to VX-445 and further enhance the trafficking correction of this variant. Partial inhibition of protein translation also mildly sensitizes P67L CFTR to VX-445 correction, supporting a role for translational dynamics in the rescue mechanism of VX-445. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize nonresponsive CFTR variants to known and available correctors.

Association of body mass index and bloodstream infections in patients on extracorporeal membrane oxygenation: a single-centre, retrospective, cohort study.

BACKGROUND: Obesity is associated with poor clinical outcomes in critically ill patients. However, under some clinical conditions, obesity has protective effects. Bloodstream infections (BSI) are among the most common nosocomial infections associated with extracorporeal membrane oxygenation (ECMO). BSI during ECMO is associated with higher mortality rates and poorer clinical outcomes. AIM: To analyse whether body mass index (BMI) is associated with BSI during ECMO or with in-hospital mortality. METHODS: All adult patients who had received ECMO support for >48 h were included in the analysis. The analysis of total duration of ECMO support, in-hospital mortality and BSI was stratified by BMI category. The Cox proportional hazards model was used to compare the risk of BSI among BMI categories. FINDINGS: In total, 473 patients were enrolled in the study. The average age was 56.5 years and 65.3% were men. The total duration of ECMO was approximately 11.8 days, with a mortality rate of 47.1%. The incidence rates of BSI and candidaemia were 20.5% and 5.5%, respectively. The underweight group required ECMO for respiratory support, whereas the overweight and obese groups required ECMO for cardiogenic support (P<0.0001). No significant difference in BSI rate was found (P=0.784). However, after adjusting for clinical factors, patients in Group 4 (BMI 25.0-<30.0 kg/m2) exhibited lower mortality compared with patients in Group 2 (normal BMI) (P=0.004). CONCLUSION: BMI was not associated with risk of BSI, but patients with higher BMI showed lower in-hospital mortality associated with ECMO support.

Initial phase establishment of an in vitro method for developmental neurotoxicity test using Ki-67 in human neural progenitor cells.

Building a precise alternative neurotoxicological test is of great importance to respond to societal and ethical requirements. In this study, a new developmental neurotoxicity test (DNT) was established with the human neural progenitor cell line. ReNcell CX cells were exposed to neurotoxic chemicals (aphidicolin, hydroxyurea, cytosine arabinoside, 5-fluorouracil, and ochratoxin A) or non-neurotoxic chemicals (sodium gluconate, sodium bicarbonate, penicillin G, and saccharin). Propidium iodide (PI) was used to evaluate cell viability. BrdU and Ki-76 were employed to determine cell proliferation. Based on the cell viability and proliferation, mathematical models were built by linear discriminant analysis. Furthermore, the neurotoxic-considered chemicals inhibited cell cycle progression at the protein level, supporting the biomolecular rationale for the predictive model. Overall, these results show that the new test method can be used to determine the potential developmental neurotoxicants or new drug candidates.

Engineered tRNAs suppress nonsense mutations in cells and in vivo.

Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into  efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

Hierarchical settlement behaviours of coral larvae to common coralline algae.

Natural regeneration of degraded reefs relies on the recruitment of larvae to restore populations. Intervention strategies are being developed to enhance this process through aquaculture production of coral larvae and their deployment as spat. Larval settlement relies on cues associated with crustose coralline algae (CCA) that are known to induce attachment and metamorphosis. To understand processes underpinning recruitment, we tested larval settlement responses of 15 coral species, to 15 species of CCA from the Great Barrier Reef (GBR). CCA in the family Lithophyllaceae were overall the best inducer across most coral species, with Titanoderma cf. tessellatum being the most effective species that induced at least 50% settlement in 14 of the coral species (mean 81%). Taxonomic level associations were found, with species of Porolithon inducing high settlement in the genus Acropora; while a previously understudied CCA, Sporolithon sp., was a strong inducer for the Lobophyllidae. Habitat-specific associations were detected, with CCA collected from similar light environment as the coral inducing higher levels of settlement. This study revealed the intimate relationships between coral larvae and CCA and provides optimal coral-algal species pairings that could be utilized to increase the success of larval settlement to generate healthy spat for reef restoration.

