Capturing Community Context of Human Response to Forest Disturbance by Insects: A Multi-Method Assessment

The socioeconomic and environmental features of local places (community context) influence the relationship between humans and their physical environment. In times of environmental disturbance, this community context is expected to influence human perceptual and behavioral responses. Residents from nine Colorado communities experiencing a large outbreak of mountain pine beetles (Dendroctonus ponderosae) were surveyed in 2007. Multiple analytic methods including ordinary least squares regression and multilevel modeling techniques were used to evaluate a community-context conceptual model of factors influencing individual actions in response to forest disturbance by beetles. Results indicated that community biophysical and socioeconomic characteristics had important impacts on participation in beetle-related actions and influenced the relationships of individual-level variables in the conceptual model with beetle-related activities. Our findings have implications for natural resource management and policy related to forest disturbances, and for developing a methodology appropriate to measure the general community context of human-environment interactions

Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes

The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease) and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide) treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein)/PS1 (presenilin 1) Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein) and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B

A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30–1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52–0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Background risk of breast cancer and the association between physical activity and mammographic density

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Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration-UV-vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K (1)' = 5.3-5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event

Robotic-assisted transoral removal of a bilateral floor of mouth ranulas

<p>Abstract</p> <p>Objective</p> <p>To describe the management of bilateral oral ranulas with the use of the da Vinci Si Surgical System and discuss advantages and disadvantages over traditional transoral resection.</p> <p>Study Design</p> <p>Case Report and Review of Literature.</p> <p>Results</p> <p>A 47 year old woman presented to our service with an obvious right floor of mouth swelling. Clinical evaluation and computerized tomography scan confirmed a large floor of mouth ranula on the right and an incidental asymptomatic early ranula of the left sublingual gland. After obtaining an informed consent, the patient underwent a right transoral robotic-assisted transoral excision of the ranula and sublingual gland with identification and dissection of the submandibular duct and lingual nerve. The patient had an excellent outcome with no evidence of lingual nerve paresis and a return to oral intake on the first postoperative day. Subsequently, the patient underwent an elective transoral robotic-assisted excision of the incidental ranula on the left sublingual gland.</p> <p>Conclusion</p> <p>We describe the first robotic-assisted excision of bilateral oral ranulas in current literature. The use of the da Vinci system provides excellent visualization, magnification, and dexterity for transoral surgical management of ranulas with preservation of the lingual nerve and Wharton's duct with good functional outcomes. However, the use of the robotic system for anterior floor of mouth surgery in terms of improved surgical outcomes as compared to traditional transoral surgery, long-term recurrence rates, and cost effectiveness needs further validation.</p

Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells

Contains fulltext : 170288.pdf (publisher's version ) (Open Access)CD4+FOXP3+ Treg are essential for immune tolerance. Phase-1 clinical trials of Treg-therapy to treat graft-versus-host-disease reported safety and potential therapeutic efficacy. Treg-based trials have started in organ-transplant patients. However, efficient ex vivo expansion of a stable Treg population remains a challenge and exploring novel ways for Treg expansion is a pre-requisite for successful immunotherapy. Based on the recent finding that CD28-signaling is crucial for survival and proliferation of mouse Treg, we studied single-CD28 stimulation of human Treg, without T cell receptor stimulation. Single-CD28 stimulation of human Treg in the presence of recombinant human IL-2(rhIL-2), as compared to CD3/CD28/rhIL-2 stimulation, led to higher expression levels of FOXP3. Although the single-CD28 expanded Treg population was equally suppressive to CD3/CD28 expanded Treg, pro-inflammatory cytokine (IL-17A/IFNgamma) production was strongly inhibited, indicating that single-CD28 stimulation promotes Treg stability. As single-CD28 stimulation led to limited expansion rates, we examined a CD28-superagonist antibody and demonstrate a significant increased Treg expansion that was more efficient than standard anti-CD3/CD28-bead stimulation. CD28-superagonist stimulation drove both naive and memory Treg proliferation. CD28-superagonist induction of stable Treg appeared both PI3K and mTOR dependent. Regarding efficient and stable expansion of Treg for adoptive Treg-based immunotherapy, application of CD28-superagonist stimulation is of interest

Cost-effectiveness of Sertraline in primary care according to initial severity and duration of depressive symptoms: findings from the PANDA RCT

