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Supplementary Figure 4 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Supplementary Figure 3 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Supplementary Figure Legends 1-5 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Supplementary Figure 1 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Supplementary Figure 2 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Supplementary Figure 5 from Combined Depletion of Cell Cycle and Transcriptional Cyclin-Dependent Kinase Activities Induces Apoptosis in Cancer Cells

Selective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non–small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates. (Cancer Res 2006; 66(18): 9270-80)

Decreased PG constrains PSI activity due to inhibition of transcript and polypeptide abundance of light-harvesting and reaction center polypeptides generating a reversible, yellow phenotype during cold acclimation of pgp1. Cold acclimation of the Arabidopsis pgp1 mutant at 5 °C resulted in a pale-yellow phenotype with abnormal chloroplast ultrastructure compared to its green phenotype upon growth at 20 °C despite a normal cold-acclimation response at the transcript level. In contrast, wild type maintained its normal green phenotype and chloroplast ultrastructure irrespective of growth temperature. In contrast to cold acclimation of WT, growth of pgp1 at 5 °C limited the accumulation of Lhcbs and Lhcas assessed by immunoblotting. However, a novel 43 kD polypeptide of Lhcb1 as well as a 29 kD polypeptide of Lhcb3 accumulated in the soluble fraction which was absent in the thylakoid membrane fraction of cold-acclimated pgp1 which was not observed in WT. Cold acclimation of pgp1 destabilized the Chl-protein complexes associated with PSI and predisposed energy distribution in favor of PSII rather than PSI compared to the WT. Functionally, in vivo PSI versus PSII photochemistry was inhibited in cold-acclimated pgp1 to a greater extent than in WT relative to controls. Greening of the pale-yellow pgp1 was induced when cold-acclimated pgp1 was shifted from 5 to 20 °C which resulted in a marked decrease in excitation pressure to a level comparable to WT. Concomitantly, Lhcbs and Lhcas accumulated with a simultaneous decrease in the novel 43 and 29kD polypeptides. We conclude that the reduced levels of phosphatidyldiacylglycerol in the pgp1 limit the capacity of the mutant to maintain the structure and function of its photosynthetic apparatus during cold acclimation. Thus, maintenance of normal thylakoid phosphatidyldiacylglycerol levels is essential to stabilize the photosynthetic apparatus during cold acclimation.

The 2019 map of residual gravity anomalies of the Taupō Volcanic Zone and adjacent region is an update of the map of Stagpoole and Bibby (1999). An additional 1795 observations have been used in the 2019 compilation, bringing the total to 9189. All data used for the map have been uniformly processed and anomalies calculated using high resolution digital terrain models. The regional gravity field, used to separate the residual gravity anomalies from Bouguer anomalies, is from Stagpoole and Nicol (2008). GMT software was used for gridding the data and a 1:250,000 map was produced with the QGIS geographic information system. The 2019 map shows features in more detail than the 1999 map. Both the Taupō Volcanic Zone and the wider Central Volcanic Region are within a negative residual gravity anomaly. The whole eastern margin of the Taupō Volcanic Zone and western margin from Ruapehu to Tokoroa coincide with steep gravity gradients. North of Tokoroa, the margin of the Taupō Volcanic Zone defined from volcanism is not associated with a clearly observable gravity gradient. The negative residual gravity anomaly defining the area referred to as the Central Volcanic Region widens towards the Bay of Plenty coast in a series of steps, possibly related to older northeast-trending faults. Volcanic calderas in the Taupō Volcanic Zone identified from geological mapping correspond with prominent low-gravity features. There is also a gravity low at Mihi that is not presently defined as a caldera but may be related to caldera collapse. Low-gravity features north and northwest of Rotorua have unknown origins, although they may be partly related to thick, elevated, low-density volcanic material. Offshore, in the Bay of Plenty, a low-gravity feature corresponds with a caldera inferred from interpretation of seismic reflection data. Sedimentary basins outside the Taupō Volcanic Zone also have low residual gravity. Within the Taupō Volcanic Zone, a relative gravity high coincides with greywacke basement outcrops east of Paengaroa. Other high-gravity features may be related to near-surface greywacke basement or old andesitic volcanic centres buried beneath younger and less dense volcanic material. (auth)

