Differential effects of rapalogues, dual kinase inhibitors on human ovarian carcinoma cells in vitro

Ovarian cancer is the second most common gynaecological malignancy and was diagnosed in over 7,000 women in 2011 in the UK. There are currently no reliable biomarkers available for use in a regular screening assay for ovarian cancer and due to characteristic late presentation (78% in stages III and IV) ovarian cancer has a low survival rate (35% after 10 years). The mTOR pathway is a central regulator of growth, proliferation, apoptosis and angiogenesis; providing balance between available resources such as amino acids and growth factors, and stresses such as hypoxia, to control cellular behaviour accordingly. Emerging data links mTOR with the aetiopathogenesis of ovarian cancer. We hypothesised that mTOR inhibitors could play a therapeutic role in ovarian cancer treatment. In this study we began by validating the expression of four main mTOR pathway components, mTOR, DEPTOR, rictor and raptor, at gene and protein level in in vitro models of endometrioid (MDAH2774) and clear cell (SKOV3) ovarian cancer using qPCR and ImageStream technology. Using a wound healing assay we show that inhibition of the mTOR pathway using rapamycin, rapalogues, resveratrol and NVP BEZ-235 induces a cytostatic and not cytotoxic response up to 18 h in these cell lines. We extended these findings up to 72 h with a proliferation assay and show that the effects of inhibition of the mTOR pathway are primarily mediated by the dephosphorylation of p70S6 kinase. We show that mTOR inhibition does not involve alteration of mTOR pathway components or induce caspase 9 cleavage. Preclinical studies including ovarian tissue of ovarian cancer patients, unaffected controls and patients with unrelated gynaecological conditions show that DEPTOR is reliably upregulated in ovarian cancer

Cost of care for cancer patients in England: evidence from population-based patient-level data

background: Health systems are facing the challenge of providing care to an increasing population of patients with cancer. However, evidence on costs is limited due to the lack of large longitudinal databases. methods: We matched cost of care data to population-based, patient-level data on cancer patients in England. We conducted a retrospective cohort study including all patients age 18 and over with a diagnosis of colorectal (275 985 patients), breast (359 771), prostate (286 426) and lung cancer (283 940) in England between 2001 and 2010. Incidence costs, prevalence costs, and phase of care costs were estimated separately for patients age 18–64 and greater than or equal to65. Costs of care were compared by patients staging, before and after diagnosis, and with a comparison population without cancer. results: Incidence costs in the first year of diagnosis are noticeably higher in patients age 18–64 than age greater than or equal to65 across all examined cancers. A lower stage diagnosis is associated with larger cost savings for colorectal and breast cancer in both age groups. The additional costs of care because of the main four cancers amounts to £1.5 billion in 2010, namely 3.0% of the total cost of hospital care. conclusions: Population-based, patient-level data can be used to provide new evidence on the cost of cancer in England. Early diagnosis and cancer prevention have scope for achieving large cost savings for the health system

Barriers and facilitators to informal healthcare provider engagement in the national tuberculosis elimination program of India: An exploratory study from West Bengal

India has a high burden of Tuberculosis (TB), accounting for a significant portion of global cases. While efforts are being made to engage the formal private sector in the National TB Elimination Program (NTEP) of India, there remains a significant gap in addressing the engagement of Informal Healthcare Providers (IPs), who serve as the first point of contact for healthcare in many communities. Recognizing the increasing evidence of IPs' importance in TB care, it is crucial to enhance their engagement in the NTEP. Therefore, this study explored various factors influencing the engagement of IPs in the program. A qualitative study was conducted in West Bengal, India, involving 23 IPs and 11 Formal Providers (FPs) from different levels of the formal health system. Thematic analysis of the data was conducted following a six-step approach outlined by Braun and Clarke. Three overarching themes were identified in the analysis, encompassing barriers and facilitators to IPs' engagement in the NTEP. The first theme focused on IPs' position and capacity as care providers, highlighting their role as primary care providers and the trust and acceptance extended by the community. The second theme explored policy and system-level drivers and prohibitors, revealing barriers such as role ambiguity, competing tasks, and quality of care issues. Facilitators such as growing recognition of IPs' importance in the health system, an inclusive incentive system, and willingness to collaborate were also identified. The third theme focused on the relationship between the formal and informal systems, highlighting a need to strengthen the relationship between the two. This study sheds light on factors influencing the engagement of IPs in the NTEP of India. It emphasizes the need for role clarity, knowledge enhancement, and improved relationships between formal and informal systems. By addressing these factors, policymakers and stakeholders can strengthen the engagement of IPs in the NTEP

Heat loss from non-circulating domestic hot water pipes increases water consumption and energy demand

