MicroRNA Markers For Oral Cancer

MicroRNAs may possibly be used as biomarkers for oral cancer.  Early diagnosis of cancer would be helpful for treatment – catch it early. Abstract:

BACKGROUND:

Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns.

OBJECTIVE:

Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer.

METHODS:

A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer.

RESULTS:

In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/β-catenin signaling, Notch signaling, and TGF-β/SMAD signaling pathway.

CONCLUSIONS:

A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility.

CLINICAL RELEVANCE:

These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.

Cognitive Decline With Aging

Experiments with mice suggest that the aging brain accumulates astrocyte cells with an inflammatory phenotype that lose their normal function and release factors toxic to neurons.  This may also contribute to mental decline in aging humans.  These findings can eventually lead to approaches to reverse these processes.  Abstract:

The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury.

Chemotherapy Conundrum

Chemotherapy is usually effective against cancer, but recurrence/resistance can occur.  Senescence – stopping of cell cycle and cell growth – is typically considered good for malignant cancer cells, stop them from dividing as a therapy.  But here we see that chemotherapy-induced senescence changes cancer cells so that if they are released from senescence and re-enter cell cycle growth, they are more dangerous than before – with more stem cell like properties and more aggressive growth.  This needs to be addressed.  Abstract:

Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells

Bacteriophages More Effective In The Presence Of Human Cells

Some good news: bacteriophage (viruses that infect and kill bacteria) can kill pathogenic bacteria better when in the presence of human cells than when just “in a test tube.”  Abstract:

Bacteriophage therapeutic development will clearly benefit from understanding the fundamental dynamics of in vivo phage-bacteria interactions. Such information can inform animal and human trials, and much can be ascertained from human cell-line work. We have developed a human cell-based system using Clostridium difficile, a pernicious hospital pathogen with limited treatment options, and the phage phiCDHS1 that effectively kills this bacterium in liquid culture. The human colon tumorigenic cell line HT-29 was used because it simulates the colon environment where C. difficile infection occurs. Studies on the dynamics of phage-bacteria interactions revealed novel facets of phage biology, showing that phage can reduce C. difficile numbers more effectively in the presence of HT-29 cells than in vitro. Both planktonic and adhered Clostridial cell numbers were successfully reduced. We hypothesise and demonstrate that this observation is due to strong phage adsorption to the HT-29 cells, which likely promotes phage-bacteria interactions. The data also showed that the phage phiCDHS1 was not toxic to HT-29 cells, and phage-mediated bacterial lysis did not cause toxin release and cytotoxic effects. The use of human cell lines to understand phage-bacterial dynamics offers valuable insights into phage biology in vivo, and can provide informative data for human trials.

Plant Compound Against Breast Cancer

A plant-derived natural compound inhibits breast cancer cell growth and metastasis by repressing Wnt signaling.  Abstract:

Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/β-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/β-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and β-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) β-catenin protein levels, but not total β-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/β-catenin signaling pathway.

A Judicious Update: Alzheimer’s Disease

By ADEAR: "Alzheimer's Disease Education and Referral Center, a service of the National Institute on Aging." - http://www.nia.nih.gov/NR/rdonlyres/A01D12CE-17E3-4D3D-BCEF-9ABC4FF91900/0/TANGLES_HIGH.JPG, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4476425

Here is a review of possible therapies for Alzheimer’s disease.  Current drugs have not been very successful; what may be needed are more direct treatments against the more direct molecular/cell causes of the disease, with effective blood-brain barrier delivery of these therapies being a major hurdle that needs to be overcome.  Abstract:

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and-2 genes. AD progresses through accumulation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.