The absorption spectra and vibrational circular dichroism (VCD) spectra in the mid-IR range 1600-950 cm(-1) of 10 camphor-related compounds have been recorded and compared to DFT calculated spectra at the B3PW91/TZ2P level and have been examined together with the corresponding data of the parent molecules. The rigidity of the bridged structure common to all compounds investigated permits (a) identification of three spectroscopic regions in the mid-IR range that can be "used" separately by the interested stereochemist for structural diagnosis and assignment of some major characteristics of the VCD spectra in these regions to what we call "skeletal chiral sense" and (b) recognition of possible conformers for flexible substituent groups, when present. VCD spectra of the 10 molecules have been recorded and analyzed also in the CH-stretching region, 3100-2800 cm(-1). Here, we have been able to identify and characterize features of vibrational excitons by comparison of data within the 10-molecule class. To find a theoretical justification of result (a), we have examined the potential energy distribution of the normal modes in the mid-IR range, the partitioning of the calculated rotational strengths in terms of contributions from all couples of internal coordinates, the angle formed by the two vectors, the electric dipole transition moment and the magnetic dipole transition moment, and finally the overlap of normal modes of different molecules. A discussion is provided as to the usability of the introduced algorithms.

Purpose: E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G1 arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN).Experimental Design: Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m2 over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to immunohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation.Results: Because none of the first 15 patients achieved progression-free survival > 4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49–73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1–5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment.Conclusions: At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.

Near-infrared vibrational circular dichroism (VCD) spectra in the region 1500−850 nm are recorded for both enantiomers of camphor and fenchone using a home-built dispersive instrument. Two CH-stretching overtone regions and two CH-stretching/HCH-bending combination regions are investigated. The near-infrared VCD data are examined and compared with the corresponding previously published data of (3R)-(+)-methylcyclopentanone and (3R)-(+)-methylcyclohexanone. The absorption spectra of both the fundamental and overtone regions are also considered, and the fundamental CH-stretching VCD data are taken into account, where possible. An empirical assignment of the spectra is first considered, with special regard to the second CH-stretching overtone region. This region is then investigated by a heuristic approach based on DFT calculations, using the hybrid functional B3LYP at the 6-31G** basis set level. Subsequently rotational strengths have been evaluated by use of a classical model based on the contribution of p...

The myosin family of motor proteins is implicated in mediating actin-based growth cone motility, but the roles of many myosins remain unclear. We previously implicated myosin 1c (M1c; formerly myosin Iβ) in the retention of lamellipodia (Wang et al., 1996). Here we address the role of myosin II (MII) in chick dorsal root ganglion neuronal growth cone motility and the contribution of M1c and MII to retrograde F-actin flow using chromophore-assisted laser inactivation (CALI). CALI of MII reduced neurite outgrowth and growth cone area by 25%, suggesting a role for MII in lamellipodial expansion. Micro-CALI of MII caused a rapid reduction in local lamellipodial protrusion in growth cones with no effects on filopodial dynamics. This is opposite to micro-CALI of M1c, which caused an increase in lamellipodial protrusion. We used fiduciary beads (Forscher et al., 1992) to observe retrograde F-actin flow during the acute loss of M1c or MII. Micro-CALI of M1c reduced retrograde bead flow by 76%, whereas micro-CALI of MII or the MIIB isoform did not. Thus, M1c and MIIB serve opposite and nonredundant roles in regulating lamellipodial dynamics, and M1c activity is specifically required for retrograde F-actin flow.

