More On Cervical Cancer

Deregulated Wnt signaling is lined to various forms of cancer, mot prominently colorectal cancer. In this paper, we see a potential link to cervical cancer.  Chibby, an inhibitor of Wnt signaling, is downregulated in advanced cervical cancer, thus associating Wnt signaling to the disease and opening up potential new therapeutics for this form of cancer.  Abstract:

Chibby has been identified as a putative tumor suppressor and antagonist to β-catenin, thereby controlling the Wnt signaling pathway. Chibby is typically downregulated in numerous types of cancer and may be associated with tumorigenesis. The present study aimed at clarifying the following: i) Whether Chibby antagonizes β-catenin in cervical cancer; ii) whether Chibby and β-catenin mRNA expression is associated with cancer progression; and iii) whether Chibby and β-catenin expression may be used as a biomarker. A total of 87 paraffin-embedded cervical sections with distinct cervical intraepithelial neoplasia (CIN) stages (chronic cervicitis, CIN 1, CIN 2, CIN 3 and invasive squamous cell carcinoma) were collected between June 2004 and October 2012 The mRNA expression level of Chibby and β-catenin was determined using the polymerase chain reaction. Protein expression and cellular localization of Chibby and β-catenin were determined using immunohistochemistry. Chibby and β-catenin were analyzed for possible association with the progression of cervical cancer. Chibby mRNA expression and the Chibby/β-catenin ratio were identified to be downregulated in invasive tumors. Positive cytoplasmic and nuclear staining for Chibby was associated with CIN staging and decreased as the CIN stage increased. In addition, the cytoplasmic and membrane intensity of β-catenin was associated with invasive tumors, in which a significantly increased level of protein expression was detected. Chibby may be a tumor suppressor in cervical cancer, since the dysregulation of Chibby expression is associated with tumorigenesis in cervical cancer. Chibby and β-catenin expression together may potentially to a biomarker for disease progression in cervical cancer.

The urgency of time

Every morning, we wake up, prep and go into metal contraptions on wheels to get to places that we usually dislike. These “places”, however, pay for our food and roof. So that we can eat, sleep, recover overnight and cycle back to the “places”.

At one point or another, even if we like our jobs, all of us start to ask, “Is this it? Is this my life?”

Even the Mustards, who work for themselves, ask these questions; watch How To Focus On The Good Things In Life! (episode 91):

 
Maybe a few are lucky to find their perfect place of bliss. Mr. Free at 33 moved to Thailand and seems to have found his happy place, where he does not seek answers to nagging questions on the meaning of life.  Or maybe not?


The AstreamLife couple also seems to be content with whatever happens next:

Recently, I decided that it is a waste of time to ask such questions. Don’t we have to live in the moment and pay attention to every second of our life? 

Also, it is best to use the time to create something, rather the consume anything. So, here are a few ground rules for me before New Year.  



What not to do 

1. Do not watch any movies

My goal in the next months is to structure my “free” time in a better way. During “down” time, my first reaction is to become a mindless consumer...

Do not worry, not a material consumer!  I consume free entertainment. Usually, I go on YouTube and watch the most predictable Hallmark movies. It is comfortable to know what will happen, but it is a waste of time. In fact, it might be a waste to watch any movie. I recently took a few DVDs from the library and discovered that my habit of watching YouTube videos at minimum of 1.25x speed has made me intolerant to protracted movie plots. Within the first 10-15 minutes of watching any movie, I find myself reading the movie plot on Wikipedia and stopping the DVD. Decision: stop watching movies.



2. Do not explore how to save more

I have been wasting lots of time listening to podcasts and reading blogs on how to save money, live a frugal life and be a minimalist. I found this to be a waste of time, since I am a natural minimalist and frugal person. Current circumstances do not allow me to downscale further my lifestyle. Therefore, my second decision is to not waste time on anyone’s podcast or blog finding out how to become more frugal.



What to do

1. Assume that your life is better than any of the movie plots and play according to your own script. 

As part of my script, I am very interested in “translating” traditional unhealthy recipes into healthy recipes that would make my family happy at the table. My inspiration comes from Pinterest, newsletters, and even mystery novels! Recently, I read Raspberry Danish Murder by Joanne Fluke:

 The book is full of recipes laden with butter and sugar. I loved the recipe for Raspberry Danish and will try a healthy version with substitutes for some ingredients. I will update the readers whether the result is edible.





 
2. I need to find out how to earn more money beyond my salary. My current salary would not grow, unless there is a miracle. Therefore, I need to look for side hustles. Recently I found this video on side hustles and found it informative: 

I have not tried any of these side hustles mainly because I have no time right now. (A sorrowful excuse, I know.)