Salmonella And Colon Cancer

Public Domain, https://commons.wikimedia.org/w/index.php?curid=450281 

Salmonella, at least in mouse models, can promote colon cancer, at least in part by affecting Wnt signaling factors.  The microbial population in your body is one of the major determinants of healyh, in one form or another.  Abstract:

Salmonella infection is a major public health concern, and colonization in humans can be chronic and increases the risk of cancers. Wnt signaling is a key pathway for intestinal renewal and development, inflammation, and tumorigenesis. In the current study, we report a novel role of Wnt1 in infection and colon cancer using cell culture models, a Salmonella-colitis colon cancer model, and human samples. In contrast to the bacteria-induced increases in Wnt2 and Wnt11, Salmonella colonization significantly reduced the level of Wnt1 in intestinal epithelial cells in vivo and in vitro. The bacterial AvrA protein is known to activate the canonical Wnt pathway. Wnt1 expression level was downregulated by AvrA-expressing Salmonella but stabilized by AvrA-deficient Salmonella in the intestine of Salmonella-colitis mice. In a chronic Salmonella-infected cancer model, the Wnt1 protein level was decreased in the AvrA+ infected group. Thus, we further assessed the functional role of Wnt1 downregulation in the inflammatory response and colorectal cancer (CRC) progression. Moreover, downregulation of Wnt1 by the Crispr-Cas9 method promoted cancer cell invasion and migration. Interestingly, we found that Wnt1 was downregulated in human CRC tissue, and Wnt1 downregulation may be correlated with cancer progression. Our study provides insights into mechanisms by which enteric bacteria regulate Wnt1 expression and potentially contribute to infection-associated colon cancer.

Exercise As An Anti-Depressant

Regular exercise can reduce depressive symptoms to an extent that can mimic chronic antidepressant treatment (of course, one likely won’t hear about this from most doctors or from the pharmaceutical companies pushing their samples onto those doctors), and there are molecular mechanisms for this, apparently involving the Wnt signaling pathway. Abstract:

Regular exercise reduces depressive-like behavior activation. In this study, we look for exact roles of exercise on molecular and neuronal mechanisms for antidepressant action by studying the hippocampal neuroplasticity and proliferation. Increased hippocampal neurogenesis with exercise has potential significance for depression. Exercise promotes brain health in the molecular levels in the hippocampus and also affects behavior in a similar way to chronic antidepressant treatment. Wingless (Wnt) and frizzled signaling system plays an important role in cell proliferation, growth, and differentiation during development. Our results demonstrate complicated, differential effects of antidepressants on Wnt signaling system, and assume a role for selected signaling molecules in the neurogenic activity of antidepressant care. Our review suggests that exercise may preserve brain function by increasing neurogenesis through activating Wnt signaling pathway in the psychiatric disorders, such as depression.

Maybe exercise rather than popping pills should be the first line treatment for many mental, as well as more directly physical, disorders?  First, ask you doctor about it - an informed doctor - and follow his or her advice.  Everyone is different.  Some people may require medication, others may only need exercise.  Get the medical consultation you require to figure out which category you may be in, if you require such help.

Drugs And The Gut Microbiota

Non-antibiotic drugs can alter the gut microbiota. Given the profound effects that microbiota can have on human health and behavior, one wonders whether any of the effects or, especially and likely, side-effects of these drugs is at least partially due to disruption of the intestinal ecology. Abstract:

A few commonly used non-antibiotic drugs have recently been associated with changes in gut microbiome composition, but the extent of this phenomenon is unknown. Here, we screened more than 1,000 marketed drugs against 40 representative gut bacterial strains, and found that 24% of the drugs with human targets, including members of all therapeutic classes, inhibited the growth of at least one strain in vitro. Particular classes, such as the chemically diverse antipsychotics, were overrepresented in this group. The effects of human-targeted drugs on gut bacteria are reflected on their antibiotic-like side effects in humans and are concordant with existing human cohort studies. Susceptibility to antibiotics and human-targeted drugs correlates across bacterial species, suggesting common resistance mechanisms, which we verified for some drugs. The potential risk of non-antibiotics promoting antibiotic resistance warrants further exploration. Our results provide a resource for future research on drug-microbiome interactions, opening new paths for side effect control and drug repurposing, and broadening our view of antibiotic resistance.

