Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is one of the major cellular signaling pathways that plays an important role in basic intracellular ...functions. The PI3K/Akt/mTOR pathway regulates cell proliferation, growth, cell size, metabolism, and motility. Component genes of this pathway have been extensively studied and found to be commonly activated in human cancer. Inhibition of this pathway has been shown to lead to regression of human tumors and has been studied in preclinical setup and evaluated in many clinical trials at various levels. Some inhibitors of this pathway are approved by the Food and Drug Administration after their potency and safety have been shown in clinical trials. This review discusses the recent trends in exploiting the PI3K/Akt/mTOR pathway towards the molecular targeted therapy using small molecule inhibitors in human cancer.
This paper argues that contemporary processes of extended urbanisation, which include suburbanisation, post-suburbanisation and peri-urbanisation, may result in increased vulnerability to infectious ...disease spread. Through a review of existing literature at the nexus of urbanisation and infectious disease, we consider how this (potential) increased vulnerability to infectious diseases in peri- or suburban areas is in fact dialectically related to socio-material transformations on the metropolitan edge. In particular, we highlight three key factors influencing the spread of infectious disease that have been identified in the literature: demographic change, infrastructure and governance. These have been chosen given both the prominence of these themes and their role in shaping the spread of disease on the urban edge. Further, we suggest how a landscape political ecology framework can be useful for examining the role of socio-ecological transformations in generating increased risk of infectious disease in peri- and suburban areas. To illustrate our arguments we will draw upon examples from various re-emerging infectious disease events and outbreaks around the world to reveal how extended urbanisation in the broadest sense has amplified the conditions necessary for the spread of infectious diseases. We thus call for future research on the spatialities of health and disease to pay attention to how variegated patterns of extended urbanisation may influence possible outbreaks and the mechanisms through which such risks can be alleviated.
A consistent variational theory of the higher–order nonlocal gradient elasticity is conceived to appropriately introduce the nonlocality to the higher-order strain gradient theory. The abstract ...variational approach, based on appropriate functional spaces of test fields, is applied to establish the higher–order nonlocal gradient mechanics of elastic beams in flexure. Two nonlocal and two gradient characteristic lengths are exploited to describe the size–dependent response of continua with nano–structures. Integral convolutions of the higher–order constitutive law are restored to the equivalent differential problem endowed with non–standard boundary conditions of constitutive–type. The higher–order strain gradient theory, higher–order nonlocal elasticity and modified nonlocal strain gradient theory, extensively adopted in the community of Engineering Science, are demonstrated to be particular cases of the introduced higher-order nonlocal gradient theory. The well-posedness of the developed higher-order nonlocal gradient problem is revealed by studying the flexural response of structures with wide-ranging applications in nano-engineering. Exact analytical solution for elastostatic deflections of nano-beams is derived and new benchmark examples of nano-mechanics interest are detected. The higher-order nonlocal gradient elasticity theory can effectively characterize nanoscopic phenomena in advanced nano–composites and nano–structures.
Supplier selection is a multi-faceted strategic decision but there is no research that considers factors like sustainability and risk, simultaneously. Moreover, when selection criteria are subjective ...and require decision makers' judgment, and each candidate supplier dominates a separate selection criterion, the decision-making process becomes more complex and traditional DEA models cannot differentiate between potential candidates. In this paper, we propose a multi-method approach based on quantitative empirical investigations, and analytical modeling. We utilize interval type-2 fuzzy sets to quantify decision makers' inputs and propose an extended super-efficiency DEA model, which includes both desirable and undesirable inputs and outputs to evaluate suppliers. This approach simultaneously incorporates sustainability and suppliers' risk factors into the supplier selection problem. The model is developed for both risk-neutral and risk-averse decision-makers. The efficiency and applicability of the proposed framework is demonstrated through a real case. Results show that considering sustainability criteria or risk factors separately results in inappropriate decisions.
This study examined the protective effect of Kaempferol against streptozotocin-induced diabetic nephropathy (DN) in rats and studies the underlying mechanisms. Rats were divided into 4 groups as ...control, control + Kaempferol, STZ, and STZ + Kaempferol. All treatments were conducted for 8 weeks daily after the induction of diabetes. Kaempferol prevented STZ-induced weight and food loss and attenuated renal damage and the alterations in all biochemical related parameters. Concomitantly, Kaempferol reduced renal levels of TNF-α and IL-6, cleaved caspase-3, p38, and Bax, suppressing JNK phosphorylation and NF-κB p65 transactivation, and upregulation of Bcl-2. In both control and STZ-diabetic rats, Kaempferol reduced fasting glucose levels, increased fasting insulin levels and HOMA-β, reduced the levels of ROS and MDA, stimulated SOD and GSH levels, and increased the expression of Nrf2 and HO-1. In conclusion, Kaempferol prevents STZ-induced diabetic nephropathy, mainly, by antioxidant potential, mediated by the upregulation of the Nrf-2/HO-1 axis.
