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91.
IntroductionThe human immunodeficiency virus 1 (HIV‐1) pandemic is characterized by numerous distinct sub‐epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses.MethodsWe used HIV‐1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV‐1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW‐specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi‐Square statistics.ResultsWe identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2‐fold increase in the number of NSW‐specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above‐average growth rate (>1.5 sequences / 6‐months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals.ConclusionsThe large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE.  相似文献   
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Tetrahydrocortisol, -cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 M, 24 h) and -cyclodextrin tetradecasulfate (100 M, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 M, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studies. Tetrahydrocortisol and -cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14×5mg/kg, days 4–18) and cyclophosphamide (3×150 mg/kg, days, 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.Abbreviations 14(SO4)ßCD -cyclodextrin tetradecasulfate - THC tetrahydrocortisol - CDDP cis-diamminedichloroplatinum(II) - 4-HC 4-hydroperoxycyclophosphamide - BCNU N,N-bis(2-chloroethyl)-N-nitrosourea - CAM chick embryo chorioallantoic membrane; IC50, concentration of a drug required to kill 50% of the cells This work was supported by NIH grant P01-CA38493 and a grant from Bristol-Myers-Squibb, Inc., Wallingford, Connecticut  相似文献   
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Evidence that the shift of services from secondary to primary care is creating extra work for GPs is limited. A study showed that it is possible to quantify additional workload for GPs, but that certain aspects, such as measuring the time input, remain problematic. Future research needs to agree workload definitions, employ sensitive measures other than consultation rates, and distinguish between workload in practices and that of individual practitioners.  相似文献   
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Previous studies have shown that hyperthermia is an effective modulator of cis-diamminedichloroplatinum(II) (CDDP) cytotoxicity. We have examined the potential of inhibitors of the arachidonic acid metabolism to increase the antitumor activity of CDDP and hyperthermia. Sulindac and diflunisal are cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs (NSAIDS) and phenidone is a lipoxygenase inhibitor. Using the FSaIIC in vivo-in vitro excision assay, neither five daily injections of sulindac nor diflunisal added to the killing of FSaIIC cells achieved by one injection of CDDP at normal temperature. When the i.p. injection of CDDP and the NSAIDS were followed immediately by hyperthermia treatment to the tumor bearing limb at 43-degrees-C for 30 min, the cell killing achieved was increased by 2-3-fold by diflunisal over the dose range of CDDP examined but was unaffected by sulindac. Phenidone did not alter the cell killing achieved by CDDP at normal temperature or when the CDDP was followed by local hyperthermia, but use of a combination of sulindac or diflunisal plus phenidone increased the cell killing achieved by 2-10-fold when used with local hyperthermia over the dose range of CDDP tested. In tumor growth delay (TGD) studies, addition of five daily injections of sulindac, diflunisal or phenidone did not increase the TGD achieved by CDDP at normal temperature and neither diflunisal nor phenidone markedly increased the TGD produced by CDDP in conjunction with local hyperthermia, but the administration of sulindac resulted in about a 3-fold increase in TGD as did use of a combination of diflunisal or sulindac plus phenidone. These results indicate that inhibitors of arachidonic acid metabolism can increase the cell killing and the tumor growth delay produced by CDDP plus local hyperthermia.  相似文献   
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EMT-6/Parent and EMT-6/CDDP and EMT-6/CTX in vivo alkylating agent resistant cells were grown as spheroids or as monolayers and their response to cis-diamminedichloroplatinum(II) or 4-hydroperoxycyclophosphamide exposure for 1 h alone or in combination with TNP-470 or SR-4233 was determined. When grown as spheroids, each of the three cell lines were less responsive to cis-diamminedichloroplatinum(II) and 4-hydroperoxycyclophosphamide exposure than when the cells were grown and drug-treated in monolayer. The hypoxic cell selective cytotoxic agent SR-4233 was additive in cytotoxicity with the antitumor alkylating agents in both the monolayer and spheroid cultures as determined by isobologram analysis. The antiangiogenic agent TNP-470 was synergistic in cytotoxicity in combination with cis-diammedichloroplatinum in each of the three cell lines when the cells were grown in monolayer and was additive in cytotoxicity with cis-diamminedichloroplatinum(II) when the cells were grown as spheroids. The combination of TNP-470 and 4-hydroperoxycyclophosphamide resulted in additive cytotoxicity toward both monolayer cultures and spheroids. Thus, co-exposure with TNP-470 or SR-4233 increased the cytotoxicity of the antitumor alkylating agents in both the parental and drug resistant cells grown as monolayers or spheroids.  相似文献   
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DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of antitumor drugs. Laboratory studies have indicated that cells sensitive to these drugs contain elevated levels of topo I. In this study, we immunostained 49 cases of transitional cell carcinoma from the urinary bladder with a monoclonal antibody directed against human topo I. We found elevated expression of the enzyme in 77% (38 of 49). This included three of six grade I tumors (50%), 9 of 15 grade II tumors (60%), 14 of 15 grade III tumors (93%) and 12 of 13 grade IV tumors (92%). Because the number of cycling cells in a tumor also may be an important determinant of topo I drug response, a proliferation index (topo II-alpha) also was performed for each case. The average topo II-alpha index of grade I tumors was 7.5 x 3.8; for grade II tumors, 20.1+/-10.5; for grade III tumors, 40.3 x 8.2; and for grade IV tumors, 50.5+/-13.0. Because a functional p53 tumor suppressor gene may be necessary for anticancer drug response, we also evaluated our cases for alteration in p53 function. Mutations in the p53 tumor suppressor gene, estimated by immunohistochemical staining, were common, occurring in 23 of 49 cases (47%). The number of cases with elevated topo I, a large growth fraction, and a functional p53 tumor suppressor gene was 4 of 49 (8%). Our results suggest that a small population of patients with transitional cell carcinoma of the urinary bladder may have tumors with molecular features suggesting responsiveness to the new anticancer drugs targeting topo I.  相似文献   
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This pilot study's aim was to determine, using magnetic resonance imaging (MRI), if and to what extent asymptomatic intracranial hemorrhage occurs in normal term neonates after uncomplicated vaginal deliveries. Eight normal, term, vaginally delivered infants and three cesarean-section deliveries used as controls underwent cranial MRI. No sedation was administered. Small subdural hematomas of the falx cerebri or tentorium cerebelli were found in half of those with an uneventful vaginal delivery. Pediatric follow-up, on average 3.9 years after the MRI study was performed, demonstrated normal growth and development. It appears that more data is needed to confirm the observation that the intracranial hemorrhages described should not be considered the etiology for neurologic abnormalities present in symptomatic neonates.  相似文献   
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