Serotonergic Psychedelics And Personality

For general interest, abstract:

Serotonergic psychedelics act as agonists at cortical 5-HT2A receptors and seem to induce personality changes. We conducted a systematic review of studies assessing the effects of these drugs on personality. Papers published from 1985-2016 were included from PubMed, LILACS, and SciELO databases. Three hundred and sixty-nine studies were identified, and 18 were included. Specific personality traits, such as Absorption and Self-Transcendence, seem to influence the effects of psychedelics, and psychedelic drug users and nonusers appear to differ in some personality traits. Psychedelics administered in controlled settings may induce personality changes, such as increased Openness and Self-Transcendence. Increases in global brain entropy induced by acute psychedelic administration predicted changes in Openness, and Self-Transcendence was negatively correlated with cortical thinning of the posterior cingulate cortex in long-term religious ayahuasca users. Acute and long-term use of psychedelics is associated with personality changes that appear to be modulated by 5-HT2A receptors. These changes seem to induce therapeutic effects that should be further explored in randomized controlled studies.

The Taste Of Fats

There does not seem to be a significant genetic component to fat taste sensitivity in humans; abstract:

BACKGROUND:

Individuals with impaired fat taste (FT) sensitivity have reduced satiety responses after consuming fatty foods, leading to increased dietary fat intake. Habitual consumption of dietary fat may modulate sensitivity to FT, with high consumption decreasing sensitivity [increasing fatty acid taste threshold (FATT)] and low consumption increasing sensitivity (decreasing FATT). However, some individuals may be less susceptible to diet-mediated changes in FATT due to variations in gene expression.

OBJECTIVE:

The objective of this study was to determine the effect of an 8-wk low-fat or high-fat diet on FATT while maintaining baseline weight (<2.0 kg variation) to assess heritability and to explore the effect of genetics on diet-mediated changes in FATT.

DESIGN:

A co-twin randomized controlled trial including 44 pairs (mean ± SD age: 43.7 ± 15.4 y; 34 monozygotic, 10 dizygotic; 33 women, 10 men, 1 gender-discordant) was conducted. Twins within a pair were randomly allocated to an 8-wk low-fat (<20% of energy from fat) or high-fat (>35% of energy from fat) diet. FATT was assessed by a 3-alternate forced choice methodology and transformed to an ordinal scale (FT rank) at baseline and at 4 and 8 wk. Linear mixed models were fit to assess diet effect on FT rank and diet effect modification due to zygosity. A variance components model was fit to calculate baseline heritability.

RESULTS:

There was a significant time × diet interaction for FT rank after the 8-wk trial (P < 0.001), with the same conclusions for the subset of participants maintaining baseline weight (low-fat; n = 32; high-fat: n = 35). There was no evidence of zygosity effect modification (interaction of time × diet × zygosity: P = 0.892). Heritability of baseline FT rank was 8%.

CONCLUSIONS:

There appears to be little to no genetic contribution on heritability of FATT or diet-mediated changes to FATT. Rather, environment, specifically dietary fat intake, is the main influencer of FT sensitivity, regardless of body weight. This trial was registered with the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au/ as ACTRN12613000466741.

Related: salt promotes passive overconsumption of dietary fat in humans.

Take home point: eating more salt and fat will likely lead to even more fat consumption.

Looping The Clock

Controlling chromatin loops and hence affecting gene expression can modulate circadian gene expression – controlling the biological clock.  Abstract:

Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors (TF) that comprise molecular clocks. Core clock TFs bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. Here we demonstrate that circadian gene expression in mouse liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive TF of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 corepressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.

Fad Diets Not Necessary

More support for the ides that “fad” diets – like low carb – are not necessary for weight control and dealing with metabolic syndrome. Take home point: “any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes.”  Abstract:

In the past, different types of diet with a generally low-carbohydrate content (< 50-< 20 g/day) have been promoted, for weight loss and diabetes, and the effectiveness of a very low dietary carbohydrate content has always been a matter of debate. A significant reduction in the amount of carbohydrates in the diet is usually accompanied by an increase in the amount of fat and to a lesser extent, also protein. Accordingly, using the term "low carb-high fat" (LCHF) diet is most appropriate. Low/very low intakes of carbohydrate food sources may impact on overall diet quality and long-term effects of such drastic diet changes remain at present unknown. This narrative review highlights recent metabolic and clinical outcomes of studies as well as practical feasibility of low LCHF diets. A few relevant observations are as follows: (1) any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes; (2) short-term LCHF studies show both favorable and less desirable effects; (3) sustained adherence to a ketogenic LCHF diet appears to be difficult. A non-ketogenic diet supplying 100-150 g carbohydrate/day, under good control, may be more practical. (4) There is lack of data supporting long-term efficacy, safety and health benefits of LCHF diets. Any recommendation should be judged in this light. (5) Lifestyle intervention in people at high risk of developing type 2 diabetes, while maintaining a relative carbohydrate-rich diet, results in long-term prevention of progression to type 2 diabetes and is generally seen as safe.

