PGK1 : An Essential Player in Modulating Tumor Metabolism.

Phosphoglycerate kinase 1 (PGK1) is the first enzyme in glycolysis to generate a molecule of ATP in the conversion of 1,3-bisphosphoglycerate (1,3-BPG) to 3-phosphoglycerate (3-PG). In addition to the role of glycolysis, PGK-1 acts as a polymerase alpha cofactor protein, with effects on the tricarboxylic acid cycle, DNA replication and repair. Posttranslational modifications such as methylation, phosphorylation, and acetylation have been seen to activate PGK1 in cancer. High levels of intracellular PGK1 are associated with tumorigenesis and progression, and chemoradiotherapy resistance. However, high levels of extracellular PGK1 suppress angiogenesis and subsequently counteract cancer malignancy. Here we have summarized the current knowledge on the mechanisms and effects of PGK1 in various tumor types and evaluated its potential prognostic and therapeutic value in cancer. The data summarized here aims at providing molecular information and new ideas of employing natural products to combat cancer associated with PGK1.

Evaluating Lower Computational Burden Approaches for Calibration of Large Environmental Models.

Realistic environmental models used for decision making typically require a highly parameterized approach. Calibration of such models is computationally intensive because widely used parameter estimation approaches require individual forward runs for each parameter adjusted. These runs construct a parameter-to-observation sensitivity, or Jacobian, matrix used to develop candidate parameter upgrades. Parameter estimation algorithms are also commonly adversely affected by numerical noise in the calculated sensitivities within the Jacobian matrix, which can result in unnecessary parameter estimation iterations and less model-to-measurement fit. Ideally, approaches to reduce the computational burden of parameter estimation will also increase the signal-to-noise ratio related to observations influential to the parameter estimation even as the number of forward runs decrease. In this work a simultaneous increments, an iterative ensemble smoother (IES), and a randomized Jacobian approach were compared to a traditional approach that uses a full Jacobian matrix. All approaches were applied to the same model developed for decision making in the Mississippi Alluvial Plain, USA. Both the IES and randomized Jacobian approach achieved a desirable fit and similar parameter fields in many fewer forward runs than the traditional approach; in both cases the fit was obtained in fewer runs than the number of adjustable parameters. The simultaneous increments approach did not perform as well as the other methods due to inability to overcome suboptimal dropping of parameter sensitivities. This work indicates that use of highly efficient algorithms can greatly speed parameter estimation, which in turn increases calibration vetting and utility of realistic models used for decision making.

Multifaceted Roles of Long Non-coding RNAs in Head and Neck Cancer.

The majority of RNA transcripts are non-coding RNA (ncRNA) transcripts with lengths exceeding 200 nucleotides that are not translated into protein. Unlike microRNAs (miRNAs), long ncRNAs (lncRNAs) are not confined to a single mechanism of action but have a large and diverse role in biological processes as they can function as transcription regulators, decoys, scaffolds, and enhancer RNAs. Currently, many lncRNA molecules are under investigation for their role in tumorigenesis, metastasis, and prognosis in different types of cancer. This review not only summarizes the characteristics and functions of lncRNAs but also discusses the therapeutic implications and applications of lncRNAs with roles associated with head and neck cancer. Our aim is to pinpoint the potential way to perturb specific lncRNAs for future therapeutic use.

PI3K Isoform-Selective Inhibitors in Cancer.

PI3K inhibitors are a common area of research in finding a successful treatment of cancer. The PI3K pathway is important for cell growth, apoptosis, cell metabolism, cell survival, and a multitude of other functions. There are multiple isoforms of PI3K that can be broken down into three categories: class I, II, and III. Each isoform has at least one subunit that helps with the functionality of the isoform. Mutations found in the PI3K isoforms are commonly seen in many different types of cancer and the use of inhibitors is being tested to stop the cell survival of cancer cells. Individual PI3K inhibitors have shown some inhibition of the pathway; however, there is room for improvement. To better treat cancer, PI3K inhibitors are being combined with other pathway inhibitors. These combination therapies have shown better results with cancer treatments. Both the monotherapy and dual therapy treatments are still currently being studied and data collected to better understand cancer and other treatment options.