Selective cyclin-dependent kinase (cdk) 2 inhibition is readily compensated. However, reduced cdk2 activity may have antiproliferative effects in concert with other family members. Here, inducible RNA interference was used to codeplete cdk2 and cdk1 from NCI-H1299 non–small cell lung cancer and U2OS osteosarcoma cells, and effects were compared with those mediated by depletion of either cdk alone. Depletion of cdk2 slowed G1 progression of NCI-H1299 cells and depletion of cdk1 slowed G2-M progression in both cell lines, with associated endoreduplication in U2OS cells. However, compared with the incomplete cell cycle blocks produced by individual depletion, combined depletion had substantial consequences, with G2-M arrest predominating in NCI-H1299 cells and apoptosis the primary outcome in U2OS cells. In U2OS cells, combined depletion affected RNA polymerase II expression and phosphorylation, causing decreased expression of the antiapoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis (XIAP), effects usually mediated by inhibition of the transcriptional cdk9. These events do not occur after individual depletion of cdk2 and cdk1, suggesting that reduction of cdk2, cdk1, and RNA polymerase II activities all contribute to apoptosis in U2OS cells. The limited cell death induced by combined depletion in NCI-H1299 cells was significantly increased by codepletion of cdk9 or XIAP or by simultaneous treatment with the cdk9 inhibitor flavopiridol. These results show the potency of concomitant compromise of cell cycle and transcriptional cdk activities and may guide the selection of clinical drug candidates. (Cancer Res 2006; 66(18): 9270-80)

E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G(1) arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN).Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m(2) over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to immunohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation.Because none of the first 15 patients achieved progression-free survival4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49-73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1-5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment.At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.

Transformed cells are selectively sensitized to apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol after their recruitment to S phase. During S phase, cyclin A-dependent kinase activity neutralizes E2F-1 allowing orderly S phase progression. Inhibition of cyclin A-dependent kinase by flavopiridol could cause inappropriately persistent E2F-1 activity during S phase traversal and exit. Transformed cells, with high baseline levels of E2F-1 activity, may be particularly sensitive to cyclin A-dependent kinase inhibition, as the residual level of E2F-1 activity that persists may be sufficient to induce apoptosis. Here, we demonstrate that flavopiridol treatment during S phase traversal results in persistent expression of E2F-1. The phosphorylation of E2F-1 is markedly diminished, whereas that of the retinoblastoma protein is minimally affected, so that E2F-1/DP-1 heterodimers remain bound to DNA. In addition, manipulation of E2F-1 levels leads to predictable outcomes when cells are exposed to flavopiridol during S phase. Tumor cells expressing high levels of ectopic E2F-1 are more sensitive to flavopiridol-induced apoptosis during S phase compared with parental counterparts, and high levels of ectopic E2F-1 expression are sufficient to sensitize nontransformed cells to flavopiridol. Furthermore, E2F-1 activity is required for flavopiridol-induced apoptosis during S phase, which is severely compromised in cells homozygous for a nonfunctional E2F-1 allele. Finally, the response to flavopiridol during S phase is blunted in cells expressing a nonphosphorylatable E2F-1 mutant incapable of binding cyclin A, suggesting that the modulation of E2F-1 activity produced by flavopiridol-mediated cyclin-dependent kinase inhibition is critical for the apoptotic response of S phase cells.

Sorting of mRNA to specific compartments of the cell determines cell asymmetry. This sorting occurs in oocytes and embryos as well as somatic cells such as fibroblasts and neurons. Translation of localized mRNAs spatially directs protein synthesis. The cellular signals that direct specific RNA sequences to particular cellular compartments have recently been examined in fibroblasts, neurons, and Drosophila embryos. This chapter examines the regulation of mRNA localization through signal transduction pathways in organisms and their tissues.

This work was undertaken to investigate two systems for producing light-cured earmoulds, in order to evaluate the factors which influence the efficacy of such procedures. It was shown that there were variations in light intensity in the light boxes, and that the depth and age of gel in which curing takes place was important. Degree of cure of the materials was assessed by hardness measurements for hard materials and resistance to tearing for hard materials. Light-cured technology has great potential for the rapid production of ear-moulds.