BACKGROUND: Antidepressants are commonly prescribed for depression, but it is unclear whether treatment efficacy depends on severity and duration of symptoms and how prescribing might be targeted cost-effectively. OBJECTIVES: We investigated the cost-effectiveness of the antidepressant sertraline compared with placebo in subgroups defined by severity and duration of depressive symptoms. METHODS: We undertook a cost-effectiveness analysis from the perspective of the NHS and Personal and Social Services (PSS) in the UK alongside the PANDA (What are the indications for Prescribing ANtiDepressants that will leAd to a clinical benefit?) randomised controlled trial (RCT), which compared sertraline with placebo over a 12-week period. Quality of life data were collected at baseline and at 2, 6, and 12 weeks post-randomisation using EQ-5D-5L, from which we calculated quality-adjusted life years (QALYs). Costs (in 2017/18£) were collected using patient records and from resource use questionnaires administered at each follow-up interval. Differences in mean costs and mean QALYs and net monetary benefits were estimated. Our primary analysis used net monetary benefit regressions to identify any interaction between the cost-effectiveness of sertraline and subgroups defined by baseline symptom severity (0-11; 12-19; 20+ on the Clinical Interview Schedule-Revised) and, separately, duration of symptoms (greater or less than 2 years duration). A secondary analysis estimated the cost-effectiveness of sertraline versus placebo, irrespective of duration or severity. RESULTS: There was no evidence of an association between the baseline severity of depressive symptoms and the cost-effectiveness of sertraline. Compared to patients with low symptom severity, the expected net benefits in patients with moderate symptoms were £24 (95% CI - £280 to £328; p value 0.876) and the expected net benefits in patients with high symptom severity were £37 (95% CI - £221 to £296; p value 0.776). Patients who had a longer history of depressive symptoms at baseline had lower expected net benefits from sertraline than those with a shorter history; however, the difference was uncertain (- £27 [95% CI - £258 to £204]; p value 0.817). In the secondary analysis, patients treated with sertraline had higher expected net benefits (£122 [95% CI £18 to £226]; p value 0.101) than those in the placebo group. Sertraline had a high probability (> 95%) of being cost-effective if the health system was willing to pay at least £20,000 per QALY gained. CONCLUSIONS: We found insufficient evidence of a prespecified threshold based on severity or symptom duration that GPs could use to target prescribing to a subgroup of patients where sertraline is most cost-effective. Sertraline is probably a cost-effective treatment for depressive symptoms in UK primary care. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN84544741

Changes in the status of p53 affect drug sensitivity to thymidylate synthase (TS) inhibitors by altering TS levels

Colorectal cancer (CRC) resistance to fluoropyrimidines and other inhibitors of thymidylate synthase (TS) is a serious clinical problem often associated with increased intracellular levels of TS. Since the tumour suppressor gene p53, which is mutated in 50% of CRC, regulates the expression of several genes, it may modulate TS activity, and changes in the status of p53 might be responsible for chemoresistance. Therefore, this study was aimed to investigate TS levels and sensitivity to TS inhibitors in wild-type (wt) and mutant (mt) p53 CRC cells, Lovo and WiDr, respectively, transfected with mt and wt p53. Lovo 175X2 cells (transfected with mt p53) were more resistant to 5-fluorouracil (5-FU; 2-fold), nolatrexed (3-fold), raltitrexed (3-fold) and pemetrexed (10-fold) in comparison with the wt p53 parental cells Lovo 92. Resistance was associated with an increase in TS protein expression and catalytic activity, which might be caused by the loss of the inhibitory effect on the activity of TS promoter or by the lack of TS mRNA degradation, as suggested by the reversal of TS expression to the levels of Lovo 92 cells by adding actinomycin. In contrast, Lovo li cells, characterized by functionally inactive p53, were 3-13-fold more sensitive to nolatrexed, raltitrexed and pemetrexed, and had a lower TS mRNA, protein expression and catalytic activity than Lovo 92. However, MDM-2 expression was significantly higher in Lovo li, while no significant differences were observed in Lovo 175X2 cells with respect to Lovo 92. Finally, mt p53 WiDr transfected with wt p53 were not significantly different from mt p53 WiDr cells with respect to sensitivity to TS inhibitors or TS levels. Altogether, these results indicate that changes in the status of p53, can differently alter sensitivity to TS inhibitors by affecting TS levels, depending on activity or cell line, and might explain the lack of clear correlation between mutations in p53 and clinical outcome after chemotherapy with TS inhibitors