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib.

BACKGROUND: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. METHODS: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. CONCLUSIONS: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

Water Safety and Lead Regulation: Physicians' Community Health Responsibilities.

This article reviews the regulation of lead in drinking water, highlighting its epidemiological, engineering, and ethical aspects with a focus on the Flint water crisis. We first discuss water quality policy and its implementation with a focus on lead contamination of water, primarily from pipe systems between a water treatment facility and a tap. We then discuss physicians' roles and ethical responsibilities regarding safe drinking water using a human rights framework. We argue that physicians can play an important role in safeguarding drinking water in their communities by being vigilant, honoring the community's trust in them, and warning, educating, and empowering patients and broader communities so as to protect tap water safety and public health.

Drought planning and management: using high spatial resolution as part of the solution.

Water scarcity is intensified by drought, a phenomenon that impacts many sectors of society and affects virtually all climate zones. The Palmer drought indices are widely used by scientists and policy makers to understand drought and model its components. Despite the spatial heterogeneity and variability in variables required by the Palmer model, regional index values are most commonly used for real-time drought assessment. Local stakeholders charged with developing flexible and tailored water management policies have articulated the need for drought indices calculated at finer spatial resolutions than a regional scale. We use the Pacific Northwest United States (U.S.) as a study area to demonstrate the differences between drought indices calculated for U.S. climate divisions with those calculated at a 0.5° by 0.5° latitude/longitude resolution. Our results indicate that regional values of the two cumulative Palmer drought indices do not represent finer-resolution values well. For half of the study area, the pictures of drought (as determined by regional and finer-resolution values) are drastically different more than 30% of the time. Thus, quite often water managers do not have a clear understanding of the relative severity of drought in their area, which can have serious implications for drought mitigation and adaptation.

Patterns of injury in children: a population-based approach.

OBJECTIVE: We describe the frequency and patterns of injury affecting 96 359 children between 0 and 10 years old and living in Alberta, Canada. DESIGN: This population-based, longitudinal study involved children born in the 3 fiscal years of April 1, 1985 to March 31, 1988, recruited before age 1, and who remained in the study until at least age 5. We used the International Classification of Diseases, Ninth Revision, Clinical Modification chapter-17 diagnostic codes provided by physicians. Codes were grouped into 17 categories; injury episodes were calculated, and age- and gender-specific incidence rates for each category were calculated. The age, pattern, times of greatest risk, and the effect of gender on the type and incidence of injury were determined. SETTING: Health care administrative data were obtained from all fee-for-service health care venues in Alberta between April 1, 1985 and March 31, 1998 providing services to children registered with the Alberta Health Care Insurance Plan and otherwise meeting entrance criteria. RESULTS: Nearly 84% of children received care for an injury during the study period, and in any given year approximately 21% of the population studied had at least 1 injury. Repeat injury was common (73%), and boys were more likely than girls to be injured and to have repeat injury. The most common injuries were dislocations and sprains, open wounds, and superficial injuries and contusions. Burns, poisoning, intracranial injury, and foreign bodies were the next most common, and fractures were least common. Approximately 10% of injuries were multiple-category injuries. Rates varied greatly by injury category, age, and gender. Hospitalization rates varied in a similar manner and commonly accounted for approximately 10% of all services. Males were most likely to have an injury, and aboriginal children or children who had received welfare at some time were at greatest risk. CONCLUSIONS: Administrative data can be used to estimate the incidence of injury in a pediatric population. Distinct patterns of injury occur at different ages. Recurrent injury is common. Almost identical proportions of injury (46%) are treated in emergency departments and physicians' offices.