Human Colon Reconstruction In A Mouse Model

This is an exciting paper, in which human colon stem cells were used to reconstruct human colon epithelium – a step toward colon reconstruction – in a mouse model.  The transplanted human material was stable in the mouse once the original mouse tissues were removed.  This new model allows for further experimental analysis of this system, which is not only useful for basic science, but also for regenerative medicine approaches (e.g., replacing human colon that had to be removed for medical reasons).  Abstract:

Genetic lineage tracing has revealed that Lgr5+ murine colon stem cells (CoSCs) rapidly proliferate at the crypt bottom. However, the spatiotemporal dynamics of human CoSCs in vivo have remained experimentally intractable. Here we established an orthotopic xenograft system for normal human colon organoids, enabling stable reconstruction of the human colon epithelium in vivo. Xenografted organoids were prone to displacement by the remaining murine crypts, and this could be overcome by complete removal of the mouse epithelium. Xenografted organoids formed crypt structures distinctively different from surrounding mouse crypts, reflecting their human origin. Lineage tracing using CRISPR-Cas9 to engineer an LGR5-CreER knockin allele demonstrated self-renewal and multipotency of LGR5+ CoSCs. In contrast to the rapidly cycling properties of mouse Lgr5+ CoSCs, human LGR5+ CoSCs were slow-cycling in vivo. This organoid-based orthotopic xenograft model enables investigation of the functional behaviors of human CoSCs in vivo, with potential therapeutic applications in regenerative medicine.

The Undiscovered Interstitium

It has been "discovered" now, a new organ of the body now known?  Abstract:

Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60-70 μm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues, and fascia. These anatomic structures may be important in cancer metastasis, edema, fibrosis, and mechanical functioning of many or all tissues and organs. In sum, we describe the anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium.

Engineering Immunotherapy

Engineering T cells to overcome tumor immune resistance- a possibly useful clinical strategy.  Abstract:

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 × 107 and 1.5 × 108 cells/m2 of DNRII-expressing T cells with specificity for the Epstein Barr virus-derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen-specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β-resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.

A Supplementation Failure

Here is a study asserting that Vitamin D and calcium supplementation did not prevent bone fractures in older patients.  Other studies of course may say different, but also keep in mind the possible link between excess calcium and prostate cancer in men.  Caveat emptor when looking at any one study in isolation. Abstract:

IMPORTANCE:

The increased social and economic burdens for osteoporosis-related fractures worldwide make the prevention of such injuries a major public health goal. Previous studies have reached mixed conclusions regarding the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fracture incidence in older adults.

OBJECTIVE:

To investigate whether calcium, vitamin D, or combined calcium and vitamin D supplements are associated with a lower fracture incidence in community-dwelling older adults.

DATA SOURCES:

The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to December 24, 2016, using the keywords calcium, vitamin D, and fracture to identify systematic reviews or meta-analyses. The primary randomized clinical trials included in systematic reviews or meta-analyses were identified, and an additional search for recently published randomized trials was performed from July 16, 2012, to July 16, 2017.

STUDY SELECTION:

Randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling adults older than 50 years.

DATA EXTRACTION AND SYNTHESIS:

Two independent reviewers performed the data extraction and assessed study quality. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% CIs using random-effects models.

MAIN OUTCOMES AND MEASURES:

Hip fracture was defined as the primary outcome. Secondary outcomes were nonvertebral fracture, vertebral fracture, and total fracture.

RESULTS:

A total of 33 randomized trials involving 51 145 participants fulfilled the inclusion criteria. There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, -0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, -0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration.

CONCLUSIONS AND RELEVANCE:

In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people.

Overestimating Chronic Kidney Disease Frequency?

