Comprehensive proteomics and platform validation of urinary … – BMC Medicine

Research over the past several years has uncovered potentially important urine biomarkers and tests for BC, including BTA and NMP22. BTA-stat, an FDA-approved urine biomarker, is used clinically to detect bladder tumor-associated antigen (human complement factor H-related protein) in the urine. A meta-analysis of BTA stat reported a specificity of 67% and a sensitivity of 75% after reviewing 13 studies [8]. The sensitivity levels of BTA-stat have been shown to positively correlate with increasing grade of BC [8]. However, BTA-stat has several limitations. These include lower specificity values and issues relating to false-positive results in benign conditions [6]. Hence, urine BTA-stat may have limitations in the diagnosis and monitoring of disease progression. Similarly, NNP22 is an FDA-approved urine biomarker designed to detect the NMP22 protein levels which are high due to cell turnover from tumor apoptosis. A meta-analysis of 19 studies has identified this marker to have a pooled specificity of 88% and a sensitivity of 56% [7].

As opposed to studies looking at an isolated protein in the urine, a few screens have been reported where multiple proteins were examined simultaneously. Summarized below are a couple of studies documenting biomarkers with both sensitivity and specificity values greater than or equal to 85%. Goodison et al. performed a validation study for the urinary concentrations of 14 proteins (A1AT, APOE, ANG, CA9, CCL18, CD44, IL-8, MMP-9, MMP-10, OPN, PAI-1, PTX3, SDC1, and VEGF) using an ELISA [30]. An 8-biomarker panel (ANG, APOE, CA-9, IL-8, MMP-9, MMP-10, PAI-1, and VEGF) achieved the most accurate BC diagnosis with a sensitivity of 92% and a specificity of 97%. However, a panel of 3 biomarkers (APOE, IL-8, and VEGF) also performed well with a sensitivity of 90% and a specificity of 97% for the detection of BC [30]. Kumar et al. identified a 5-biomarker panel consisting of Apolipoprotein A4, Coronin-1A, DJ-1/PARK7, Gamma synuclein, and Semenogelin-2. ELISA and western blot data obtained an AUC of 0.92 and 0.98, respectively, in diagnosing Ta/T1 BC (sensitivity 79.2% and 93.9% for ELISA; specificity 100% and 96.7% for western blot) [31]. For the diagnosis of T2/T3 BC, the panel of markers achieved an AUC of 0.94 and 1, respectively, using the same methods (sensitivity 86.4% and 100%; specificity 100%) [31].

Low-grade BC has a high recurrence rate; therefore, identifying biomarkers for the surveillance of BC is essential for the potential clinical management of the disease. Rosser et al. identified 10 biomarkers (ANG, APOE, CA9, IL-8, MMP-9, MMP-10, SDC1, SERPINA1, SERPINE1, and VEFGA) using ELISA for monitoring urine for recurrent BC. The complete panel achieved an AUC of 0.90, a sensitivity of 79%, and a specificity of 88% [32]. De Paoli et al. identified a panel of 6 biomarkers (cadherin-1, EN2, ErbB2, IL-6, IL-8, and VEGF-A) and three clinical parameters including BCG therapies, stage at the time of diagnosis, and past recurrences. The panel achieved an AUC of 0.91 and was identified through microarray and ELISA analysis [33].

There are several reasons to discriminate patients with bladder cancer from benign conditions. In patients with hematuria, it would be helpful to identify who needs cystoscopic evaluation which is invasive. Given that urine proteins are easily measurable and are compatible with point-of-care monitoring, a quick urine test could dramatically impact triage and workflow in urology outpatient clinics. Likewise, in bladder cancer surveillance, a reliable urine biomarker can help determine if cancer (like CIS) was missed or to avoid cystoscopy in marker-negative patients. Similarly, urine biomarkers that can reliably distinguish MIBC from NMIBC can inform us as to who has the more aggressive disease. When used as a routine point-of-care test (either at home or at outpatient visits), these urinary biomarkers may facilitate earlier identification of aggressive disease and design of tailored therapy.

