Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition

Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors.     

Health checks in general practice: another example of inverse care?

OBJECTIVE--To assess attendance at and the characteristics of patients attending health checks for cardiovascular disease offered in a general practice over a period of five years (1984-9). DESIGN--Medical record audit and postal questionnaire survey. SETTING--One general practice in Oxfordshire with a socially diverse population. PARTICIPANTS--1101 Men and 1110 women aged 35-64 registered with the practice. MAIN OUTCOME MEASURES--Age, sex, marital state, social class, smoking habits, alcohol consumption, and diet. RESULTS--Of the 2211 men and women in the target age group (35-64) in 1989, 1458 (65.9%) had been offered screening and 963 (43.6%) had attended for a health check. Attenders were more likely to be women, aged greater than or equal to 45, married, non-smokers, and of higher social class than patients who did not respond to the invitation. The relative likelihood of non-attendance was 1.24 for smokers, 1.20 for the overweight, 1.16 for heavy drinkers, and 1.28 for those with a less healthy diet, even after adjustment for age, sex, marital state, and social class. CONCLUSIONS--After five years of offering health checks, opportunistically (to men) and in the context of cervical smear tests (to women), less than half of the eligible patients had attended. The likelihood of acceptance of an invitation to attend was inversely related to the patient''s cardiovascular risk for all factors measured except age. A coherent strategy to reduce cardiovascular disease depends on more careful targeting of scarce health service resources and more emphasis on public health measures (such as dietary regulation and tobacco taxation). Doctors should be careful not to absolve the government of its public health obligations by substituting unproved preventive interventions aimed at the individual patient.     

Growth and fecundity of Daphnia after diapause and their impact on the development of a population

Laboratory and field investigations revealed that the life history traits of exephippial and parthenogenetic generations of Daphnia differ substantially. Daphniids hatching from resting eggs grow faster and their definitive body sizes are bigger than of hatchlings from subitaneous eggs. Size at maturity for exephippial animals is significantly larger. In spite of this, they mature a few days earlier than parthenogenetic females. In this study, the difference was 3–4 days for the laboratory experiments and 1–3 days for the field. Fecundity of the exephippial generation is markedly higher. Here, the clutch size for this generation was up to 3.5–4.0 times as large as for the parthenogenetic generation. Moreover, obtained results suggest that the relationship between clutch size and body length for both generations differ significantly.Estimates of the intrinsic rate of increase for field Daphnia populations demonstrated that life history traits of exephippial animals lead to a two or threefold higher rate of increase in the conditions of invertebrate predation pressure. Under moderate fish pressure, obtained r values for the daphniids hatching from resting eggs were larger than those from subitaneous. High growth rate of exephippial females is disadvantageous only under the conditions of severe pressure by fish. Obtained results suggest that hatchlings from diapausing eggs an acceleration of population increase by several times during the beginning of the development of a population with periodical re-establishment from resting eggs.     

Combined ipilimumab and nivolumab first‐line and after BRAF‐targeted therapy in advanced melanoma

The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.     

Intersectionality and trauma analysis in bioarchaeology

Intersectionality, the theory named by Kimberlé Crenshaw, outlines how multiple elements of an individual's social identity overlap to create and preserve societal inequalities and discrimination. Recently bioarchaeology's engagement with intersectionality has become increasingly explicit, as the field recognizes the lived experience of multiple axes of an individual's identity. Evidence of trauma can remain observable in an individual's skeleton for years, making it an ideal subject of study for intersectional analyses in bioarchaeology. Using contrasting case studies of two individuals who died in hospitals and were unclaimed after death, we explore the theoretical and methodological application of intersectionality to investigations of accidental and interpersonal trauma. Differences in identities and structural inequalities affect bone quality and health outcomes. As we demonstrate, a broken bone is the intersecting result of biological, histomorphological, sociocultural, and behavioral factors. This approach allows for a better acknowledgement of the inherent complexity of past lives, elevating and amplifying previously silenced voices. In this way, intersectionality in bioarchaeology demands social justice.     

The roles of carbonic anhydrases IX and XII in cancer cell adhesion,migration, invasion and metastasis

The main function of carbonic anhydrases (CAs) in cancer cells is the pH regulation through a conversion of H₂O and CO₂ to H⁺ and HCO₃⁻. However, the data of in vitro and in vivo studies have demonstrated that transmembrane isoforms of CA IX and CA XII are involved in various steps of cancer cell migration, invasion and metastasis. According to literature, inhibition of these CAs can affect the expression of multiple proteins. Some scientific groups have reported the possible interactions between CA IX and E-cadherin–catenin system, CA IX and integrins, CA IX, CA XII and ion transporters, which all are highly involved in cell-to-cell adhesion, the formation of membrane protrusions and focal adhesions. Nevertheless, CA IX and CA XII have a high impact on tumour growth and metastases formation. The data discussed in this review are quite recent. It highly support the role of CA IX and CA XII in various cancer metastasis processes through their interactions to other invasion proteins. Nevertheless, all findings show the great potential of these CAs in the context of research and application in clinical use.