This is the final version. Available from Elsevier via the DOI in this record. Data availability: Python code for DHW-HLP model will be made available on request. The authors do not have permission to share water consumption data.Hot water use in showers is a major contributor to residential water and energy consumption, and associated costs and carbon emissions. This study aims to quantify how heat loss from non-circulating pipes contributes to water and energy consumption in residential showers. Heat loss from pipes was modelled for detached dwellings in Melbourne, Australia, using Monte Carlo analysis to quantify variability. Sensitivity analysis was conducted to identify key factors contributing to heat loss. This is the first study to quantify the variability of the impact of heat loss from pipes into increased water (and hence energy) consumption in showers. Under Melbourne conditions, we predicted that heat loss from pipes contributes approximately 2 to 10 % in average shower hot water consumption. Longer pipes, smaller diameter, longer showers and longer intervals between showers were the primary factors driving additional hot water consumption.University of Queenslan

Bifidobacterium breve reduces apoptotic epithelial cell shedding in an exopolysaccharide and MyD88-dependent manner

Certain members of the microbiota genus Bifidobacterium are known to positively influence host well-being. Importantly, reduced bifidobacterial levels are associated with inflammatory bowel disease (IBD) patients, who also have impaired epithelial barrier function, including elevated rates of apoptotic extrusion of small intestinal epithelial cells (IECs) from villi—a process termed ‘cell shedding’. Using a mouse model of pathological cell shedding, we show that mice receiving Bifidobacterium breve UCC2003 exhibit significantly reduced rates of small IEC shedding. Bifidobacterial-induced protection appears to be mediated by a specific bifidobacterial surface exopolysaccharide and interactions with host MyD88 resulting in downregulation of intrinsic and extrinsic apoptotic responses to protect epithelial cells under highly inflammatory conditions. Our results reveal an important and previously undescribed role for B. breve, in positively modulating epithelial cell shedding outcomes via bacterial- and host-dependent factors, supporting the notion that manipulation of the microbiota affects intestinal disease outcomes

Absolutely stable proton and lowering the gauge unification scale

A unified model is constructed, based on flipped SU(5) in which the proton is absolutely stable. The model requires the existence of new leptons with masses of order the weak scale. The possibility that the unification scale could be extremely low is discussed

Branch facial nerve trauma after superficial temporal artery biopsy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Giant cell arteritis is an emergency requiring prompt diagnosis and treatment. Superficial temporal artery biopsy is the gold diagnostic standard. Complications are few and infrequent; however, facial nerve injury has been reported, leaving an untoward cosmetic outcome. This case report is to the best of our knowledge only the fourth one presented in the available literature so far regarding facial nerve injury from superficial temporal artery biopsy.</p> <p>Case presentation</p> <p>A 73-year-old Caucasian woman presented for neurological evaluation regarding eyebrow and facial asymmetry after a superficial temporal artery biopsy for presumptive giant cell arteritis-induced cephalalgia.</p> <p>Conclusion</p> <p>Damage to branches of the facial nerve may occur after superficial temporal artery biopsy, resulting in eyebrow droop. Although an uncommon and sparsely reported complication, all clinicians of various specialties involved in the care of these patients should be aware of this given the gravity of giant cell arteritis and the widespread use of temporal artery biopsy.</p

Freeze-In Production of FIMP Dark Matter

We propose an alternate, calculable mechanism of dark matter genesis, "thermal freeze-in," involving a Feebly Interacting Massive Particle (FIMP) interacting so feebly with the thermal bath that it never attains thermal equilibrium. As with the conventional "thermal freeze-out" production mechanism, the relic abundance reflects a combination of initial thermal distributions together with particle masses and couplings that can be measured in the laboratory or astrophysically. The freeze-in yield is IR dominated by low temperatures near the FIMP mass and is independent of unknown UV physics, such as the reheat temperature after inflation. Moduli and modulinos of string theory compactifications that receive mass from weak-scale supersymmetry breaking provide implementations of the freeze-in mechanism, as do models that employ Dirac neutrino masses or GUT-scale-suppressed interactions. Experimental signals of freeze-in and FIMPs can be spectacular, including the production of new metastable coloured or charged particles at the LHC as well as the alteration of big bang nucleosynthesis.Comment: 30 pages, 7 figures, PDFLaTex. References adde

The dynamics of human body weight change

An imbalance between energy intake and energy expenditure will lead to a change in body weight (mass) and body composition (fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditions resulting from prolonged energy imbalance. Here, we show that the long-term dynamics of human weight change can be captured by a mathematical model of the macronutrient flux balances and all previous models are special cases of this model. We show that the generic dynamical behavior of body composition for a clamped diet can be divided into two classes. In the first class, the body composition and mass are determined uniquely. In the second class, the body composition can exist at an infinite number of possible states. Surprisingly, perturbations of dietary energy intake or energy expenditure can give identical responses in both model classes and existing data are insufficient to distinguish between these two possibilities. However, this distinction is important for the efficacy of clinical interventions that alter body composition and mass