The present work represents the first attempt to screen>1000 urine proteins for urine biomarker candidates in BC, using a relatively novel aptamer-based screen. Systems biology analysis implicated molecular functions related to the extracellular matrix, collagen, integrin, heparin, and transmembrane tyrosine kinase signaling in BC susceptibility, with HNF4A and NFKB1 being key regulators. STEM analysis of the dysregulated pathways implicated a functional role for the immune system, complement, and interleukins in BC disease progression (Fig.3D). This study has also uncovered urine proteins that outperform current FDA-approved markers in many respects. Several urine proteins (d-dimer, Apolipoprotein A1, MMP-1, Properdin, Calgranulin B) significantly discriminate BC from UC with AUC values from 0.85 to 0.96 (p-value<0.0001). As a single biomarker, urine d-dimer was able to discriminate BC from UC with 96% accuracy (sensitivity=95%; specificity=90%). Likewise, several urine proteins (IL-8, IgA, Fibronectin, C2, Proteinase 3) significantly discriminate MIBC from NMIBC with AUC 0.840.99 (p-value<0.001). Interestingly, several of the proteins described above have been documented to be elevated in bladder cancer tissue (at the RNA or protein level) and/or implicated in tumor biology at some level, as summarized in Additional file 1: Table S5. Considering their biomarker potential and functional properties based on the literature (Additional file 1: Table S5), these urine proteins warrant further investigation, including, d-dimer [34], Apolipoprotein A1 [35, 36], Apolipoprotein L1, Calgranulin B [37, 38], complement C2 [39], Fibronectin [40,41,42,43], Ficolin-3, IL-8 [44,45,46,47,48,49], IgA [50], MMP-1 [51, 52], Properdin, and Proteinase 3 [53]. A summary of previous research on these proteins can be found in Additional file 1: Table S6. Additional markers increased in tissues are described in Additional file 1: Table S7.d-dimer is a specific cleavage product of fibrin and a symbol of hyperfibrinolysis [34]. It is the primary diagnostic tool in various diseases, such as deep venous thrombosis, systemic illness, and cancers [54]. Previous studies have reported that molecules in the coagulation/fibrinolysis system, especially plasma fibrinogen and d-dimer, are abnormal in cancer patients [34]. In the present study, urine d-dimer levels show a significant ability to differentiate BC from UC (AUC=0.96) (p<0.0001). After correcting for patient demographics, urine d-dimer is still eligible for inclusion within the 5-biomarker panel for best distinguishing BC from UC. Perhaps most impressive is the observation that urine d-dimer demonstrates a high sensitivity for the detection of BC (95%), and at a fixed specificity of 0.8, it can achieve a sensitivity of 0.97. Hence, as a single biomarker, urine d-dimer outperforms current FDA-approved biomarkers and competing biomarkers in the research literature as a sensitive biomarker for BC detection.

Apolipoproteins (Apolipoprotein A1 and Apolipoprotein L1) are proteins known to interact with the lipids of the lipoprotein core and also the aqueous environment of the plasma. Apolipoprotein A1 is the primary protein component of high-density lipoprotein while Apolipoprotein L1 is a minor component. Previous studies have validated Apolipoprotein A1 as a novel urinary biomarker for BC [35, 36]. In the current research, Apolipoprotein A1 was the second-best performing protein in terms of the AUC value (0.91) in distinguishing BC from UC.

After adjusting for demographics, this protein ranked within a 5-marker panel for distinguishing BC from UC. Similarly, Apolipoprotein L1 also ranked within the 5-marker panel for distinguishing BC from UC and MIBC from NMIBC.

Calgranulin B (S100A9) is a zinc- and calcium-binding protein that plays a prominent role in regulating inflammatory and immune responses. Several S100 proteins, including S100A9, have received attention regarding their possible role in tumor development and progression and studies report an increased expression in a variety of tumors, including ovarian, colon, gastric, and prostate cancer [37]. Increased expression of S100A9 protein in the serum has been previously associated with tumor grade [37]. Current validation results of Calgranulin B are promising as it was among the top markers in discriminating BC from UC with an AUC of 0.85.

