Rebuilding The Gallbladder/Common Bile Duct

By from public domain source http://www.pueblo.gsa.gov/cic_text/health/gallstones/digstsys.gif, Public Domain, https://commons.wikimedia.org/w/index.php?curid=56151

Here is another advance in the field of organ/tissue regeneration; human cells were bioengineered in culture and used to repair the gallbladder bile duct in a mouse model.  These are exciting times for regenerative biomedicine. Abstract:

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids in vivo and demonstrate that ECOs self-organize into bile duct-like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded in vitro.

Why Not Adjunct Administrators?

At left, is that an academic administrator? 

By http://phil.cdc.gov/PHIL_Images/20031208/87d4bff74e41427cb278526bd9cbe76a/5260_lores.jpg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=776561

Following up on this and also on this, I ask: why not have adjunct administrators?  Well, other people have already written about this.  See this summary:

Rather than fill universities with adjunct instructors, why not replace them with adjunct administrators?

Most of the growth of university costs comes from administrative bloat. Non-faculty staff has grown at more than twice the rate of instructors – you know, the people who are the ostensible reason a university exists. As tenured professors retire, administrators kill those tenure lines and replace them permanently with part timers. Administrators do this so they can gorge on a higher salary while demanding more from the refugee ration-packet salary of academics. Think I am not being generous? Some administrators earn $300,000 a year to fundraise for new football stadium skyboxes. Vice Presidents at the University of Maryland saw their salaries increase by 50 percent between 1998 and 2003, as faculty positions were slashed. All the while adjuncts try to get by with the help of Medicaid or food stamps.

Worse of all, administrators isolate themselves from students behind security doors but meddle more and more in faculty and student lives.

Indeed.  A problem is that hiring and “cost-cutting” decisions are made by administrators themselves. Guess whose positions they have an incentive to protect?

Rent-seeking behavior, anyone?

The same principles apply as to why we have outsourcing and H-1B job replacement for workers, but not for management (or lawyers, economists, politicians, mass media, etc.). Economically, it's always easier for administration (of all types) to focus on the mote in the worker's eye than the beam in their own.

Dismantling academia, part II: the parasites

This post is a sequel of my research on how the U.S. academia is being demolished.

As we have already established, according to major school administrators around the country (including the former president of Stanford University), the major reason for the high college tuition is the overblown salaries of the faculty.

The solution? Remove faculty from the equation – or at least keep them at the bare minimum. Instead of full time faculty with benefits, the higher education institutions should employ adjunct faculty and teaching assistants without benefits.

Whereas these declarations have been made public only recently, the process of switching to adjuncts has been undergoing for decades. The adjunct faculty are now the majority of the higher education instructors in the U.S.

More than 50% of all faculty appointments are part-time.  According the Association of American Association of University Professors: 
 
“This includes positions that may be classified by the institution as adjuncts, part-time lecturers, or graduate assistantships.

Many faculty in so-called “part-time” positions actually teach the equivalent of a full-time course load.

Over one-fifth of part-time appointments are held by graduate student employees, whose chances of obtaining tenure-track positions in the future are increasingly uncertain.

To support themselves, part-time faculty often commute between institutions and prepare courses on a grueling timetable, making enormous sacrifices to maintain interaction with their students.
 
Since faculty classified as part-time are typically paid by the course, without benefits, many college teachers lack access to health insurance and retirement plans” 
 
According to online records, an adjunct professor is paid $3,500 for an entire course. So, why would anyone take on this type of work that is so exacting, requires so much effort and investment of time? 

I just watched a documentary about poverty in America, and one of the featured guys was explaining that as a head busboy he was making approximately $11,000-12,000/year. This income probably does not include tips distributed among the service staff. So, instead of teaching four huge courses in nine months, why not work as a busboy or barista in Starbucks?

It might be that in some places around the country, adjuncts are paid a bit higher for a full load of teaching. Thus, according to this website, the median pay for adjunct professors is $30,000/year; whereas the average salary for all secondary / higher education lecturers / associate / assistant professors is $65,140. Obviously, our administration can save good amount of money by switching to adjunct teachers.

Are there any consequences?

According to online research, this trend damages student learning (the adjuncts do not even have offices in the colleges), faculty governance, and academic freedom (the protection of tenure is gone, so if you are not tenured, and even worse - you are an adjunct, watch your mouth and keep your opinions to yourself).

Meanwhile, no one has tried to compare the salaries of the adjunct educators to these of the administrators. But here they are, I could not find one administrator position that is paid less than $45,000. Most salaries are six figures. 

