Clonal hematopoiesis of indeterminate potential (CHIP):A potential contributor to atherlosclerotic cardio/cerebro-vascular diseases?

At least 10%of the elderly population above the age of 70 carry a condition termed clonal hematopoiesis indeterminate potential(CHIP)due to oligoclonal expansion of mutated hematopoietic stem cells.Although CHIP is known to predispose patients to a higher risk of malignant blood disorders,the recent revelation of its association with higher morbidity and mortality of atherosclerotic cardiovascular disease and ischemic stroke is rather surprising.Two independent research groups published studies indicating that Tet2 mutated monocytes from mice modeling CHIP had a causal role in accelerating the growth of atherosclerotic lesions due to their pro-inflammation activities.This important discovery points to CHIP as a risk factor and raises the prospect of novel treatment to minimize the adverse cardio/cerebro-vascular events.

Targeting both sides of the GDF15-GFRALRET receptor complex:A new approach to achieve body weight homeostasis

Obesity is a chronic,complex disease,which is associated with several comorbidities,including diabetes mellitus,hypertension,and cardiovascular diseases.It is estimated that the prevalence of obesity among both adults and children nearly tripled between 1975 and 2016,highlighting a huge unmet treatment need.However,the currently available antiobesity drugs have serious side effects,which limit their long-term use.The finding that the newly-identified brain GDF15-GFRAL-RET receptor signaling complex is involved in stress/disease-induced anorexia will certainly impact our knowledge of body weight homeostasis under healthy and disease conditions.Based on this breakthrough,a new class of GFRAL/RETbased drugs is highly anticipated for the treatment of obesity,as well as cancer-induced cachexia.

Authentication of experimental materials:A remedy for the reproducibility crisis?

Reproducibility has always been a serious challenge when medical researchers in both academia and industry have tried to build upon previously published discoveries.Blindly chasing faulty results has incurred a huge waste of human and monetary resources.The damage to the progress of scientific discoveries,as well as their application to human well-being,cannot be overestimated.According to two reports by Bayer and Amgen published in 2011 and 2012,64e89%of the socalled“landmark”results could not be reproduced in their pre-clinical validation experiments.1,2 One plausible explanation for this out of proportion irreproducibility is related to the intricacy of the scientific experiments,including the sourcing of reagent antibodies and cell lines,which are major sources of variations.To make validation meaningful,the study materials used in the original studies need to be authenticated so that variations due to the faulty materials can be prevented during follow-up studies.However,the technical complexity and the costs of authentication often discourage this practice in research laboratories.

Seeking the“mother of blood”from human pluripotent stem cells:Are we there yet?

Induced pluripotent stem cells(iPSCs)hold great promise for the treatment of human diseases,including the failure of bone marrow.Incremental progress across the past three and half decades has brought us closer to making hematopoietic stem cells from iPSCs clinical solutions.A recent innovative two-step differentiation approach successfully generated transplantable HSCs from iPSC sources.For clinical translation,the long-term safety of these gene-altered HSCs must be determined.

Mending an infarcted heart:The possibility of using iPSC technology

iPSCs hold great promise in that a large quantity of cardiomyocytes(iPSC-CM)can be generated and cultured in vitro for clinical purposes.These cells are currently being subjected to vigorous testing in animal transplantation models to ascertain their survivability and functional integration in the injured heart.So far,most of those studies have been conducted in small animals and sometimes in xenogeneic settings,and have produced mixed results.Representing a step forward,a recent study in Nature reported the transplantation of MHC-matched allogeneic monkey iPSC-CM.This was the first time iPSC-CM have been tested in a non-human primate model in an allogeneic setting,which is the next best thing to a human clinical trial.

iPSC-based treatment of age-related macular degeneration (AMD):The path to success requires more than blind faith

Induced pluripotent stem cells(iPSCs)hold great promise for the treatment of human diseases.Two recent first-of-its-kind clinical case reports on the iPSC-based treatment of age-related macular degeneration(AMD)highlight the hopes and challenges associated with the clinical application of iPSCs.