The frequency of chronic kidney disease may be overestimated due to not taking into account the normal decline in kidney function with age.  You’d think doctors, particularly nephrologists, would all know to make the necessary adjustments or normality for older patients, but apparently not. Abstract:

The process of glomerular filtration of plasma fluid has been known for over 160 years and the measurement of the rate of its formation (glomerular filtration rate, GFR) has been possible for over 80 years. Studies conducted in the 1930's to the 1950's clearly established that GFR declines, perhaps inexorably, with normal ageing, usually beginning after 30-40 years of age. The rate of decline may accelerate after age 50-60 years. This decline appears to be a part of the normal physiologic process of cellular and organ senescence and is associated with structural changes in the kidneys. In the last decade a new paradigm has been introduced in which the true or measured GFR is estimated (eGFR) by formulas based on serum creatinine levels and in which these estimates are applied to the diagnoses of chronic kidney disease (CKD) in the general population. These criteria for diagnosis of CKD include an absolute threshold for eGFR, unadjusted for the effects of age on the normal values for eGFR. A consequence of these criteria has been to overstate the frequency of CKD in the general population and to generate many "false positive" diagnoses of CKD. This paper discusses the known effects of ageing on GFR and the consequences of using a classification system for defining CKD that does not take into account the normal decline of GFR with ageing.

Childhood Cancer Genetic Landscapes

A bit of good news in the midst of an unfortunate topic: “nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.” Abstract:

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

One Potential Positive Of DNA Repair Deficiency In Cancer

Usually, defects in DNA repair are viewed as a bad thing, leading to more of the type of mutations that can lead to cancer initiation and progression.  And this is true.  However, once the cancer exists, deficiencies in mismatch repair (MMR) can also have some positive effects, such as the production of mutant proteins (neoantigens) that can be recognized by the immune system and foster immune surveillance against the tumor.  This can possibly be “exploited in therapeutic approaches.”  Abstract:

Molecular alterations in genes involved in DNA mismatch repair (MMR) promote cancer initiation and foster tumour progression. Cancers deficient in MMR frequently show favourable prognosis and indolent progression. The functional basis of the clinical outcome of patients with tumours that are deficient in MMR is not clear. Here we genetically inactivate MutL homologue 1 (MLH1) in colorectal, breast and pancreatic mouse cancer cells. The growth of MMR-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models. These results suggest that targeting DNA repair processes can increase the burden of neoantigens in tumour cells; this has the potential to be exploited in therapeutic approaches.

Coffee And Glycogen Recovery In Athletes

Coffee and athletic glycogen recovery; abstract:

Coffee is one of the most consumed beverages in the world and it can improve insulin sensitivity, stimulating glucose uptake in skeletal muscle when adequate carbohydrate intake is observed. The aim of this review is to analyze the effects of coffee and coffee components on muscle glycogen metabolism. A literature search was conducted according to PRISMA and seven studies were included. They explored the effects of coffee components on various substances and signaling proteins. In one of the studies with humans, caffeine was shown to increase glucose levels, Ca2+/calmodulin-dependent protein kinase (CaMK) phosphorylation, glycogen resynthesis rates and glycogen accumulation after exercise. After intravenous injection of caffeine in rats, caffeine increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, and glucose transport. In in vitro studies caffeine raised AMPK and ACC phosphorylation, increasing glucose transport activity and reducing energy status in rat muscle cells. Cafestol and caffeic acid increased insulin secretion in rat beta-cells, and glucose uptake into human muscle cells. Caffeic acid also increased AMPK and ACC phosphorylation, reducing the energy status and increasing glucose uptake in rat muscle cells. Chlorogenic acid did not show any positive or negative effect. The findings from the current review must be taken with caution due to the limited number of studies on the subject. In conclusion, various coffee components had a neutral or positive role in the metabolism of glucose and muscle glycogen, whilst no detrimental effect was described. Coffee beverages should be tested as an option for athlete's glycogen recovery.