Most of the administrator positions in the past were created to help faculty fulfill their functions as educators. Today, faculty serve the administrators.  And the administrators are self-propagating.  By the way, these are the defining characteristics of any parasite, look it up in a biology textbook:

"an organism that lives in or on another organism (its host) and benefits by deriving nutrients at the host's expense"

Molecular Pathway Linking Colon Cancer To A High Fat Diet (And Obesity)

By Attributed to Charles Mellin - WgF1LrUvFdNysA at Google Cultural Institute, zoom level maximum, Public Domain, https://commons.wikimedia.org/w/index.php?curid=13334241

A study has shown a molecular pathway linking obesity and a high fat diet to colon cancer.  Excerpts from the article (italics) with some of my own comments inserted:

Scientists in the U.S. have identified a molecular pathway that appears to play a key role in the link between a high-fat diet (HFD) and the development of colorectal cancer. The research, led by the Cleveland Clinic’s Sheerlarani Karunanithi, and Matthew Kalady, suggests that it may one day be possible to develop drugs that reduce tumor growth associated with obesity and a diet that is high in fat. 

Or people can lose weight and eat lower-fat diets.  What's wrong with that approach?

Their research is published today, in Stem Cell Reports, in a paper titled, “RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis.”

The Cleveland Clinic team’s review of published research indicated that high expression levels of two vitamin A signalling proteins—serum retinol binding protein (RPB4), stimulated by retinoic acid 6 (STRA6)—in colorectal cancer tumors is associated with poor prognosis, increased tumor metastasis and recurrence, and resistance to cancer therapy. The RBP4-STRA6 pathway triggers the JAK2-STAT3 signaling cascade…

That is useful information - perhaps the greatest utility is motivation to lose wright and change diets, as there is now more concrete evidence linking unhealthy eating habits and an unhealthy weight to colon cancer.

...Our data clearly indicate that RBP4-STRA6 pathway is necessary for the optimal expression of stem cell markers such as NANOG, SOX2, and LGR5, and thereby for maintaining the colon CSC pool,” the authors conclude in their published paper. "We have known the influence of diet on colorectal cancer,” commented Matthew Kalady, M.D., colorectal surgeon, and co-director of the Cleveland Clinic Comprehensive Colorectal Cancer Program. “However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk."

One could reasonably reduce the risk of a high-fat diet by no longer eating the high-fat diet.

“The interesting finding here is that the high fat diet-induced effects appear to also involve the stem cell program, which is interesting for tumor growth and has implications on therapies, as tumor stem cells are also therapeutically resistant...” 

It would seem therefore if high-fat diets maintain colon cancer stem cells - cells that can "fuel" the tumor and which may be more resistant to therapy - then one can ask: should colon cancer patients be given nutritional programs that take this into account?

There's nothing wrong with developing new therapies, but those therapies should be in addition to healthy eating, not a substitute for it.

More Against Red And Processed Meat

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Is enhanced mortality associated more with red meat/processed meat consumption or with saturated fatty acid (SFA) consumption?  Is it the meat or the saturated fats?  A recent study says meat:

Among highly educated persons, aged >45 years, a high consumption of red, total, and red + processed meat was related to increased all-cause mortality, compared with those with low consumption, whereas no significant associations were found for SFA intake. Dietary guidelines should specifically limit meat consumption and not relying only in limiting SFA intake.

And:

…replacing 100 g of vegetables, fruits & nuts or cereals by 100 g of red meat resulted in higher mortality risk.

For older individuals eating more meat, there was some effect of more SFA consumption:

In these participants, SFA intake was non-significantly associated with mortality. However, isocaloric replacement of monounsaturated fat or carbohydrates by SFA resulted in significantly higher mortality risk. 

But overall this particular study provides data pointing the finger at red meat/processed meat.  Given the consistency of this finding with that of previous studies, it looks for now that excessive consumption of red meat/processed meat is a major dietary health risk.  Looking at all studies, SFA risk is more equivocal; this study does not show, overall, a significant risk, but other studies have showed such a risk.

Limiting red meat/processed meat consumption would seem to be a prudent dietary priority.  Limiting SFA may be a good idea as well, depending upon context and whatever other dietary recommendations a person has from their physician, etc., but the meat situation would seem more important at this point.  Who knows what further studies will say about SFA.