In this in-depth review, we examine the worldwide epidemiology of SLE and summarize current knowledge on the influence of race/ethnicity on clinical manifestations, disease activity, damage ...accumulation and outcome in SLE. Susceptibility to SLE has a strong genetic component, and trans-ancestral genetic studies have revealed a substantial commonality of shared genetic risk variants across different genetic ancestries that predispose to the development of SLE. The highest increased risk of developing SLE is observed in black individuals (incidence 5- to 9-fold increased, prevalence 2- to 3-fold increased), with an increased risk also observed in South Asians, East Asians and other non-white groups, compared with white individuals. Black, East Asian, South Asian and Hispanic individuals with SLE tend to develop more severe disease with a greater number of manifestations and accumulate damage from lupus more rapidly. Increased genetic risk burden in these populations, associated with increased autoantibody reactivity in non-white individuals with SLE, may explain the more severe lupus phenotype. Even after taking into account socio-economic factors, race/ethnicity remains a key determinant of poor outcome, such as end-stage renal failure and mortality, in SLE. Community measures to expedite diagnosis through increased awareness in at-risk racial/ethnic populations and ethnically personalized treatment algorithms may help in future to improve long-term outcomes in SLE.
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•RZV immunogenicity is unaffected by co-administration.•The safety profile of RZV is unaffected by co-administration.•RZV co-administration does not significantly impact concomitant ...vaccines.
The adjuvanted recombinant zoster vaccine (RZV; Shingrix®, GSK) is a subunit vaccine that has been approved for the prevention of herpes zoster in adults. Co-administration of two vaccines in a single visit is a strategy to improve overall vaccine coverage.
This review aims to consolidate available clinical data on RZV co-administration, providing an overview of safety, reactogenicity and immunogenicity.
RZV co-administration data were obtained from five randomised, open-label, phase III clinical trials with similar study designs. The co-administered vaccines included: quadrivalent seasonal inactivated influenza vaccine (IIV4; NCT01954251), 23-valent pneumococcal polysaccharide vaccine (PPSV23; NCT02045836), reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (Tdap; NCT02052596), 13-valent pneumococcal conjugate vaccine (PCV13; NCT03439657) and COVID-19 mRNA-1273 booster (NCT05047770). Eligible participants were healthy adults aged ≥50 years.
A total of 3,974 participants were vaccinated (co-administration: 1,973; sequential: 2,001) across the five trials. Vaccine response rates to RZV were similar for co-administration (range: 95.8–99.1 %) and sequential groups (range: 95.1–99.1 %). Immune responses to RZV and the other vaccines (with the exception of pertactin) were non-inferior when the vaccines were co-administered compared with sequentially administered.
Overall incidences of solicited local and general adverse events (AEs), unsolicited AEs, serious AEs or potential immune-mediated diseases were similar after co-administration or sequential administration. Myalgia was the most common solicited systemic AE (co-administration: 38–64 %; sequential: 30–59 %). Shivering and fever were more common after co-administration (16 % and 21 %, respectively) than after sequential administration (both 7 %) of RZV and PPSV23.
Co-administration of RZV with routine vaccines does not significantly alter the reactogenicity, immunogenicity or safety of RZV or the co-administered vaccine. Healthcare practitioners should consider routine co-administration of RZV with other adult vaccines to improve vaccination coverage.
Abstract
Over the past 3 decades, advances in the molecular genetics of thyroid cancer (TC) have been translated into diagnostic tests, prognostic markers, and therapeutic agents. The main drivers in ...differentiated TC pathogenesis are single-point mutations and gene fusions in components of the Mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathways. Other important genetic alterations in the more advanced types of TC include TERT promoter, TP53, EIF1AX, and epigenetic alterations. Using this knowledge, several molecular tests have been developed for cytologically indeterminate thyroid nodules. Currently, 3 commercially available tests are in use including a DNA/RNA-based test (ThyroSeq v.3), an RNA-based test (Afirma Gene Sequencing Classifier), and a hybrid DNA/miRNA test, ThyGeNEXT/ThyraMIR. These tests are mostly used to rule out malignancy in Bethesda III and IV thyroid nodules because they all have high sensitivities and negative predictive values. Their common use, predominantly in the United States, has resulted in a significant reduction in unnecessary thyroid surgeries for benign nodules. Some of these tests also provide information on the underlying molecular drivers of TC; this may support decision making in initial TC management planning, although this practice has not yet been widely adopted. More importantly, molecular testing is essential in patients with advanced disease before using specific mono-kinase inhibitors (eg, selpercatinib for RET-altered TC) because these drugs are ineffective in the absence of a specific molecular target. This mini-review discusses the utilization of molecular data in the clinical management of patients with thyroid nodules and TC in these different clinical situations.
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