Targeting metastatic breast cancer with ANG1005, a novel peptide-paclitaxel conjugate that crosses the blood-brain-barrier (BBB)

We devoted this short interview piece with Dr Shou-Ching Tang at Augusta University to feature some promising results from a clinical phase II trial on a novel brain-penetrating peptide-paclitaxel-conjugate,ANG1005,in treating brain metastatic breast cancer.These results were presented by Dr.Tang at the recent annual meeting of the European Society for Medical Oncology(ESMO 2016 Congress).This development heralds an important step forward towards the development of effective chemotherapeutic agents,which can cross the bloodbrain-barrier and effectively treat and prevent the brain metastatic cancers.

Culturing human embryos beyond blastulation: Pushing the limits and exploring the unexplored

Two articles recently published in Nature and Nature Cell Biology reported that early human embryos were successfully cultured beyond blastulation.This development heralds an important step toward exploring the unknown molecular events driving human pregastrulation development,but it inevitably raises the ante in the decades-old ethical debate on how to define early human life and how to save human lives through research without destroying another life in the process.

CRISPR comes of age:A fairytale turned into bedside reality?

We devote this short piece to highlight one recent article published in Cell Stem Cell,reporting the correction of large chromosomal inversions of the factor VIII(F8)gene in cells from Hemophilia A patients using the CRISPR-Cas9 technology,one of the first attempts to edit large segments of chromosomes in patient cells using such methodology.The corrected cells were found free of off-target mutations and producing functional factor VIII in hemophilia mouse model.This work heralds another major advance in bringing CRISPR closer to the therapeutic reality.

Revisiting vitamin C in cancer therapy:Is“C”for cure,or just wishful thinking?

We devoted this short piece to highlight one recent article published in Science,which revisited the anti-cancer efficacy of high-dose vitamin C.Using isogeneic KRAS-and BRAF-mutated colorectal cell lines,the authors were able to demonstrate selective antitumor effects among the KRAS-and BRAF-mutated cells in culture and in ex-planted animal models treated with high-dose vitamin C.Their elegant and in-depth studies unequivocally tied the tumoricidal effect to the heightened sensitivity of the mutant cells due to the increased vitamin C uptake,leading to lethal accumulation of reactive oxygen species(ROS).This report will certainly rekindle enthusiasm in revisiting the case of vitamin C,pushing for more definitive cancer therapy trials.

For your eyes only:Harnessing human embryonic stem cell-derived retinal pigment epithelial cells to improve impaired vision

Vision loss or impairment resulting from the degeneration of the retinal pigment epithelium and photoreceptor death affects millions worldwide.Recent exciting results from clinical studies of small numbers of patients treated with human embryonic stem cell-derived retinal pigment epithelial cells may provide hope for affected individuals.

Primary Immune Deficiencies e A rapidly emerging area of basic and clinical research

In this special issue of Genes&Diseases,Primary Immune Deficiencies(PIDs)are the main focus.This is an exciting and a rapidly emerging field of basic and clinical immunology wherein upwards of 400 clinical conditions,with approximately 350 defined mutations,are now recognized.Contrary to common perception,PIDs as a group are not uncommon.Epidemiologic studies show that population prevalence of PIDs is approximately 1:2000.Statistical extrapolations of this figure would suggest that in a large country like China or India,approximately 1 million individuals would be expected to have a PID.However,at present because of lack of awareness of these conditions amongst both the laity as well as medical professionals,majority of these patients remain undiagnosed and untreated in many developing countries.This is clearly unfortunate.

Seeing is believing:Stem cells to treat blindness

The majority of clinical blindness is caused by a loss of transparency of the lens and cornea,largely due to cataracts and corneal injuries.The most common treatment used to restore the transparency is surgical removal of the damaged tissues,followed by transplantation of donated corneal tissue or an artificial lens.However,these therapies are not without limitations or untoward effects.Unraveling the intricate regulatory signals required for cornea and lens development has made it possible to harness the lineage growth potential of stem cells for cornea repair and lens regeneration,as showcased in two recent studies published in the March 17th issue of Nature.

Direct lineage conversion with pluripotency factors:A risky detour through transient pluripotency?

The advent of induced pluripotent stem cells(iPSCs)marked a giant step forward towards the reality of converting one type of primary somatic cells into different lineages capable of clinically repairing damaged tissues and organs.However,the major drawbacks of iPSCs hinder their quick translation to the bedside.These drawbacks include the time-,cost-,and labor-intensive process in production of clinical products from iPSCs,and the inherent risk of long-term tumorigenesis due to the forced expression of transcription factors associated with pluripotency,which are often implicated as aberrations within the cancerous gene circuitry.