Dried Fruit And Nuts For Type 2 Diabetes

Figure 1

Role of nutrients from nuts and dried fruits in glucose and insulin metabolism, and cellular and molecular mechanisms related to T2D/IR. CHO, carbohydrate; CMF, cellular membrane fluidity; GI, glycaemic index; IR, insulin resistance; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; T2D, type 2 diabetes. http://www.mdpi.com/2072-6643/9/7/673/htm (Figure from the open access paper)

Of course, diabetics need to follow the instructions of their physicians; however, we present this article for readers' interest.  It suggests that eating nuts and dried fruit (DF) can be beneficial for diabetics; some of the possible mechanisms are outlined in the figure (above) from the paper.  The fiber and relatively low glycemic index, healthy fats, minerals, and various bioactive compounds alter gene expression, microRNAs (RNA that control gene expression), and microbiota and so helpfully "modulate glucose and insulin metabolism." From the conclusion:

Undoubtedly, the specific composition of nuts and dried fruits means that they can be used to efficiently counteract metabolic diseases such as type 2 diabetes. Their unique profile of macronutrients, micronutrients and other bioactive compounds may explain the beneficial effects observed in clinical and epidemiological studies. However, the exact mechanisms by which they modulate glucose and insulin metabolism and influence T2D have yet to be fully discovered. They contain fiber, fat, minerals and other bioactive molecules that modulate several gene mechanisms at the cellular and molecular level. This may explain some of their beneficial effects. However, further basic and translational research is needed in order to extend their positive health benefits and to find novel mechanisms and targets to explain their contribution to the management of type 2 diabetes.

What about the sugars in the dried fruit?  The authors claim:

Carbohydrate Content—Glycaemic Index of Nuts and Dried Fruits

It should be noted that nuts are relatively low in CHO (approximately 15% of the total energy) whereas DFs have a high amount of CHO (60–80%). Nuts have a low glycaemic index and therefore increase the blood glucose level less and require less insulin secretion, thus favoring the control of T2D. However, because DFs are high in carbohydrates and fiber, their specific GI has been the object of considerable study. The GI of raisins was first evaluated in three heterogeneous groups of subjects (aerobically trained, sedentary or pre-diabetic) and was described between 49 and 69, therefore corresponding to the low-to-moderate GI foods [110]. However, later studies have reported that raisins are in the low GI category in healthy subjects (a GI of 49.4 and an insulinemic index of 47.1) [15]. This suggests a favorable postprandial glucose and insulin response [112], that could be explained by the high proportion of fructose that DFs contain.

Overall, the inclusion of both nuts and DFs in a balanced diet may reduce the overall glycaemic index of the diet, with benefits to glycaemic and insulinemic control in both healthy and T2D subjects.

Fructose of course can cause problems but when combined with the high fiber in the dried fruits that is obviated.

Cancer Field Effect

Here is a paper on the cancer field effect, an idea that states than an entire area of a tissue can be altered in some way to predispose that area to develop cancer. Of interest is the possibility that diet, lifestyle (including smoking), etc. can alter the tissue microenvironment to create a "field of susceptibility" to cancer. Hopefully such research can fulfill the promise of "personalized prevention and treatment strategies for precision medicine;" however, until then, controlling diet and lifestyle to prevent cancer, to the best of your ability, is the optimal behavior modification to do.

The term 'field effect' (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, 'etiologic field effect', which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a 'field of susceptibility' to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying 'etiologic field effect' as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an 'etiologic field effect' paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine.

The Yin to FGF19's Yang

At left, FGF19.

By Emw - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8767926

I recently wrote about the potential benefits of FGF19. However, in biology, many things are “double edged swords” and the same things that can promote useful growth in one context can, in another, promote cancer.  Abstract:

Fibroblast growth factors (FGFs) and their cognate receptors, FGF receptors (FGFRs), play critical roles in a variety of normal developmental and physiological processes. Numerous reports support a role for deregulation of FGF-FGFR signaling, whether it is at the ligand and/or receptor level, in tumor development and progression. The FGF19-FGFR4 signaling axis has been implicated in the pathogenesis of several cancers, including hepatocellular carcinomas in mice and potentially in humans. This chapter focuses on recent progress in the understanding of the molecular mechanisms of FGF19 action and its potential involvement in cancer.

This is why various cutting edge treatments must always take into account potential side effects. Now, of course, there is a difference between normal and deregulated FGF signaling and it may be possible to use FGFs in therapy responsibly: the point is that all possibilities, both positive and negative, need to be considered and evaluated.

The American dream: code blue

America, its lifestyle and opportunities have been the dream for many.

America became my own salvation when the communist bloc in Eastern Europe began to fall apart, and there were no jobs, food was scarce, and electricity was sporadic. At that time, I had a newly-minted MS degree, very little English and no prospects for work. So, I studied English on my own, took the required standardized tests (for the first time in my life) and applied to PhD programs in the U.S.

I was lucky - I was accepted in one out of the three universities I applied to. I petitioned to waive my application fee; I hardly had the money to cover the fees for the standardized tests. My parents borrowed money for my airfare and for my first month of expenses in the U.S. After the first month, I had to support myself with my stipend for the work I did in the graduate school.