High-throughput screens identify a lipid nanoparticle that preferentially delivers mRNA to human tumors in vivo.

Lipid nanoparticles (LNPs) are a clinically relevant way to deliver therapeutic mRNA to hepatocytes in patients. However, LNP-mRNA delivery to end-stage solid tumors such as head and neck squamous cell carcinoma (HNSCC) remains more challenging. While scientists have used in vitro assays to evaluate potential nanoparticles for HNSCC delivery, high-throughput delivery assays performed directly in vivo have not been reported. Here we use a high-throughput LNP assay to evaluate how 94 chemically distinct nanoparticles delivered nucleic acids to HNSCC solid tumors in vivo. DNA barcodes were used to identify LNPHNSCC, a novel LNP for systemic delivery to HNSCC solid tumors. Importantly, LNPHNSCC retains tropism to HNSCC solid tumors while minimizing off-target delivery to the liver.

Discovery of New Isotope

The new isotope ^{241}U was synthesized and systematic atomic mass measurements of nineteen neutron-rich Pa-Pu isotopes were performed in the multinucleon transfer reactions of the ^{238}U+^{198}Pt system at the KISS facility. The present experimental results demonstrate the crucial role of the multinucleon transfer reactions for accessing unexplored neutron-rich actinide isotopes toward the N=152 shell gap in this region of nuclides.

Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics.

Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knock-downs sensitize P67L to VX-445 and further enhance the correction of this variant. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors.

Impact of tuberculosis on the incidence of osteoporosis and osteoporotic fractures: a nationwide population-based cohort study.

OBJECTIVES: Despite the high prevalence of tuberculosis (TB) and the disease burden of osteoporosis and osteoporotic fractures, there is still a lack of well-designed, large-scale studies demonstrating associations among them. We aimed to investigate the effect of TB on the incidence of osteoporosis and osteoporotic fractures. STUDY DESIGN: This was a nationwide population-based cohort study. METHODS: This study was conducted using the National Health Insurance Service Database of South Korea. We included patients with newly diagnosed TB aged >40 years from January 2006 to December 2017. An uninfected control for each TB patient was randomly extracted by frequency matching for sex, age, income level, residence, and registration date at a 2:1 ratio. The primary outcome was the incidence of osteoporosis and osteoporotic fractures between the two groups, adjusted for sex, age, income level, residence, comorbidities, body mass index, blood pressure, laboratory tests, alcohol drinking, and smoking. The risk factors associated with osteoporosis or osteoporotic fractures were also investigated. RESULTS: A total of 164,389 patients with TB and 328,778 matched controls were included (71.9% males). The mean duration of follow-up was 7.00 ± 3.49 years. The incidence of osteoporosis in patients with TB was 6.1 cases per 1000 person-years, which was significantly higher than that in matched controls (adjusted hazard ratio [aHR] 1.349, 95% confidence interval [CI] 1.302-1.398, P < 0.001). The incidence of osteoporotic fractures was also higher in patients with TB than in controls (aHR 1.392, 95% CI 1.357-1.428, P < 0.001). Among fractures, the risk of hip fracture was the highest (aHR 1.703, 95% CI 1.612-1.798, P < 0.001). CONCLUSIONS: TB independently contributes to the incidence of osteoporosis and osteoporotic fractures, particularly hip fractures.