Complement proteins may promote tumor growth in the context of chronic inflammation [39]. Complement C2s relation to BC at this time is unknown. However, the present study identified this protein as the fourth best single protein for differentiating MIBC from the NMIBC stage. Properdin is also a member of the complement system, controlling the alternate pathway of complement activation. Research on properdin in BC is limited. However, in the current study, properdin demonstrated the third highest AUC value (AUC=0.89, p<0.0001) in discriminating BC from UC. These biomarker findings are consistent with the observation that changes in complement activation constitute one of the major pathways that predict BC disease progression, based on STEM analysis (Fig.3D).

Fibronectin is a glycoprotein component of the extracellular matrix. Tumor cells can attach to fibronectin via integrins or other cell surface receptors [55]. Its effectiveness as a urine biomarker for BC has been explored in a variety of studies [40,41,42,43]. Here, fibronectin showed the third best discriminatory ability in identifying MIBC compared to NMIBC. The marker exhibited an AUC value of 0.87 (p<0.0001).

IL-8 is a proinflammatory CXC chemokine. It has previously been associated with the promotion of neutrophil chemotaxis and degranulation [56]. Increased expression of IL-8 has been associated with endothelial cells, infiltrating neutrophils, tumor-associated macrophages, and cancer cells [56]. Therefore, IL-8 may be a significant regulatory factor within the tumor microenvironment. Previous studies have identified urinary IL-8 as a potential marker for BC [44,45,46,47,48,49]. In the present study, urine IL-8 was the best-performing protein in the MIBC vs NMIBC comparison, with an AUC of 0.99 (p<0.0001), although its specificity was modest at a fixed sensitivity of 80%. Taken together with a wealth of supporting literature, this marker has the potential to be a monitoring tool for BC disease progression and warrants further analysis in this context.

IgA is an immunoglobulin and is often the first line of defense in the resistance against infections, particularly in mucosal tissues. A correlation of intra-tumor IgA1 and poor overall survival in BC patients has been identified in a previous study [50]. However, research regarding IgA in BC urine is limited. The data presented in this study indicated that urinary IgA may differentiate MIBC from NMIBC (AUC=0.89, p<0.0001). Overall, IgA performed 2nd best out of a total of 30 urinary markers validated for this comparison. Of particular note, urine IgA exhibited the highest specificity of 80% for MIBC, at 80% sensitivity, out-performing IL-8.

Matrix metalloproteinases (MMP) are a group of zinc-dependent proteolytic enzymes. Their role involves remodeling of the extracellular matrix. Many studies have evaluated the levels of MMPs in cancer patients and have reported the vital roles of some MMPs as potential diagnostic and prognostic biomarkers in tumorigenesis [57]. The current study has uncovered MMP-1 as the fourth best-performing molecule for distinguishing BC from UC (AUC=0.89, p<0.0001). This protein was also included in a 5-marker panel for distinguishing BC from UC. At the mechanistic level, one can envision tissue matrix remodeling as an important pre-requisite for cancer progression.

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Comprehensive proteomics and platform validation of urinary ... - BMC Medicine

What makes blood stem cells transform? Regulation of RNA splicing … – Science Daily

Researchers at Lund University Faculty of Medicine have determined a novel mechanism linking the metabolism of ribonucleic acids, RNA, to the development of leukemia in myelodysplastic syndrome patients, MDS. In a study published in the Molecular Cell journal, they explain what makes hematopoietic stem cells acquire malignant traits in cancer.

RNA splicing is a major nexus of gene expression regulation, shaping cellular identity during development, frequently altered in human cancers. This process is mediated by a complex molecular machinery known as the spliceosome, which enables the production of multiple and functionally distinct proteins from single genes.

A team of researchers led by Dr. Cristian Bellodi recently discovered a hardwired genetic control mechanism modulating individual spliceosomal components, known as splicing factors, in cells harboring oncogenic lesions common in human cancers.