In vivo room temperature chlorophyll a fluorescence coupled with CO{dollar}\sb2{dollar} and O{dollar}\sb2{dollar} exchange are measured to determine the effect of cold-hardening on the photosynthetic capacity and the susceptibility to photoinhibition of six cultivars of wheat (Triticum aestivum L.), covering a range of freezing tolerance. The role of the photosystem II (PSII) repair cycle in resistance to, and recovery from, photoinhibition is assessed at both low temperatures (5{dollar}\sp\circ{dollar}C & {dollar}-3\sp\circ{dollar}C) and in the presence of the 70S protein synthesis inhibitor, chloramphenicol. The effect of long-term, repeated photoinhibitory events and sustained reduction in PSII efficiency on net carbon gained is also assessed.;Winter wheat cultivars grown at 5{dollar}\sp\circ{dollar}C show light-saturated rates of CO{dollar}\sb2{dollar} exchange and apparent photon yields for CO{dollar}\sb2{dollar} exchange and O{dollar}\sb2{dollar} evolution that are equal to or greater than those of winter cultivars grown at 20{dollar}\sp\circ{dollar}C. In contrast, spring wheat cultivars grown at 5{dollar}\sp\circ{dollar}C show 35% lower apparent photon yields for CO{dollar}\sb2{dollar} exchange and 25% lower light-saturated rates of CO{dollar}\sb2{dollar} exchange compared to 20{dollar}\sp\circ{dollar}C grown controls. The lower CO{dollar}\sb2{dollar} exchange capacity is not associated with a lower efficiency of PSII activity measured as either the apparent photon yield for O{dollar}\sb2{dollar} evolution or the variable to maximal fluorescence ratio, and is most likely associated with carbon metabolism. In addition, cold-hardened spring wheat cultivars are more sensitive to short-term photoinhibition at low temperatures than cold-hardened winter cultivars. This greater resistance of the winter cultivars is associated with the winter phenotype rather than freezing tolerance per se and is due to an increase in the capacity of cold-hardened winter wheat to keep the primary electron acceptor for PSII, Q{dollar}\sb{lcub}\rm A{rcub},{dollar} oxidised at high irradiance (Oquist et al, 1991a).;Repeated photoinhibition (daily reductions in {dollar}F\sb{lcub}\rm V{rcub}/F\sb{lcub}\rm M{rcub}{dollar} of up to 40%) and sustained depression of PSII efficiency are shown to have no negative effects of net carbon accumulation in both cold-hardened winter and spring wheat. This is related to the finding that up to 50% of the loss in photon yield during photoinhibition is not due to irreversible damage to PSII. It is due instead to a rapidly reversible form on photoinhibition that recovers at temperatures as low as {dollar}-3\sp\circ{dollar}C and without de novo protein synthesis. It is suggested that this rapidly reversible form of photoinhibition is evidence of PSII quenching centres resulting from light induced, reversible modifications to the PSII reaction centre. It is proposed that these rapidly reversible quenching centres act as a regulatory mechanism, adjusting the yield of electron transport to match utilisation by photosynthetic carbon reduction. Thus, in situations where photosynthesis may be limited by factors other than light availability. PSII efficiency can be regulated by these wheat cultivars such that the photosynthetic apparatus is protected from over excitation.

Infrared, Raman, and vibrational circular dichroism (VCD) spectra have been recorded in the region 3100-2000 cm/sup -1/ for (S)-(+)-1-phenylethane-1-d/sub 1/, (S)-(+)-1-phenylethane-1,2-d/sub 2/, (S)-(+)-1-phenylethane-1,2,2-d/sub 3/, and (S)-(+)-1-phenylethane-1,2,2,2-d/sub 4/. From these spectra the authors have been able to assign fully the aliphatic CD and CH stretching vibrations in all four molecules. Using a harmonic force field which fits the observed frequencies, they have calculated the dipole and rotational strengths of these modes on the basis of the charge flow model. These calculations show that this model underestimates the VCD intensities of these stretching modes. However, the model can be improved through the introduction of polarization terms. Generally applicable analytical expressions for such terms are derived. When applied to the phenylethanes, they lead to the correct orders of magnitude for the rotational strengths.