Well, this is not my complete list of resolutions. I am still compiling it. It is in progress, as we all need to evolve.  

Evolution is great, but we need to remember that out time on Earth is limited.

The Circadian Clock And Cancer Therapy

The circadian clock, that controls many cellular activities in a ‘timed” fashion, affects cancer and tumor development; hence targeting the clock can be a novel cancer therapeutic approach.  Some nuclear hormone receptors are important components of the circadian clock; agonists (activators) of these receptors have specific anti-cancer activity, which is an important and encouraging finding and can lead to innovative therapies.  Abstract:

The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response. Perturbations of these processes are hallmarks of cancer and chronic circadian rhythm disruption predisposes individuals to tumour development. This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock. Here we show that two agonists of REV-ERBs-SR9009 and SR9011-are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms.

Targeting KRAS Mutations

Targeting KRAS mutant cancers; mutations of KRAS are frequent in many forms of cancer therefore this is an excellent therapeutic strategy.  Abstract:

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Mushrooms Against Cancer

Factors from edible and medicinal mushrooms seem to have anti-cancer properties.  These sort of food-based therapies need to be studied better.  Abstract:

Cancer is the leading cause of morbidity and mortality around the globe. For certain types of cancer, chemotherapy drugs have been extensively used for treatment. However, severe side effects and the development of resistance are the drawbacks of these agents. Therefore, development of new agents with no or minimal side effects is of utmost importance. In this regard, natural compounds are well recognized as drugs in several human ailments, including cancer. One class of fungi, "mushrooms," contains numerous compounds that exhibit interesting biological activities, including antitumor activity. Many researchers, including our own group, are focusing on the anticancer potential of different mushrooms and the underlying molecular mechanism behind their action. The aim of this review is to discuss PI3K/AKT, Wnt-CTNNB1, and NF-κB signaling pathways, the occurrence of genetic alterations in them, the association of these aberrations with different human cancers and how different nodes of these pathways are targeted by various substances of mushroom origin. We have given evidence to propose the therapeutic attributes and possible mode of molecular actions of various mushroom-originated compounds. However, anticancer effects were typically demonstrated in in vitro and in vivo models and very limited number of studies have been conducted in the human population. It is our belief that this review will help the research community in designing concrete preclinical and clinical studies to test the anticancer potential of mushroom-originated compounds on different cancers harboring particular genetic alteration(s).

Rimonabant And Colorectal Cancer

Targeted killing of neoplastic colon cells; abstract:

Colorectal cancer (CRC), like other tumor types, is a highly heterogeneous disease. Within the tumor bulk, intra-tumoral heterogeneity is also ascribable to Cancer Stem Cells (CSCs) subpopulation, characterized by high chemoresistance and the unique ability to retain tumorigenic potential, thus associated to tumor recurrence. High dynamic plasticity of CSCs, makes the development of winning therapeutic strategies even more complex to completely eradicate tumor fuel. Rimonabant, originally synthesized as antagonist/inverse agonist of Cannabinoid Receptor 1, is able to inactivate Wnt signaling, both in vitro and in vivo, in CRC models, through inhibition of p300-histone acetyltransferase activity. Since Wnt/β-Catenin pathway is the main player underlying CSCs dynamic, this finding candidates Rimonabant as potential modulator of cancer stemness, in CRC. In this work, using established 3D cultures of primary colon CSCs, taking into account the tumor heterogeneity through monitoring of Wnt activity, we demonstrated that Rimonabant was able to reduces both tumor differentiated cells and colon CSCs proliferation and to control their survival in long term cultures. Interestingly, in ex vivo model of wild type human organoids, retaining both architecture and heterogeneity of original tissue, Rimonabant showed no toxicity against cells from healthy colon epithelium, suggesting its potential selectivity toward cancer cells. Overall, results from this work provided new insights on anti-tumor efficacy of Rimonabant, strongly suggesting that it could be a novel lead compound for CRC treatment.

Wild Mice And Microbiota

Wild mice have different gut microbiota than lab mice and giving the lab mice the natural microbiota of the wild mice enhanced the health of the lab mice. There is much significance here, including the importance of the microbiota for health and fitness.  Abstract:

Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals.