Cancer Stem Cells And Lipid Metabolism

Cancer stem cells are highly dependent upon lipid metabolism; abstract:

Cancer stem cells (CSCs) are an uncommon subset of tumor cells capable of self-renewal, differentiating, and recreating the parental tumor when transplanted into the murine background. Over the past two decades, efforts toward understanding CSC biology culminated into identifying a set of signaling pathways sustaining "stemness". Nevertheless, while metabolic rewiring is nowadays considered a hallmark of cancer, no consensus has been reached on the metabolic features underlying the plastic nature of CSCs, which are capable of residing in a dormant state, and able to rapidly proliferate when the need to repopulate the tumor mass arises. An emerging concept in the field of CSC metabolism is that these cells are extremely reliant on the activity of enzymes involved in lipid metabolism, such as stearoyl-CoA desaturase 1 (SCD1) and 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR). Indeed, SCD1 and HMG-CoAR have been described as key factors for the correct function of a number of concatenated pathways involved in CSC fate decision, such as Hippo and Wnt. In the present review, we describe metabolic futures of CSCs with a special focus on lipid metabolism, which until now represents an underappreciated force in maintaining CSCs and an attractive therapeutic target.

Besides being a potential therapeutic target one can speculate if this is involved – even if indirectly – in the link between obesity and cancer.

Insulin For Gestational Diabetes

This paper may be of interest for those who have gestational diabetes.  Abstract:

BACKGROUND:

Gestational diabetes mellitus (GDM) is associated with short- and long-term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre-specified treatment targets with diet and lifestyle interventions will require anti-diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti-diabetic pharmacological therapies, non-pharmacological interventions and insulin regimens.

OBJECTIVES:

To evaluate the effects of insulin in treating women with gestational diabetes.

SEARCH METHODS:

We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (1 May 2017) and reference lists of retrieved studies.

SELECTION CRITERIA:

We included randomised controlled trials (including those published in abstract form) comparing:a) insulin with an oral anti-diabetic pharmacological therapy;b) with a non-pharmacological intervention;c) different insulin analogues;d) different insulin regimens for treating women with diagnosed with GDM.We excluded quasi-randomised and trials including women with pre-existing type 1 or type 2 diabetes. Cross-over trials were not eligible for inclusion.

DATA COLLECTION AND ANALYSIS:

Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy.

MAIN RESULTS:

We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty-six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants.Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality. The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison. Insulin versus oral anti-diabetic pharmacological therapyFor the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti-diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate-quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti-diabetic pharmacological therapy for the risk of pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate-quality evidence); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate-quality evidence); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate-quality evidence). The risk of undergoing induction of labour for those treated with insulin compared with oral anti-diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate-quality of evidence). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti-diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD -1.60 kg, 95% CI -6.34 to 3.14; one study, 167 women; low-quality evidence) or one year postpartum (MD -3.70, 95% CI -8.50 to 1.10; one study, 176 women; low-quality evidence). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies.For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti-diabetic pharmacological therapies for the risk of being born large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate-quality evidence); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low-quality evidence);, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate-quality evidence); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low-quality evidence); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI -3.77 to 0.57; one study, 82 infants; moderate-quality evidence); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI -2.33 to 0.73; random-effects; one study, 82 infants; very low-quality evidence); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI -0.49 to 1.49; one study, 318 children; low-quality evidence). Low-quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood: hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies.We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons.

AUTHORS' CONCLUSIONS:

The main comparison in this review is insulin versus oral anti-diabetic pharmacological therapies. Insulin and oral anti-diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency.For the other comparisons of this review (insulin compared with non-pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high-quality evidence to determine differences for key health outcomes.Long-term maternal and neonatal outcomes were poorly reported for all comparisons.The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti-diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes.

Wnt Signaling And Brain Injury Repair

Wnt signaling has been shown to contribute to blood vessel repair after traumatic brain injury.  Thus suggests to me that Wnt agonists (agents that boost Wnt signaling) may eventually have a therapeutic role in treating such injuries.  Abstract:

Recent data suggest that repairing the cerebral vasculature after traumatic brain injury (TBI) may help to improve functional recovery. The Wnt/β-catenin signaling pathway promotes blood vessel formation during vascular development, but its role in vascular repair after TBI remains elusive. In this study, we examined how the cerebral vasculature responds to TBI and the role of Wnt/β-catenin signaling in vascular repair. We induced a moderate controlled cortical impact in adult mice and performed vessel painting to visualize the vascular alterations in the brain. Brain tissue around the injury site was assessed for β-catenin and vascular markers. A Wnt transgenic mouse line was utilized to evaluate Wnt gene expression. We report that TBI results in vascular loss followed by increases in vascular structure at seven days post injury (dpi). Immature, non-perfusing vessels were evident in the tissue around the injury site. β-catenin protein expression was significantly reduced in the injury site at 7 dpi. However, there was an increase in β-catenin expression in perilesional vessels at 1 and 7 dpi. Similarly, we found increased number of Wnt-GFP-positive vessels after TBI. Our findings suggest that Wnt/β-catenin expression contributes to the vascular repair process after TBI.