Diagnostic test accuracy of D-dimer with or without a clinical decision rule in peripartum patients with suspected venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: Pregnancy and the peripartum period is a hypercoagulable state increasing the risk of venous thromboembolism (VTE). There may be a role in utilising D-dimer in the peripartum setting. AIMS: The purpose of this review was to summarise the latest evidence regarding the diagnostic accuracy of D-dimer in the peripartum setting with or without the addition of clinical decision rules. METHODS: We searched PubMed and CENTRAL databases to identify articles that included studies of women who had suspected VTE, underwent a D-dimer index test to rule out VTE and where radiological imaging or clinical follow-up, to a minimum of 30 days, was used as the reference standard. RESULTS: We included 11 studies in the systematic review and meta-analysis. The log diagnostic odds ratio (DOR) for identifying VTE using D-dimer was 1.56 (95% confidence interval (CI) 0.59-2.52). The pooled sensitivity was 87% (95% CI 76.8-93%), specificity was 63.2% (95% CI 47.1-76.7%), and the area under receiver operator characteristic (ROC) curves was 0.76. We included four studies evaluating D-dimer combined with YEARS to detect VTE. The log DOR for identifying VTE using D-dimer combined with YEARS was 1.13 (95% CI 0.005-2.25). The pooled sensitivity was 89.8% (95% CI 60.2-98.1%), specificity was 65.7% (95% CI 54.7-75.2%) and the area under ROC for studies included with the YEARS clinical decision rule was 0.49. CONCLUSION: This review highlighted that D-dimer use in the peripartum period for detection of VTE had a high sensitivity and high DOR but a poor area under ROC, which may limit its use in clinical practice.

Comparing the efficacy of different methods of faecal microbiota transplantation via oral capsule, oesophagogastroduodenoscopy, colonoscopy, or gastric tube.

BACKGROUND: The increasing prevalence of multidrug-resistant organism (MDRO) carriage poses major challenges to medicine as healthcare costs increase. Recently, faecal microbiota transplantation (FMT) has been discussed as a novel and effective method for decolonizing MDRO. AIM: To compare the efficacy of different FMT methods to optimize the success rate of decolonization in patients with MDRO carriage. METHODS: This prospective cohort study enrolled patients with MDRO carriages from 2018 to 2021. Patients underwent FMT via one of the following methods: oral capsule, oesophagogastroduodenoscopy (EGD), colonoscopy, or gastric tube. FINDINGS: A total of 57 patients underwent FMT for MDRO decolonization. The colonoscopy group required the shortest time for decolonization, whereas the EGD group required the longest (24.9 vs 190.4 days, P = 0.022). The decolonization rate in the oral capsule group was comparable to that in the EGD group (84.6% vs 85.7%, P = 0.730). An important clinical factor associated with decolonization failure was antibiotic use after FMT (odds ratio = 6.810, P = 0.008). All four groups showed reduced proportions of MDRO species in microbiome analysis after FMT. CONCLUSION: Compared to other conventional methods, the oral capsule is an effective FMT method for patients who can tolerate an oral diet. The discontinuation of antibiotics after FMT is a key factor in the success of decolonization.

Evaluating antitumor activity of Escherichia coli purine nucleoside phosphorylase against head and neck patient-derived xenografts.

BACKGROUND: Purine nucleoside phosphorylase (PNP) gene transfer represents a promising approach to treatment of head and neck malignancies. We tested recombinant adenovirus already in phase I/II clinical testing and leading-edge patient-derived xenografts (PDX) as a means to optimize this therapeutic strategy. METHODS: Our experiments investigated purine base cytotoxicity, PNP enzyme activity following treatment of malignant tissue, tumor mass regression, viral receptor studies, and transduction by tropism-modified adenovirus. RESULTS: Replication deficient vector efficiently transduced PDX cells and mediated significant anticancer effect following treatment with fludarabine phosphate in vivo. Either 6-methylpurine or 2-fluoroadenine (toxic molecules generated by the PNP approach) ablated head and neck cancer cell proliferation. High levels of adenovirus-3 specific receptors were detected in human tumor models, and vector was evaluated that utilizes this pathway. CONCLUSIONS: Our studies provide the scientific foundation necessary to improve PNP prodrug cleavage and advance a new treatment for head and neck cancer.