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Micrometeorites (MMs) recovered from the Earth's surface may have undergone significant changes prior to their collection, including weathering while residing in the terrestrial environment. These alteration processes, such as the precipitation of hydrous phases, may overprint both primary and atmospheric entry features, obscuring pre-existing material properties. In addition, weathering exerts a prominent control on the geochemical interactions, such as species mobility, between extraterrestrial material and the terrestrial environment, particularly in Antarctica. In this study, we have characterised the textural and compositional consequences of weathering on an unmelted, fine-grained, Antarctic MM, which includes the mapping of nanometre-scale features using atom probe tomography. In particular, we investigate geochemical behaviour across textural boundaries in the MM and observe nanoscale elemental heterogeneity within complex alteration assemblages. In one sample region, a compositional boundary is highlighted by distinct elemental differences, consistent with a weathering encrustation of mixed mineralogies, while analyses in other targeted regions show evidence for nanoscale elemental networks, as well as a grain boundary adjacent to a carbon-rich region. We discuss our findings in the context of terrestrial weathering as a dominant cause for the nanoscale features observed. Weathering processes responsible for these features include the leaching of extraterrestrial material, precipitation of secondary alteration products with associated layering, and the influence of mechanical stress on pre-existing weaknesses. From these results, we derive a weathering sequence to explain the formation of the alteration product assemblage and highlight the controls on MM geochemistry in the terrestrial environment. Our observations show that nanoscale carbonaceous material may be preserved in oxy-hydroxides under icy conditions, which can also act as tracers for local environmental changes. [ABSTRACT FROM AUTHOR]

Proliferative verrucous leukoplakia (PVL) is a rare form of oral leukoplakia with a relatively high transformation rate resulting in oral squamous cell carcinoma (OSCC). Molecular analysis of PVL at the genome level is limited and has only identified molecular similarities between PVL and OSCC. However, the clinical profile of PVL suggests that molecular differences may be more important. Whole exome sequencing of 5 PVL-associated OSCC (PVL-OSCC) and paired blood samples was used to identify somatic mutations common to the tumors. Whole methylome analysis of samples from 4 PVL-associated OSCC and 3 OSCC of non-PVL origin samples was conducted to explore differential methylation. In contrast to conventional OSCC, PVL-associated OSCC showed infrequent TP53 mutation and altered spectra of PIK3CA and NOTCH1 mutations. Unsupervised hierarchical clustering identified 63 probes that discriminated between PVL-associated OSCC and OSCC of non-PVL origin. Differences in methylation were most significant for divalent metal ion transport, particularly calcium movement. Specific differences in mutation and methylation profiles between PVL-derived OSCC and OSCC of non-PVL origin suggest differences in their transformation pathways. Further studies of early PVL lesions may identify markers of transformation that are also applicable to more common oral premalignant disorders such as oral epithelial dysplasia. [ABSTRACT FROM AUTHOR]

Abstract: We present a 74-year-old male ex-smoker presenting with a 6-week history of personality change, confusion and headache. Magnetic resonance imaging revealed multiple supratentorial and infratentorial parenchymal masses, predominately in the frontal and parietal lobe white matter. A thin enhancing halo was demonstrated with central low signal intensity on T1-and T2-weighted imaging compatible with calcification. A tiny extra-axial lesion was also noted near the right cerebellopontine angle. Computed tomography (CT) scan confirmed the finding of a ‘target’ lesion with a central core of calcification and a ring of enhancement. The ‘target sign’ of intracerebral tuberculomata was first described in 1979 and reported to be pathognomic for this diagnosis in 1988. However, cerebral tuberculosis was considered unlikely clinically because the patient had recently completed a 12-month course of therapy for Mycobacterium avium complex respiratory infection with agents also active against Mycobacterium tuberculosis. He was afebrile and blood tests did not support an inflammatory process. Subsequent histopathology demonstrated metastatic papillary adenocarcinoma and immunohistochemical studies revealed the origin to be that of primary lung carcinoma. A spiculated pulmonary nodule was seen on CT scan but previous bronchoscopy failed to demonstrate malignant cells. In summary, the ‘target sign’ is a non-specific radiologic finding but most commonly indicates cerebral tuberculoma or metastatic adenocarcinoma in the appropriate clinical context. [Copyright &y& Elsevier]