Different Roles Of Dkk1 In Cancer Metastasis

Wnt signaling is involved in the development and progression of a variety of cancers, and researchers have typically approached Wnt-targeted therapeutics with the aim of suppressing this signaling. Dkk1 is an inhibitor of Wnt signaling, and so this molecule has been thought to be useful with respect to cancer therapy.  But in the paper linked here, it was shown that while Dkk1 inhibits metastasis of lung cancer, it can actually promote metastasis of breast cancer to bone.  This demonstrates that particular therapeutic approaches may need to be specifically targeted to particular cancer types; it also suggests that suppression of signaling is not always the best approach.  There has been some work suggesting boosting cell signaling to abnormally high levels can cause cancer cell death as well; this is a topic worth revisiting in the future.  Abstract:

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

Aging And Body Repair

Aging is associated with a decline in the ability of the body to repair itself, including tissue and (at least partial) body part regeneration, with mechanisms that may include: “aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration.” This will enable, as the authors also state “safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.”  Abstract:

Aging is associated with a significant decline of tissue repair and regeneration, ultimately resulting in tissue dysfunction, multimorbidity, and death. Salamanders possess remarkable regenerative abilities and have been studied with the prospect of inducing regeneration in humans and counteracting regenerative decline with aging. However, epimorphic regeneration, the full replacement of amputated structures, also occurs in mammals. One of the best studied models is digit tip regeneration, which is described for mice, and occurs in humans in a comparable manner. To accomplish regeneration, the amputated digit tip has to undergo three interdependent, overlapping steps: (i) wound healing without formation of a scar; (ii) formation of a blastema, a highly proliferative cell mass; and (iii) spatiotemporally regulated differentiation to generate a pattern similar to the original structure. Aging likely interferes with each of these steps. In this article, we provide an overview of the critical signaling pathways for regeneration, as revealed by investigating mammalian digit regeneration, the possible impact of aging on these pathways, and approaches to induce regeneration in the elderly. We hypothesize that with aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration. Knowledge about the impact of aging on regenerative mechanisms will enable us to safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies.

Leaf Extract Against Colorectal cancer

Here is a study suggesting that Ginkgo biloba L. leaf extract may be beneficial against colorectal cancer by affecting important cell signaling pathways that mediate that disease. The authors state: “The outcomes of the present investigation encourage the use of Ginkgo biloba L. leaf extract as a complementary and alternative therapeutic approach to abate CRC.”  As always consult your own physician; in my opinion, “complementary” may be useful, but “alternative” (as in use this but do not use traditional medical treatments) is a mistake. I have heard of too many horror stories of patients eschewing regular treatment for alternatives and then dying if a curable cancer because they realized, too late, that the alternative was really no alternative at all.  But, again, I am not a medical doctor and I am only giving my own opinion based on scientific background as well as personal experience and anecdote.  I would urge all cancer patients to follow the advice of their oncologists and, of course, ask whether other things can complement treatment.

HIF Repression Cancer Therapy

Hypoxia – lack of oxygen – promotes the expression of  hypoxia-inducible factors that mediate cancer progression, including angiogenesis (blood vessel formation) that helps bring oxygen to the tumors.  Blocking those factors is a new form of therapy, described here.  Abstract:

Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC

Exercise Isn't Helping

By Tibor Végh (Tenerife 2010 124.JPG) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons

Americans are more obese than ever and exercise does not really help that much.

Some take medications. Or, you can just eat less.