The charge flow model is applied to the vibrational circular dichroism associated with oriented species. Expressions are derived for the three rotational strengths associated with light propagating along three orthogonal axes. The relevance of these expressions for the determination of the vibrational electric quadrupole transition moment is discussed.

Expressions are derived for the A terms, B terms, and associated partial anisotropy factors relevant for the magnetic vibrational circular dichroism (MVCD) spectra of molecules with nondegenerated ground states. These expressions are derived subject to the approximations of the harmonic fixed partial charge model and the condition of magnetic coupling among only the ground electronic state vibrational levels. Numerical values for partial anisotropy factors calculated from these expressions, when taken in conjunction with the recent MVCD data of Keiderling, suggest the importance of magnetic coupling of the ground electronic state with higher electronic states in the case of B terms. Symmetry constraints on the nonvanishing of such coupling terms also suggest the possible utility of MVCD data for providing spectroscopic and molecular structural information.

Contrairement aux predictions les signes du dichroisme circulaire des 2 composes cites sont opposes bien que les 2 molecules aient la meme configuration absolue

Contrairement aux predictions les signes du dichroisme circulaire des 2 composes cites sont opposes bien que les 2 molecules aient la meme configuration absolue

Infrared, Raman, and vibrational circular dichroism (VCD) spectra have been recorded in the region 3100-2000 cm/sup -1/ for (S)-(+)-1-phenylethane-1-d/sub 1/, (S)-(+)-1-phenylethane-1,2-d/sub 2/, (S)-(+)-1-phenylethane-1,2,2-d/sub 3/, and (S)-(+)-1-phenylethane-1,2,2,2-d/sub 4/. From these spectra the authors have been able to assign fully the aliphatic CD and CH stretching vibrations in all four molecules. Using a harmonic force field which fits the observed frequencies, they have calculated the dipole and rotational strengths of these modes on the basis of the charge flow model. These calculations show that this model underestimates the VCD intensities of these stretching modes. However, the model can be improved through the introduction of polarization terms. Generally applicable analytical expressions for such terms are derived. When applied to the phenylethanes, they lead to the correct orders of magnitude for the rotational strengths.

Choleragen (cholera toxin) catalyzed the NAD-dependent auto-ADP-ribosyltation of its A1 peptide. The number of ADP-ribose moieties incorporated into ech A1 peptide was dependent on incubation conditions and time as well as toxin concentration. There was no evidence for the formation of poly(ADP-ribosylated) toxin. The formation of mono- and multi-(ADP-ribosylated) A1 peptides was prevented by the addition of arginine, an alternative ADP-ribose acceptor. Triton X-100 polyacrylamide gel electrophoresis separated the A1 peptide of choleragen from the B complex and multi-(ADP-ribosylated) A1 peptides from unmodified A1. The A1 peptides ADP-ribosylated in the presence of [32P]NAD contained approximately 1, 2, or 3 ADP-ribose molecules/23,500-dalton units; under the conditions used for electrophoresis, the mobilities of the A1 peptides were enhanced by incorporation of ADP-ribose. The mono- and multi-(ADP-ribosylated) A1 peptides catalyzed the NAD-dependent ADP-ribosylation of arginine methyl ester. The turnover numbers of the mono- and multi-(ADP-ribosylated) A1 peptides were consistently 30 to 50% higher than that of the A1 peptide from native toxin.

