TERRA and the alternative lengthening of telomeres: a dangerous affair

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TERRA and the alternative lengthening of telomeres: a dangerous affair

The long noncoding RNA TERRA controls telomere length homeostasis in human cancers with an activated alternative lengthening of telomeres (ALT) mechanism. Telomeric R-loops formed between TERRA and telomeric DNA (telR-loops) promote telomere elongation through homology-directed repair. However, if not properly regulated, TERRA and telR-loops can lead to rapid cleavage of telomeric DNA and telomere loss.


Eukaryotic telomeres are transcribed into the long noncoding RNA TERRA. A fraction of TERRA remains associated with telomeres by forming RNA:DNA hybrids dubbed telR-loops. TERRA and telR-loops are essential to promote telomere elongation in human cancer cells that maintain telomeres through a homology-directed repair pathway known as alternative lengthening of telomeres or ALT. However, TERRA and telR-loops compromise telomere integrity and cell viability if their levels are not finely tuned. The study of telomere transcription in ALT cells will enormously expand our understanding of the ALT mechanism and of how genome integrity is maintained. Moreover, telomere transcription, TERRA and telR-loops are likely to become exceptionally suited targets for the development of novel anti-cancer therapies.

A life‐time of hematopoietic cell function: ascent, stability, and decline

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A life-time of hematopoietic cell function: ascent, stability, and decline

Here we review the aging of the hematopoietic system from its earliest stages in the embryo through fetal and adult life. We focus on the waves of hematopoietic cell generation during embryonic life and how cells of varying lineages, functions and life spans contribute to the normal development of the adult blood system and its progressive gain/loss of function in the aged adult.


Aging is a set of complex processes that occur temporally and continuously. It is generally a unidirectional progression of cellular and molecular changes occurring during the life stages of cells, tissues and ultimately the whole organism. In vertebrate organisms, this begins at conception from the first steps in blastocyst formation, gastrulation, germ layer differentiation, and organogenesis to a continuum of embryonic, fetal, adolescent, adult, and geriatric stages. Tales of the “fountain of youth” and songs of being “forever young” are dominant ideas informing us that growing old is something science should strive to counteract. Here, we discuss the normal life stages of the blood system, particularly the historical recognition of its importance in the early growth stages of vertebrates, and what this means with respect to progressive gain and loss of hematopoietic function in the adult.

High expression of autotaxin is associated with poor recurrence‐free survival in cholangiocarcinoma

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Abstract

Background and Aim

Autotaxin (ATX) is an extracellular lysophospholipase D that catalyzes the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA). Recent accumulating evidence indicates the biological roles of ATX in malignant tumors. However, the expression and clinical implications of ATX in human cholangiocarcinoma (CCA) remain elusive.

Methods

In this study, the expression of ATX in 97 human CCA tissues was evaluated by immunohistochemistry. Serum ATX levels were determined in CCA patients (n = 26) and healthy subjects (n = 8). Autotaxin expression in cell types within the tumor microenvironment was characterized by immunofluorescence staining.

Results

High ATX expression in CCA tissue was significantly associated with a higher frequency of lymph node metastasis (p = 0.050). High ATX expression was correlated with shorter overall survival (p = 0.032) and recurrence-free survival (RFS) (p = 0.001) than low ATX expression. In multivariate Cox analysis, high ATX expression (p = 0.019) was an independent factor for shorter RFS. Compared with low ATX expression, high ATX expression was significantly associated with higher Ki-67-positive cell counts (p < 0.001). Serum ATX levels were significantly higher in male CCA patients than in healthy male subjects (p = 0.030). In the tumor microenvironment of CCA, ATX protein was predominantly expressed in tumor cells, cancer-associated fibroblasts, plasma cells, and biliary epithelial cells.

Conclusions

Our study highlights the clinical evidence and independent prognostic value of ATX in human CCA.