Gut Micriobiota And Therapy For Aging-Related Diseases

Here’s an interesting paper linking the gut microbiota with therapies for aging-related diseases. Abstract:

Aging-associated alterations in composition, diversity and functional features of intestinal microbiota are well-described in the modern literature. They are suggested to be caused by an age-related decline in immune system functioning (immunosenescence) and a low-grade chronic inflammation (inflammaging), which accompany many aging-associated pathologies. The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health and aging by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of fat deposition and metabolism and prevention of insulin resistance. Recently, a high effectiveness and safety of novel therapeutic application such as fecal microbiota transplantation in the prevention and treatment of age-related pathological conditions including atherosclerosis, type 2 diabetes and Parkinson's disease has been demonstrated. In this review, recent research findings are summarized on the role of gut microbiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine.

The importance of the gut microbiota for overall good health and healthy aging cannot be overestimated. Interactions between the microbiota, the immune system, and prevalent diseases and disorders are an important emerging field in biomedicine and one which we will be watching closely.

Microglia Cells In Brain Disease

By Frontiers in cellular neuroscience - http://journal.frontiersin.org/Journal/10.3389/fncel.2013.00049/full, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=31788649

Microglia cells, immune cells of the central nervous system, are increasingly being linked as involved with a number of brain/neurodegenerative diseases.  This opens up the way for possible therapies; abstract:

There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

"Big Papi" CRISPR Screening Approach

The "Big Papi" (paired aureus and pyogenes for interactions) approach to CRISPR screening will uncover new genetic-to-phenotype interactions that will be helpful for both basic science and for discovering new therapeutics for eventual clinical applications.  Abstract:

Combinatorial genetic screening using CRISPR-Cas9 is a useful approach to uncover redundant genes and to explore complex gene networks. However, current methods suffer from interference between the single-guide RNAs (sgRNAs) and from limited gene targeting activity. To increase the efficiency of combinatorial screening, we employ orthogonal Cas9 enzymes from Staphylococcus aureus and Streptococcus pyogenes. We used machine learning to establish S. aureus Cas9 sgRNA design rules and paired S. aureus Cas9 with S. pyogenes Cas9 to achieve dual targeting in a high fraction of cells. We also developed a lentiviral vector and cloning strategy to generate high-complexity pooled dual-knockout libraries to identify synthetic lethal and buffering gene pairs across multiple cell types, including MAPK pathway genes and apoptotic genes. Our orthologous approach also enabled a screen combining gene knockouts with transcriptional activation, which revealed genetic interactions with TP53. The "Big Papi" (paired aureus and pyogenes for interactions) approach described here will be widely applicable for the study of combinatorial phenotypes.

DNA Nanorobots Against Cancer

DNA nanorobots against cancer.

From article:

DNA nanorobots are a somewhat new concept for drug delivery. They work by getting programmed DNA to fold into itself like origami and then deploying it like a tiny machine, ready for action.

DNA nanorobots, Nature Biotechnology 2018

The scientists behind this study tested the delivery bots by injecting them into mice with human breast cancer tumors. Within 48 hours, the bots had successfully grabbed onto vascular cells at the tumor sites, causing blood clots in the tumor's vessels and cutting off their blood supply, leading to their death.

Remarkably, the bots did not cause clotting in other parts of the body, just the cancerous cells they'd been programmed to target, according to the paper.

The scientists were also able to demonstrate the bots did not cause clotting in the healthy tissues of Bama miniature pigs, calming fears over what might happen in larger animals.