To determine whether compression ultrasonography or clinical examination should be considered as screening tests for the diagnosis of deep vein thrombosis (DVT) after total hip or knee arthroplasty in patients receiving warfarin prophylaxis postoperatively.A prospective cohort study.A single tertiary care orthopedic centre.One hundred and eleven patients who underwent elective total hip or knee arthroplasty were enrolled. Postoperatively the warfarin dose was adjusted daily to maintain the international normalized ratio between 1.8 and 2.5. Eighty-six patients successfully completed the study protocol.Before they were discharged from hospital, patients were assessed for DVT by clinical examination, bilateral compression ultrasonography of the proximal venous system and bilateral contrast venography.DVT was found in 29 patients (34%; 95% confidence interval [CI] 24% to 45%), and 6 patients (7%; 95% CI 3% to 15%) had proximal DVT. DVT developed in 18 (40%) of 45 patients who underwent total knee arthroplasty and in 11 (27%) of 41 patients who underwent total hip arthroplasty. The sensitivity of compression ultrasonography for the diagnosis of proximal DVT was 83% (95% CI 36% to 99%) and the specificity was 98% (95% CI 91% to 99%). The positive predictive value of compression ultrasonography was 71%. In contrast, clinical examination for DVT had a sensitivity of 11% (95% CI 2% to 28%) and a positive predictive value of 25%.DVT is a common complication after total hip or knee arthroplasty. Compression ultrasonography appears to be a relatively accurate noninvasive test for diagnosing postoperative proximal DVT. In contrast, clinical examination is a very insensitive test. Whether routine use of screening compression ultrasonography will reduce the morbidity of venous thromboembolism after joint arthroplasty requires confirmation in a prospective trial involving long-term follow-up of patients.

The continuing worldwide epidemic of adult HIV/AIDS has led to an increase in the number of HIV-positive children mainly through perinatal transmission. Although national data are available, there is no published report of the epidemiology of HIV/AIDS in children in Jamaica. A multicentre retrospective analysis of 183 HIV seropositive children admitted to hospitals in Jamaica between 1990 and 1996 was conducted. Ages at diagnosis were available for 172 patients with 61% diagnosed in the first year of life. Clinical histories were available for 129 patients with the primary presenting symptoms of infected children being failure to thrive, pneumonia, diarrhoea, dermatitis and lymphadenopathy. Classification was possible in 128 patients: 49 were exposed, 76 were infected and three were seroreverters. Infected children had a longer hospital stay than those classified as exposed or seroreverters. As of December 31, 1997, 125 patients had defaulted, nine patients were alive and 51 were reported dead with a median age of death of 12 months. From these data, it is estimated that the hospital-based HIV incidence among children in Jamaica increased from 0.149 per 10,000 person years in 1990 to 1.331 per 10,000 person years in 1996. This study demonstrates a rise in the estimated incidence of HIV/AIDS but we were unable to estimate survival reliably since the data required were not available for 75% of children identified. These data highlight the urgent need for targeted interventions to reduce vertical transmission of HIV as well as a need for prospective studies to establish reliable data on incidence and long-term outcome for HIV-infected children.

The first results of carbon and nitrogen (δ13C, δ15N) stable isotope analyses of domestic pig (Sus domesticus Erxl., 1777) remains from three prehistoric sites are presented. Of these, comparison of the datasets from Tell Aqab in Syria and Çamlıbel Tarlası in Turkey suggests different dietary patterns, and possibly different pig husbandry practices, at these sites. The study highlights the need for supporting evidence from archaeobotanical and palaeoenvironmental investigations in the interpretation of stable isotope data.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.

Ten global harbours were assessed for sediment quality by quantifying the magnitude of anthropogenic change and ecological risk. Anthropogenic change (enrichment) was high for Derwent River and Sydney estuary, moderate for Santander Harbour, Rio de Janeiro and Dublin Port, slight for Hong Kong, minimal for Darwin. All 10 enrichment indices used showed similar results. Derwent River sediment was rated at high ecological risk, followed by Sydney and Santander estuaries with moderate risk. Auckland and Darwin sediments exhibited minimal ecological risk and sediment in the remaining harbours (Dublin, Hong Kong, Ravenna, Ria de Vigo and Rio de Janeiro) were assessed at slight ecological risk. The extraordinary variety of environments and types/quantities/qualities of data investigated resulted in as much a critique and development of methodology, as an assessment of human impact, including unique techniques for elemental normalisation and contaminant classification. Recommendations for an improved technical framework for sediment quality assessment are provided., Sí