Cholesterol Secosterol Aldehydes Induce Amyloidogenesis and Dysfunction of Wild-Type Tumor Protein p53

SummaryEpidemiologic and clinical evidence points to an increased risk for cancer when coupled with chronic inflammation. However, the molecular mechanisms that underpin this interrelationship remain largely unresolved. Herein we show that the inflammation-derived cholesterol 5,6-secosterol aldehydes, atheronal-A (KA) and -B (ALD), but not the polyunsaturated fatty acid (PUFA)-derived aldehydes 4-hydroxynonenal (HNE) and 4-hydroxyhexenal (HHE), induce misfolding of wild-type p53 into an amyloidogenic form that binds thioflavin T and Congo red dyes but cannot bind to a consensus DNA sequence. Treatment of lung carcinoma cells with KA and ALD leads to a loss of function of extracted p53, as determined by the analysis of extracted nuclear protein and in activation of p21. Our results uncover a plausible chemical link between inflammation and cancer and expand the already pivotal role of p53 dysfunction and cancer risk

Engineering crops for tolerance against abiotic stress through gene manipulation

Plant genetic engineering took birth in the mid-eighties when, for the first time, plants were successfully engineered for improved virus, herbicide and insect resistance. This sphere has been ever-increasing since then. Abiotic stresses (such as high salt levels, low water availability leading to drought, excess water leading to flooding, high and low temperature regimes, etc.) adversely affect crop plants. The genetic responses of plants to these stresses are complex involving simultaneous expression of a number of genes. Till the early-nineties it was inconceivable that there would be any success in attaining the goal of improving resistance of crop plants to abiotic stresses. Continuing efforts of the stress biologists have resulted in engineering of plants resistant to low temperature, high temperature and excess salinity. A satisfactory progress has also been achieved in the area of generating plants resistant to water stress and flooding. While what has been achieved is impressive, it is still a challenging task to pyramid useful genes for high-level resistance to such stresses. The limiting factor in extension of biotechnology to abiotic stresses is the lack of information on what are the 'useful genes'-genes which would lead to better stress tolerance. We have reviewed how these genes are being searched to enable further development of strategies for stress management in crop plants. This is important because the strategics for coping with the abiotic stresses (and also for several other applications in plant biotechnology) have also come through the research work of scientists working on as diverse organisms as bacteria and fish

Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts

PURPOSE: Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR). METHODS: Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of 1,168 patients from 12 academic centers. RESULTS: Among 3,614 patients with documented 1L treatment, BR was the most used. Among 1,265 patients age \u3c 65 years, 30.5% received cytarabine-based induction and 23.5% received ASCT. There was no significant association between ASCT and real-world time to next treatment (hazard ratio [HR], 0.84; 95% CI, 0.68 to 1.03; CONCLUSION: In this large cohort of patients treated primarily in the US community setting, only one in four young patients received cytarabine or ASCT consolidation, suggesting the need to develop treatments that can be delivered effectively in routine clinical practice. Together with the validation cohort, data support future clinical trials exploring regimens without ASCT consolidation in young patients, whereas MR should be considered for patients after 1L BR and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone

Lipidomics Reveals Multiple Pathway Effects of a Multi-Components Preparation on Lipid Biochemistry in ApoE*3Leiden.CETP Mice

Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. Methodology/Principal Findings: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p <0.001), CETP levels (-31%,

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The Clinically Relevant Half Life in Pharmacokinetics &amp; Pharmacodynamics

For the rare drug that exhibits a single half life in its elimination and is dosed via intravenous bolus, predictability in plasma concentration fluctuation and accumulation based on half life led to the association between dosing interval and half life. The overwhelming majority of drugs, however, follow multi-exponential kinetics and are dosed orally, leading to multiple half lives that describe the behavior of the drug. Current initial dosing recommendations are often guided by the terminal pharmacokinetic half life (t1/2,β) under the assumption that this slowest phase in disposition will predict drug behavior in the body. By blending modeling &amp; simulation techniques with a clinical pharmacology understanding, we here aim to develop a unique perspective on the clinically relevant half life in pharmacokinetics and pharmacodynamics, including the relevance of t1/2,β during multiple dosing. We examine cases in which the functioning of drug transporters is altered by a drug-drug interaction or genetic polymorphism and show the resulting change in distribution volume can lead to a change in drug effect or toxicity, as well as a change in half life independent of a change in clearance. We also further define and advance applications of the operational multiple dosing half lives (t1/2,op). Using Monte Carlo simulation, our results predict a way to maximize t1/2,op relative to t1/2,β by using an absorption rate constant close to the terminal elimination rate constant in formulation design. In this way, drugs that may otherwise be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times t1/2,β, maximizing compliance, while maintaining tight plasma accumulation and fluctuation. We present a tacrolimus population pharmacokinetic analysis of Native American patients, further exemplifying the utility of t1/2,op. Finally, as there is currently no unifying relationship between drugs' pharmacokinetics and pharmacodynamic measures of clinical benefit and toxicity, we present pharmacodynamic considerations based on a continuum between direct and indirect pharmacokinetic-pharmacodynamic models. Prior to intensive modeling efforts during drug development, this framework may be used to inform clinical trial and formulation design using data from relatively few patients early in clinical trials

Taming abiotic stresses in plants through genetic engineering: current strategies and perspective

During the last decade, major advances have been made in plant genetic engineering. The methods for stable genetic transformation as well as for regulation of introduced trans-genes have been optimised to a great deal. The major limiting factor in the widespread application of genetic engineering is the availability of the target genes. This is particularly true for engineering tolerance against abiotic stresses (such as those caused by high levels of salts in soils, reduced/excess availability of water and sub- and supra-optimal temperature regimes). In spite of this, the past 5 years (1993-1998) have witnessed significant achievements in terms of generating transgenics for enhanced tolerance to these stresses. For future work on producing plants with still higher level of tolerance, there is a need to expand the information on the stress-induced genes so that appropriate genes can be pyramided. The current upsurge in genomic research has the potential to catalyse efforts in elucidating new stress-responsive genes. There are also possibilities of engineering the whole cascade of multiple genetic changes through manipulation of the regulatory genes

Bipolar affective disorder and its impact on various aspects of marital relationship

Bipolar disorder (BD) is a severe mental disorder, which not only has negative consequences on the life of the patient, but also affects the immediate family members. As it often starts early in life, patients who get married often suffer from many negative consequences in their marital life due to the illness. This review focuses on studies which have evaluated marital rates, rate of marital failure, divorce, infertility, and procreation among patients with BD. In addition, this review evaluates the existing literature pertaining to marital adjustment, marital satisfaction, sexual dysfunction, and sexual satisfaction among patients with BD and their partners/spouses. Data suggest that very high proportion of patients with BD get married and marital rates are higher for patients with BD, when compared with those suffering from schizophrenia. In terms of divorce rates, studies suggest that patients with BD have higher rates of divorce. In terms of fertility rates, studies suggest that compared to those without the illness, the fertility rates among patients with BD are lower. In terms of marital adjustment, results are mixed with some studies suggesting poorer marital adjustment among patients and their spouses too. In terms of sexual dysfunction, studies suggest the presence of sexual dysfunction among one-third to half of the patients receiving lithium. To conclude, this review suggests that patients with BD experience multiple negative marital and sexual consequences