• Targeted multidrug-resistant organism screening of migrant groups can be stigmatizing and divisive. • Screening instead by risk of disseminated infection protects those most vulnerable. • Metagenomics is an emerging technology for comprehensive screening of multidrug-resistant organism carriage. Multidrug-resistant organisms (MDROs) are a major international health threat. In many low and middle-income countries poorly regulated antibiotic use, limited surveillance, and inadequate sanitation give rise to high rates of antibiotic resistance. A resulting reliance on last-line antibiotic options further contributes to the emergence of MDROs. The potential for these pathogens to spread across international borders is a matter of considerable concern. However, this problem is commonly framed as primarily a threat to the health security of countries where resistance is not yet endemic. In fact, it is little acknowledged that those at greatest risk from antibiotic treatment failure are individuals who move from regions of high MDRO prevalence to settings where standard empirical treatment options remain largely effective. In this perspective, we highlight the poor treatment outcomes for disseminated bacterial infections in individuals who have moved from settings in which MDROs are common to those where MDROs are currently less common. We discuss MDRO screening strategies that could avoid stigmatizing vulnerable populations by focusing on future risk of disseminated infection, rather than past risk of acquisition. In practical terms, this means screening individuals before childbirth, immunosuppressive treatments, major surgery, or other events associated with disseminated infection risk, rather than prioritizing screening for individuals from regions with high carriage rates. We argue that such measures would reduce antibiotic treatment failure and improve outcomes while protecting migrant populations from the divisive consequences of targeted screening programs. [ABSTRACT FROM AUTHOR]

Patients with mutated TP53 have been identified as having comparatively poor outcomes compared to those retaining wild-type p53 in many cancers, including squamous cell carcinomas of the head and neck (SCCHN). We have examined the role of p53 in regulation of metabolism in SCCHN cells and find that loss of p53 function determines the Warburg effect in these cells. Moreover, this metabolic adaptation to loss of p53 function creates an Achilles' heel for tumour cells that can be exploited for potential therapeutic benefit. Specifically, cells lacking normal wild-type p53 function, whether through mutation or RNAi-mediated downregulation, display a lack of metabolic flexibility, becoming more dependent on glycolysis and losing the ability to increase energy production from oxidative phosphorylation. Thus, cells that have compromised p53 function can be sensitised to ionizing radiation by pre-treatment with a glycolytic inhibitor. These results demonstrate the deterministic role of p53 in regulating energy metabolism and provide proof of principle evidence for an opportunity for patient stratification based on p53 status that can be exploited therapeutically using current standard of care treatment with ionising radiation. What is already known • TP53 mutations are the most common genetic mutation in many cancers, including head and neck cancers. •Patients with mutated p53 display poor prognosis but no method exists for selectively treating these patients What this study adds •We identify and confirm that p53 status (mutant or normal) determines tumour cell metabolic profile •Metabolic changes induced by loss of p53 function determine sensitivity to metabolic inhibition in combination with the mainstay of current therapy-radiation, and provide an opportunity to increase radiation sensitivity in p53 mutated cells •The results suggest that a strategy for treating patients with mutations in TP53 could be readily developed combining the current standard of care (radiotherapy) with short term inhibition of a metabolic pathway (glycolysis). [ABSTRACT FROM AUTHOR]

There is a pressing need to identify ways of sensitising squamous cell carcinomas of the head and neck (SCCHN) to the effects of current treatments, both from oncological and functional perspectives. Alteration to cellular metabolism is now widely considered a hallmark of the cancer phenotype; presents a potentially attractive therapeutic target in this regard; and as such has received renewed research interest in recent years. However, whilst metabolic disruption may occur to some degree in all tumours, there is undoubtedly heterogeneity and detailed study of individual tumour types is paramount if effective therapeutic strategies targeting metabolism are to be developed and effectively deployed. In this review we outline current understanding of altered tumour metabolism and how these adaptations promote tumorigenesis generally. We relate this specifically to SCCHN by focusing on several recent key studies specific to SCCHN, and by discussing the role TP53 mutation may play in this metabolic switch, given the fundamental role of this oncogenic event in SCCHN tumorigenesis. Finally, we also offer insight into the potential therapeutic implications this may have in the clinical setting and make recommendations for future study. [ABSTRACT FROM AUTHOR]

Although the role of p53 as a tumour suppressor in renal cell carcinoma (RCC) is unclear, our recent analysis suggests that increased wild-type p53 protein expression is associated with poor outcome. A growing body of evidence also suggests that p53 expression and increased co-expression of MDM2 are linked with poor prognosis in RCC. We have therefore examined whether an MDM2 antagonist; Nutlin-3, might rescue/increase p53 expression and induce growth inhibition or apoptosis in RCC cells that retain wild-type p53. We show that inhibition of p53 suppression by MDM2 in RCC cells promotes growth arrest and p53-dependent senescence – phenotypes known to mediate p53 tumour suppression in vivo. We propose that future investigations of therapeutic strategies for RCC should incorporate MDM2 antagonism as part of strategies aimed at rescuing/augmenting p53 tumour suppressor function. [ABSTRACT FROM AUTHOR]