Infection And Neurodegeneration

Infections can trigger age-related neurodegenerative diseases; experiments with worms demonstrate that a neuropeptide may mediate these effects, linking infection with nervous system diseases (a link that has already been established via the problem of autoimmunity triggered by infections with microbes that have antigens that mimic the host’s nervous system).  Abstract: 

Infections have been identified as possible risk factors for aging-related neurodegenerative diseases, but it remains unclear whether infection-related immune molecules have a causative role in neurodegeneration during aging. Here, we reveal an unexpected role of an epidermally expressed antimicrobial peptide, NLP-29 (neuropeptide-like protein 29), in triggering aging-associated dendrite degeneration in C. elegans. The age-dependent increase of nlp-29 expression is regulated by the epidermal tir-1/SARM-pmk-1/p38 MAPK innate immunity pathway. We further identify an orphan G protein-coupled receptor NPR-12 (neuropeptide receptor 12) acting in neurons as a receptor for NLP-29 and demonstrate that the autophagic machinery is involved cell autonomously downstream of NPR-12 to transduce degeneration signals. Finally, we show that fungal infections cause dendrite degeneration using a similar mechanism as in aging, through NLP-29, NPR-12, and autophagy. Our findings reveal an important causative role of antimicrobial peptides, their neuronal receptors, and the autophagy pathway in aging- and infection-associated dendrite degeneration.

Sudden Cardiac Arrest In Sports

Sudden cardiac arrest when playing sports is rare.  However, keep in mind that particular individuals may be at higher risk, which is why you should consult with a physician before starting any sort of exercise program or sport; a possibility exists of a heart defect or other abnormality.  Abstract:

BACKGROUND:

The incidence of sudden cardiac arrest during participation in sports activities remains unknown. Preparticipation screening programs aimed at preventing sudden cardiac arrest during sports activities are thought to be able to identify at-risk athletes; however, the efficacy of these programs remains controversial. We sought to identify all sudden cardiac arrests that occurred during participation in sports activities within a specific region of Canada and to determine their causes.

METHODS:

In this retrospective study, we used the Rescu Epistry cardiac arrest database (which contains records of every cardiac arrest attended by paramedics in the network region) to identify all out-of-hospital cardiac arrests that occurred from 2009 through 2014 in persons 12 to 45 years of age during participation in a sport. Cases were adjudicated as sudden cardiac arrest (i.e., having a cardiac cause) or as an event resulting from a noncardiac cause, on the basis of records from multiple sources, including ambulance call reports, autopsy reports, in-hospital data, and records of direct interviews with patients or family members.

RESULTS:

Over the course of 18.5 million person-years of observation, 74 sudden cardiac arrests occurred during participation in a sport; of these, 16 occurred during competitive sports and 58 occurred during noncompetitive sports. The incidence of sudden cardiac arrest during competitive sports was 0.76 cases per 100,000 athlete-years, with 43.8% of the athletes surviving until they were discharged from the hospital. Among the competitive athletes, two deaths were attributed to hypertrophic cardiomyopathy and none to arrhythmogenic right ventricular cardiomyopathy. Three cases of sudden cardiac arrest that occurred during participation in competitive sports were determined to have been potentially identifiable if the athletes had undergone preparticipation screening.

CONCLUSIONS:

In our study involving persons who had out-of-hospital cardiac arrest, the incidence of sudden cardiac arrest during participation in competitive sports was 0.76 cases per 100,000 athlete-years. The occurrence of sudden cardiac arrest due to structural heart disease was uncommon during participation in competitive sports. (Funded by the National Heart, Lung, and Blood Institute and others.).

Holiday inspirations

Do you relax by looking at Nature, beautiful gardens and interior design? Then probably you will have great time on this blog site.

Even without translation to English, I had a magical time going through the photography. A sense of quiet slowly seeped from every image.  We all need a little of relaxation during the holidays.

If you need a super-treat for the Holidays, try this raw vegan fudge from Jenny Mustard. The video itself is a feast for the senses.

And if you have more energy, start prepping for Thanksgiving. Below is a great recipe for cornbread. I might have taken it years ago from a magazine, but made a few healthy substitutions that worked out well.

Cornbread
 
Ingredients:
4 oz apple sauce
1 ¼ flour (1:1 white and whole wheat)
2 ¼ cornmeal
2 tsp salt and some black pepper
1 ½ baking powder
¾ tsp baking soda
3 large eggs
2 ¼ cups water
1 cup corn kernels (I use canned)
2 jalapeno peppers, no seeds, minced
1 small red bell pepper, diced
1 cup cheddar cheese, grated

Instructions:
Preheat the oven to 375°F. Oil two muffin pans (the recipe makes 24 muffins). Mix together the eggs, water and apple sauce. In a large bowl, combine the cornmeal, flour, salt, pepper, baking soda and baking powder. Make a well in the middle and the pour egg mixture. Stir in the corn, peppers and cheese. Bake 20-30 minutes. Enjoy!  I am freezing a few muffins for the days after Thanksgiving.