Fido's Cancer: Cell Signaling Problems

Cancer in dogs apparently exhibits similar problems of cell signaling as in humans; dog cancer may therefore be a useful model for studying the human variety.  Abstract:

Prostate cancer is a heterogeneous disease with high levels of clinical and gene heterogeneity, consequently offering several targets for therapy. Dogs with naturally occurring prostate cancer are useful models for molecular investigations and studying new treatment efficacy. Three genes and proteins associated with the WNT pathway (β-catenin, APC and E-cadherin) and Caveolin-1 (CAV-1) were evaluated in canine pre-neoplastic proliferative inflammatory atrophy (PIA), prostate cancer and metastatic disease. The APC gene methylation status was also investigated. As in human prostate cancer, cytoplasmic and nuclear β-catenin, which are fundamental for activating the canonical WNT pathway, were found in canine prostate cancer and metastasis. Membranous E-cadherin was also lost in these lesions, allowing cellular migration to the stroma and nuclear localization of β-catenin. In contrast to human prostate tumours, no APC downregulation or hypermethylation was found in canine prostate cancer. The CAV-1 gene and protein overexpression were found in canine prostate cancer, and as in humans, the highest levels were found in Gleason scores ≥8. In conclusion, as with human prostate cancer, β-catenin and E-cadherin in the WNT pathway, as well as Caveolin-1, are molecular drivers in canine prostate cancer. These findings provide additional evidence that dogs are useful models for studying new therapeutic targets in prostate cancer.

More Dangers From Fructose

By That kiwi guy - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=32395910

Whatever we want to say about glucose consumption, it is still better than consuming fructose, as yet another animal study makes clear; abstract:

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

While glucose increased triglycerides, it at least seemed somewhat protective with respect to certain metabolic syndrome phenotypes, while fructose consumption was simply devastating.

A Bizarre Story For Friday The Thirteenth

Unauthorized vaccine for herpes:

A Southern Illinois University professor is being investigating for allegedly injecting people with an unauthorized vaccine for herpes.

The FDA is investigating William Halford for administering his experimental vaccine to patients without safety oversight from the organization or an institutional review board. Halford, who died in June, gave participants the vaccine in St. Kitts and Nevis, islands in the southern Caribbean, in 2016, and in Illinois hotel rooms in 2013, Kaiser Health News reported.

The professor, 48, gave the vaccine to at least 20 herpes patients in St. Kitts and Nevis and to at least eight herpes patients at a Holiday Inn Express and a Crown Plaza Hotel near his research lab at the university in Carbondale, Illinois.

Authorities are uncertain where Halford manufactured the vaccine.

Now, the FDA's Office of Criminal Investigations is looking into whether people at Halford's former company, Rational Vaccines, or Southern Illinois University had knowledge of his actions and violated FDA regulations by assisting him in unauthorized research, four people familiar with the situation told Kaiser Health News.

Although the FDA rarely prosecutes research violations, the agency may move forward with this case and pursue the unauthorized development of the vaccine as a crime. These violations are severe because Halford is not a medical doctor and provided an experimental vaccine without supervision, which is a possible violation of human-subject guidelines.

The university told Kaiser Health News it's cooperating with the FDA's investigation and admitted Halford violated university rules and the law. However, university officials deny any knowledge of his actions and say they are not responsible, the sources said.

Rational Vaccines did not comment. The company assisted in the Caribbean trial but was not founded at the time the hotel-room injections occurred.

Attention: Vegans

The following is I think self-explanatory.  Even if you don’t want to eat actual animals, why not at least eggs and dairy?  Even most people lactose intolerant can eat certain yogurts and cheeses low in lactose, and there is also LACTAID and other lactase supplements.  Abstract:

OBJECTIVE:

We describe a case of irreversible subacute sclerotic combined degeneration of the spinal cord in a Western vegan subject.

METHODS:

A 57-y-old man, member of a vegan cult for 13 y, developed weakness, paraplegia, hyper-reflexia, distal symmetric muscular hypotrophy, impairment of superficial sensation in the hands and feet, loss of deep sensation in the lower limbs, and neurogenic bladder and bowel. Magnetic resonance imaging of the cervical and dorsal spine disclosed abnormally increased signal intensity on T(2)-weighted sections in the posterior and lateral columns. Subacute sclerotic combined degeneration of the spinal cord was diagnosed and treatment with cobalamin was started.