Looking back, I believe that America saved me from the prematurely aged, toothless and nervous wreck I could have become in my own country. The reality in a disintegrating socialist country killed many. It killed my best friend. Sometimes I doubt that I would have survived, if I had stayed home.

America gave me a PhD degree, job, and family. America gave me opportunities and hopes.

However, would America give the same to my child? What does America offer to the young generation today?

Today, college is a barrier that everyone needs to jump over, but once on the other side, there are not too many opportunities to apply the college degree to. Instead, the graduates are staring at an ugly debt.

And even when one finds a job, how many college-degree jobs are stable today? I think, none. Even my present job is about to expire within the next few years, as academia contracts into a quasi-online model that employs adjuncts, teaching assistants and an exorbitant number of administrators. This would be the end of my career as a PhD graduate.

When I look back at my parents’ trajectory, I perceive that their stories could have been the most extreme example of the American dream. The irony is that they grew up and lived in a socialist country, not in the U.S.

My father was born and raised in a remote, small village in the middle of nowhere. I wanted to visit the place a few years ago, and I was told that there were only a few houses left. His parents may or may have not attended elementary school. After leaving the village and joining the workforce at age of 14, my father survived on very little until the political changes in the country pulled him from the bottom and gave him opportunities. The socialist system helped him finish high school and vocational school, and eventually, brought him into a military academy in the USSR. My father became a skillful and knowledgeable electrical engineer, he rose to the rank of colonel and was given a high-responsibility position in the Ministry of Defense. He was considered for a general and a leader of a military factory next. However, by that time the stress and speed of rising took their toll. My father gave in to a psychosis-ridden burnout and was unable to function at his high-ranked position.

Despite this ending, my father’s story is this of tremendous success – his journey was this from a speck of a village, through numerous towns and jobs, and finally to the capital. He put lots of effort, work, diligence and determination on this path. But he was also helped by the system. If my father was to go to a grad school in the U.S. today, he would not have had a chance! You see, candidates like him are considered an unacceptable risk for the schools. Candidates like him are not offered any scholarships. Back then – more than 50 years ago, my father paid not a single penny for his education. The education in the socialist countries was free.

My mom was raised in a family that was more stable financially; however, her parents also did not have too much of a formal education. My mom graduated from a specialized college to become a highly accomplished teacher in science. Again, the education was free.

Despite their education, my parents received the standard socialist salaries – at that time everyone was receiving more or less the same amount of money for being a medical doctor, colonel, teacher, or janitor. My mom and dad never got a penny from their own parents; however, they were able to establish a home and raise two children. Both my brother and I received free education and obtained masters’ degrees. At the time of graduation, we did not have a penny of debt.

Of course, whereas the socialist system was good and helpful to some, to others, the same system turned out to be cruel and unforgiving. I met some of these people - they had been raised in affluent families, they were smart, well educated, and talented. And yet, when the socialist system was established, these people found themselves under attack. After all, their mothers, fathers and/or grandparents have served the monarch! These people were banned from certain schools, they were not given jobs. Every system has its own flaws, the socialist system had plenty.

And yet, when I look at the future of this land of opportunities, I see only shrinking ones. For me, for my husband, for my child, for the majority of the population.

I do not see the solutions that great leaders should offer the greatest nation in the world.

Where is the grand vision?

Our children are the future of this country. Our priority in visioning should be to take good care of them, give them opportunities to learn, find their interests, realize themselves and be able and free of debt to apply their talents where their hearts are.

We should also make sure that these children grow up in stable families, families in which mom and dad have jobs.

FGF19 Against Muscle Wasting

https://i.ytimg.com/vi/uKMVIfas12k/hqdefault.jpg

Muscle wasting occurs in a variety of diseases as well as aging (sarcopenia). This study shows that a growth factor called FGF 19 increases muscle size in mice and increases human muscle cell size in culture.  In addition, mice with induced muscle wasted were helped by FGF19.  Therefore, this has possible clinical applications for various human disorders.  Abstract:

The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro. These effects were not elicited by FGF21, a closely related endocrine FGF member. Both in vitro and in vivo, FGF19 stimulates the phosphorylation of the extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and the ribosomal protein S6 kinase (S6K1), an mTOR-dependent master regulator of muscle cell growth. Moreover, mice with a skeletal-muscle-specific genetic deficiency of β-Klotho (KLB), an obligate co-receptor for FGF15/19 (refs. 2,3), were unresponsive to the hypertrophic effect of FGF19. Finally, in mice, FGF19 ameliorates skeletal muscle atrophy induced by glucocorticoid treatment or obesity, as well as sarcopenia. Taken together, these findings provide evidence that the enterokine FGF19 is a novel factor in the regulation of skeletal muscle mass, and that it has therapeutic potential for the treatment of muscle wasting