How CBX proteins regulate normal and leukemic blood cells

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How CBX proteins regulate normal and leukemic blood cells

CBX proteins are epigenetic reader proteins that can recognize histone modifications and thereby dictate cell fate. In this review, we describe how CBX proteins dictate cell fate in normal hematopoiesis and leukemia. In addition, we discuss which CBX proteins can promote leukemic cell growth and whether pharmacological inhibition of CBX proteins can reverse leukemic cell fate.


Hematopoietic stem cell (HSC) fate decisions are dictated by epigenetic landscapes. The Polycomb Repressive Complex 1 (PRC1) represses genes that induce differentiation, thereby maintaining HSC self-renewal. Depending on which chromobox (CBX) protein (CBX2, CBX4, CBX6, CBX7, or CBX8) is part of the PRC1 complex, HSC fate decisions differ. Here, we review how this occurs. We describe how CBX proteins dictate age-related changes in HSCs and stimulate oncogenic HSC fate decisions, either as canonical PRC1 members or by alternative interactions, including non-epigenetic regulation. CBX2, CBX7, and CBX8 enhance leukemia progression. To target, reprogram, and kill leukemic cells, we suggest and describe multiple therapeutic strategies to interfere with the epigenetic functions of oncogenic CBX proteins. Future studies should clarify to what extent the non-epigenetic function of cytoplasmic CBX proteins is important for normal, aged, and leukemic blood cells.

Risk of colorectal cancer in patients with primary sclerosing cholangitis and concomitant inflammatory bowel disease compared with primary sclerosing cholangitis only

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Risk of colorectal cancer in patients with primary sclerosing cholangitis and concomitant inflammatory bowel disease compared with primary sclerosing cholangitis only

Although primary sclerosing cholangitis (PSC) is frequently linked to inflammatory bowel disease, a known risk factor for colorectal cancer, it remains uncertain whether PSC alone poses an independent risk for colorectal cancer. Our retrospective cohort study conducted at a tertiary medical center reveals that individuals with PSC have an increased risk of colorectal cancer compared with the general population. Our findings suggest that PSC patients may benefit from more frequent colonoscopy screening when compared with individuals without PSC.


Abstract

Aim

Primary sclerosing cholangitis (PSC) increases the risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients; however, there is a paucity of literature to suggest PSC alone as an independent risk factor for CRC. We aimed to determine if PSC is an independent risk factor for CRC in a large tertiary care medical center. Optimizing screening intervals is of great importance, given the burden and risks associated with a lifetime of colonoscopy screening.

Methods

This retrospective cohort study consists of patients diagnosed with PSC preceding IBD (PSC–IBD) and PSC-only before January 6, 2023 from a large, tertiary, academic medical center. Patients diagnosed with IBD concurrently or before PSC were excluded to reduce IBD's impact on CRC risk. Demographic data and colonoscopy findings were collected and assessed.

Results

Overall, 140 patients from all NYU Langone Health clinical settings were included. Patients with PSC–IBD were more likely to be diagnosed with CRC (23.3% vs. 1.8%, p < 0.01) and either low-grade or uncharacterized dysplasia (16.7% vs. 0.0%, p < 0.01) compared with those with PSC-only. Among PSC-only patients, the estimated CRC risk was significantly elevated compared with that expected of the standard NYU Langone population (SIR 9.2, 95% CI 1.1, 33.2).

Conclusions

Our study revealed a significantly heightened CRC risk in PSC–IBD patients compared with those with PSC-only. Importantly, individuals with PSC-only also face a greater CRC risk compared with the general population. Individuals with PSC-alone may require extended screening and surveillance colonoscopy intervals compared with those with PSC–IBD, yet still require more frequent monitoring than screening guidelines recommend for the general population.

Impact of electrical muscle stimulation on serum myostatin level and maintenance of skeletal muscle mass in patients undergoing living‐donor liver transplantation: Single‐center controlled trial

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Abstract

Aim

Sarcopenia is reportedly associated with a poor prognosis in patients who undergo living-donor liver transplantation (LDLT), most of whom are not able to tolerate muscle strengthening exercise training. Myostatin is one of the myokines and a negative regulator of skeletal muscle growth. The clinical feasibility of an electrical muscle stimulation (EMS) system, which exercises muscle automatically by direct electrical stimulation, has been reported. In this study, we aimed to determine the effect of perioperative application of SIXPAD, which is a type of EMS system, with reference to the serum myostatin and sarcopenia in LDLT patients.