RESULTS:

Despite rehabilitative treatment, the patient developed spastic hypertonia with mild improvement of paresthesias. Six months later, vitamin B12 plasma levels and hematological analysis were normal. One year later, spastic paraplegia was still present and the patient was unable to walk despite improvement on magnetic resonance imaging.

CONCLUSION:

Irreversible subacute sclerotic combined degeneration of the spinal cord is a rare but possible effect of a strict vegetarian diet.

High Fat Diet And the Aging Mouse Brain

A high fat diet seems not to be very good for aging of the mouse brain.  Fasting and a low fat diet seemingly have different effects.  Abstract:

Fasting may be exploited as a possible strategy for prevention and treatment of several diseases such as diabetes, obesity, and aging. On the other hand, high-fat diet (HFD) represents a risk factor for several diseases and increased mortality. The aim of the present study was to evaluate the impact of fasting on mouse brain aging transcriptome and how HFD regulates such pathways. We used the NCBI Gene Expression Omnibus (GEO) database, in order to identify suitable microarray datasets comparing mouse brain transcriptome under fasting or HFD vs aged mouse brain transcriptome. Three microarray datasets were selected for this study, GSE24504, GSE6285, and GSE8150, and the principal molecular mechanisms involved in this process were evaluated. This analysis showed that, regardless of fasting duration, mouse brain significantly expressed 21 and 30 upregulated and downregulated genes, respectively. The involved biological processes were related to cell cycle arrest, cell death inhibition, and regulation of cellular metabolism. Comparing mouse brain transcriptome under fasting and aged conditions, we found out that the number of genes in common increased with the duration of fasting (222 genes), peaking at 72 h. In addition, mouse brain transcriptome under HFD resembles for the 30% the one of the aged mice. Furthermore, several molecular processes were found to be shared between HFD and aging. In conclusion, we suggest that fasting and HFD play an opposite role in brain transcriptome of aged mice. Therefore, an intermittent diet could represent a possible clinical strategy to counteract aging, loss of memory, and neuroinflammation. Furthermore, low-fat diet leads to the inactivation of brain degenerative processes triggered by aging.

One can speculate about the human situation.

How Much Protein Can The Body Use In A Single Meal For Muscle-Building?

There is controversy about how much protein can be properly utilized by the body per meal for purposes of muscle building.  There is a school of thought that says that, essentially, anything over 20-25 grams per meal will be wasted; on the other hand, bodybuilding tradition advocated considerably higher per meal intakes (leading to much higher per day intakes compared to the typical recommendations).  A study examines the question and comes down on the side supporting the higher levels of protein intake; they write: “The preponderance of data indicate that while consumption of higher protein doses (> 20 g) results in greater AA oxidation, this is not the fate for all the additional ingested AAs as some are utilized for tissue-building purposes. Based on the current evidence, we conclude that to maximize anabolism one should consume protein at a target intake of 0.4 g/kg/meal across a minimum of four meals in order to reach a minimum of 1.6 g/kg/day. Using the upper daily intake of 2.2 g/kg/day reported in the literature spread out over the same four meals would necessitate a maximum of 0.55 g/kg/meal.”  Abstract:

Controversy exists about the maximum amount of protein that can be utilized for lean tissue-building purposes in a single meal for those involved in regimented resistance training. It has been proposed that muscle protein synthesis is maximized in young adults with an intake of ~ 20-25 g of a high-quality protein; anything above this amount is believed to be oxidized for energy or transaminated to form urea and other organic acids. However, these findings are specific to the provision of fast-digesting proteins without the addition of other macronutrients. Consumption of slower-acting protein sources, particularly when consumed in combination with other macronutrients, would delay absorption and thus conceivably enhance the utilization of the constituent amino acids. The purpose of this paper was twofold: 1) to objectively review the literature in an effort to determine an upper anabolic threshold for per-meal protein intake; 2) draw relevant conclusions based on the current data so as to elucidate guidelines for per-meal daily protein distribution to optimize lean tissue accretion. Both acute and long-term studies on the topic were evaluated and their findings placed into context with respect to per-meal utilization of protein and the associated implications to distribution of protein feedings across the course of a day. The preponderance of data indicate that while consumption of higher protein doses (> 20 g) results in greater AA oxidation, this is not the fate for all the additional ingested AAs as some are utilized for tissue-building purposes. Based on the current evidence, we conclude that to maximize anabolism one should consume protein at a target intake of 0.4 g/kg/meal across a minimum of four meals in order to reach a minimum of 1.6 g/kg/day. Using the upper daily intake of 2.2 g/kg/day reported in the literature spread out over the same four meals would necessitate a maximum of 0.55 g/kg/meal.