No Evidence For Exercise Benefit For Depression And Cognition?

Contrary to popular conceptions, a study here and another one here did not find any positive effect of exercise (at least aerobic exercise) on depression or cognition. However, this is not the last word, and more studies are necessary.  Even if these two studies are correct, exercise has enormous health benefits for physical fitness and overall physical and psychological well-being.

Fetus-In-Fetu

By Nisreen M Khalifa et al - Khalifa NM, Maximous DW, Abd-Elsayed AA. Fetus in fetu: a case report. J Med Case Reports. 2, 2. 2008. doi:10.1186/1752-1947-2-2. PMID 18186928., CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=4260020

Although there is nothing practical to learn, for daily living, from this interesting case of fetus-in-fetu, it is nevertheless interesting to read about.  Perhaps the study of such abnormalities can be useful for studies of cancer and other aberrations of developmental processes.  Abstract:

A case of fetus-in- fetu is reported. It occurred in an 8-week-old Korean boy who had been born by cesarean section due to abdominal distension. The fetus-in- fetu was connected to the superior mesenteric artery and consisted of two masses, apparently representing two portions of an acardiac monster. There was an amniotic membrane covering both masses, and the umbilical cord clearly was identifiable. One mass included the brain, eye, trachea, salivary glands, thyroid, pancreas, spleen, etc., while the other mass contained extremity bones, vertebrae, testis, adrenals, and intestinal loops. This is probably a case of separated fetus-in- fetu that showed unusually well-developed internal organs.

The Decrepit Adult

Contrary to previous belief, it seems that in humans, formation of new neurons in the hippocampus, important for learning and memory, essentially stops in childhood.  Abstract:

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

Contraceptives And Breast Cancer

The use of hormonal contraceptives increases the risk of breast cancer in women, associated with duration of use.  The risk increase was relatively small, but nevertheless real.  Abstract:

BACKGROUND:

Little is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer.

METHODS:

We assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders.

RESULTS:

Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen-progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.

CONCLUSIONS:

The risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.).

Hemophilia Gene Therapy Success

Advances in hemophilia gene therapy; abstract:

BACKGROUND:

The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia.

METHODS:

We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×1011 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.

RESULTS:

No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion.

CONCLUSIONS:

We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).

A modern-life fairy tale

Do you like restoring houses and planting gardens? Or at least are you tempted by the thought of doing these activities? Of course, there will be the constraints of time and finances. You will also need imagination, grit and physical resilience. If you would like to relive your fantasies, then watch Escape to the Chateau.

 [Update: there is always a copyright issue, so the links would not work. You may need to search what is available at this time on YouTube.]

The show follows a British couple buying a chateau in France. The building dates back to the 1860s, when it was raised upon the foundations of a 15th-century fort. There are 45 rooms, a moat, 12 sprawling acres of land, and much more. The building has been empty for 40 years, when the couples buys it.

From reconstruction and rebuilding, to orchards and pigs, to boudoirs and gourmet seven-course dinners, it is all in the roller coaster of experiences. It is unbelievable how this couple makes it work.
 
The show is a mix of a fairy tale with incredible amount of work. And this is the reality – enormous effort has to supplement the flights of our imagination. There is no magic wand that we can wave. Here is the website of the creative couple.

Another version of a modern tale is this of the five from Honey Grove farm:

We are a family cohort of makers, bakers, gardeners and beekeepers. We are eaters, too, emboldened by the concepts of commensality and convivality. Our home and land is the inspiration behind all of our creative endeavours and we'd truly love to share it with you...

There are four young people living on six acres on Vancouver Island, BC, Canada, and you can find out more about them on their website. You may ask, who is the fifth on the farm? Well, it is Gus Sims, the dog who "offers workshops on unconditional love and forgiveness."

And now I am back to binge-watching Escape to the Chateau.  Au Revoir!

More On Macular Degeneration

Macular degeneration is a major cause of blindness, and researchers have discovered a new mechanism whereby retinal pigmented epithelium degenerates, casing disease. These discoveries can lead to new treatments for this disease.  Abstract:

Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.