Method

Thirty patients scheduled for LDLT were divided into a SIXPAD group (n = 16) and a control group (n = 14). In the SIXPAD group, EMS was applied to the thighs twice daily. The serum myostatin was measured in samples obtained before use of SIXPAD and immediately before LDLT. The psoas muscle index (PMI) at the level of the third lumbar vertebra and the quadriceps muscle area were compared on computed tomography images before use of SIXPAD and 1 month after LDLT.

Results

The preoperative serum myostatin was found to be higher in LDLT patients than in healthy volunteers and EMS significantly reduced the serum myostatin. Electrical muscle stimulation prevented a postoperative reduction not only in the area of the quadriceps muscles but also in the PMI despite direct stimulation of the thigh muscles.

Conclusion

Stimulation of muscles by EMS decreases the serum myostatin and helps to maintain skeletal muscle in patients who have undergone LDLT.

Resveratrol and its metabolites elicit neuroprotection via high‐affinity binding to the laminin receptor at low nanomolar concentrations

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Resveratrol and its metabolites elicit neuroprotection via high-affinity binding to the laminin receptor at low nanomolar concentrations

Using ligand binding and molecular docking, we found that trans-resveratrol, its glucuronide and sulfate conjugates, and dihydro-resveratrol bind with high affinities to polyphenol- and glycosaminoglycan-binding motifs, which are present within the peptide G region of the 67-kDa laminin receptor (67LR). Neuronal cells were protected from death via 67LR/cAMP-mediated signaling pathways by preconditioning with low nanomolar concentrations of resveratrol-glucuronide.


Resveratrol prevents various neurodegenerative diseases in animal models despite reaching only low nanomolar concentrations in the brain after oral administration. In this study, based on the quenching of intrinsic tryptophan fluorescence and molecular docking, we found that trans-resveratrol, its conjugates (glucuronide and sulfate), and dihydro-resveratrol (intestinal microbial metabolite) bind with high affinities (K d, 0.2–2 nm) to the peptide G palindromic sequence (near glycosaminoglycan-binding motif) of the 67-kDa laminin receptor (67LR). Preconditioning with low concentrations (0.01–10 nm) of these polyphenols, especially resveratrol-glucuronide, protected neuronal cells from death induced by serum withdrawal via activation of cAMP-mediated signaling pathways. This protection was prevented by a 67LR-blocking antibody, suggesting a role for this cell-surface receptor in neuroprotection by resveratrol metabolites.

Interlinked bi‐stable switches govern the cell fate commitment of embryonic stem cells

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Interlinked bi-stable switches govern the cell fate commitment of embryonic stem cells

Nanog and Oct4 are the key regulatory genes that govern the developmental dynamics of embryonic stem cells to trophectoderm and primitive endoderm by maintaining specific steady-state expression patterns. Herein, we hypothesize stepwise switching and mushroom-like bifurcation dynamics for Oct4 and Nanog, respectively, that align well with the existing experimental findings and shed light on fate-determination events.


The development of embryonic stem (ES) cells to extraembryonic trophectoderm and primitive endoderm lineages manifests distinct steady-state expression patterns of two key transcription factors—Oct4 and Nanog. How dynamically such kind of steady-state expressions are maintained remains elusive. Herein, we demonstrate that steady-state dynamics involving two bistable switches which are interlinked via a stepwise (Oct4) and a mushroom-like (Nanog) manner orchestrate the fate specification of ES cells. Our hypothesis qualitatively reconciles various experimental observations and elucidates how different feedback and feedforward motifs orchestrate the extraembryonic development and stemness maintenance of ES cells. Importantly, the model predicts strategies to optimize the dynamics of self-renewal and differentiation of embryonic stem cells that may have therapeutic relevance in the future.