This conclusion is supported by this other study, which also advocates higher per meal protein intakes.

Please note that this advice – from these studies and not from this blog – deals with effects on muscle building and not overall health.  Whether or not additional protein intake is good for you is something that you need to determine in conjunction with your physician, nutritionist, etc.  For example, people with kidney problems or some digestive disorders probably should not be consuming this much protein, and then there is the issue of how much saturated fat is being consumed, if animal proteins are utilized.

So what is best for muscle building and what is best for overall health are not the same thing.

Rising Collge Tuition

Related to this post, we read this article about rising college tuition and what you can do about it.  Note the part about “amenities.”  Providing such fluff is not only an incentive to draw students in, it is also a justification for the rapidly proliferating administrative parasites.  After all, why does a college or university require 10,000 deans (slight exaggeration) and more “student affairs” personnel than there are grains of sand on a beach (another very slight exaggeration)?  To provide those “amenities” and “enrich the student experience.”  It’s not only the “student experience” that is getting “enriched,” that’s for sure.  And the article touches upon another issue: education inflation; today, a college degree is required for jobs that in the past required only a high school diploma.  Eventually, one will need a PhD, MD, or JD for even the most mundane entry-level job, and then even that won’t be enough.

The cornerstone article may be useful to you, so take a look.

Aging And Dementia Links

Aging and dementia has common links, including the mitochondrial α-F1 -ATP synthase (ATP5A), which can be a target for the Alzheimer's disease drug candidate J147.  The mTOR signaling pathway is involved with this; abstract:

Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F1 -ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two.

The Education Of Playful Boys: Class Clowns In The Classroom

“Playful” boys are initially well-perceived by classmates but are labeled “class clowns” by teachers, with negative connotations.  Thus leads to a negative perception by classmates (and self) in addition to the teacher, leading to “lethal” educational outcomes.  By contrast, girl’s “playfulness” was not considered “intrusive” or “rebelliousness” and there were no negative consequences.  This is more evidence that the educational system is increasingly hostile to male students. Abstract:

This longitudinal study identified degrees of playfulness in 278 kindergarten-aged children, and followed them through their next three school years to determine how playfulness was viewed by the children themselves, their classmates, and teachers. Perceptions of the social competence, disruptiveness, and labeling as the class clown, were assessed from all perspectives in each of first through third grades. Hierarchical linear modeling was conducted to account for the nesting of the data (children within classrooms within schools) and for the lack of independence between the measures. A central finding confirmed extant literature in that gender differences were dominant, with playful boys regarded as distinct from their less playful counterparts, while no such discrepancies appeared for girls. Playful boys were increasingly negatively regarded as rebellious and intrusive and were labeled as the "class clown" by their teachers. These findings were in direct contrast with children's self-perceptions and those of their peers, who initially regarded more playful boys as appealing and engaging playmates. The data further revealed that the playful boys were stigmatized by their teachers, and this was communicated through verbal and non-verbal reprimands, and classmates assimilated this message and became increasingly denigrating of the playful quality in the boys. In stark contrast, girls' playfulness levels were not a consideration in ratings by teachers or peers at any grade, nor did their classroom behaviors show significant variation. These negative perceptions were likely transferred by teachers to peers and to the children themselves, whereupon they changed their positive perceptions to be increasingly negative by third grade. The results contribute to the literature by demonstrating that playfulness in boys (but not girls) is often associated with the "class clown" designation, and is viewed as an increasingly lethal characteristic in school classrooms, where compelling efforts are undertaken to discourage its expression and persistence