This work highlighted core splicing proteins, including SF3B1, frequently mutated in various cancers. Splicing factor mutations are particularly prevalent in MDS, a group of heterogeneous hematological disorders characterized by defective blood stem cells and a high risk of leukemia development. "Accumulating evidence is highlighting a role for aberrant splicing in cancer even in the absence of splicing factors mutations. However, little is known about the contribution of the non-mutated splicing factors in tumor evolution," explain the researchers.

The team began by investigating how the levels of non-mutated SF3B1, a core spliceosome component, contribute to the MDS disease. With Prof. Eva Hellstrm-Lindberg's group at the Karolinska Institute, Maciej Ciela and coworkers discovered dynamic regulation of SF3B1 levels during the malignant transformation from MDS to leukemia.

"Strikingly, we found that SF3B1 protein accumulates in MDS patients to ensure genome integrity via splicing regulation. Blocking this mechanism drastically accelerates progression to aggressive leukemia," remarks Maciej Ciela, a postdoctoral fellow in the RNA and Stem Cell Biology group at tLund University Stem Cell Center and first author of the study. Now, a group leader at IMOL, Poland.

The authors further investigated the molecular determinants controlling the SF3B1 production during the transition to leukemia. These studies led to the breakthrough discovery that SF3B1 synthesis depends on a single RNA chemical modification mark, known as N6-methyladenosine, m6A, deposited on its messenger RNA.

"We found that the presence of m6A RNA modification provides a "stop signal" that regulates SF3B1 production, a critical event that impacts accumulation of DNA damage in leukemic cells," explains Maciej Ciela.

"Our results revealing a new critical connection between RNA metabolism and genome integrity in leukemic stem cells, provide important insights into the complex underlying mechanisms fueling cancer development in MDS patients. Our findings are particularly timely, as increasing evidence indicates that RNA modification and splicing alterations represent new therapeutic vulnerabilities for treating hematological and solid cancer patients," concludes Cristian Bellodi, Associate Professor, Division of Molecular Hematology and Lund Stem Cell Center, Lund University.

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UCLA-led study uses base editing to correct mutation that causes … – UCLA Newsroom

Key takeaways

A new UCLA-led study suggests that advanced genome editing technology could be used as a one-time treatment for the rare and deadly genetic disease CD3 delta severe combined immunodeficiency.

The condition, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein that is needed for the normal development of T cells from blood stem cells.

Without T cells, babies born with CD3 delta SCID are unable to fight off infections and, if untreated, often die within the first two years of life. Currently, bone marrow transplant is the only available treatment, but the procedure carries significant risks.

In a study published in Cell, the researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells.

The potential therapy is the result of a collaboration between the laboratories of Dr. Donald Kohn and Dr. Gay Crooks, both members of the Eli and Edythe Broad Center ofRegenerative Medicine and Stem Cell Research at UCLA and senior authors of the study.

UCLA Broad Stem Cell Research Center

Dr. Donald Kohn and Dr. Gay Crooks

Kohns lab has previously developed successful gene therapies for several immune system deficiencies, including other forms of SCID. He and his colleagues turned their attention to CD3 delta SCID at the request of Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Childrens Hospital Research Institute in Canada, who reached out in search of a better treatment option for her patients.

CD3 delta SCID is prevalent in the Mennonite community that migrates between Canada and Mexico. Because newborns are not screened for SCID in Mexico, I often see babies who have been diagnosed late and are returning to Canada quite sick, Wright said.

When Kohn presented Wrights request to his lab, Grace McAuley, then a research associate who joined the lab at the end of her senior year at UCLA, stepped up with a daring idea.

Grace proposed we try base editing, a very new technology my lab had never attempted before, said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, and of pediatrics.

Base editing is an ultraprecise form of genome editing that enables scientists to correct single-letter mutations in DNA. DNA is made up of four chemical bases that are referred to as A, T, C and G; those bases pair together to form the rungs in DNAs double-helix ladder structure.

While other gene editing platforms, like CRISPR-Cas9, cut both strands of the chromosome to make changes to DNA, base editing chemically changes one DNA base letter into another an A to a G, for example leaving the chromosome intact.

I had a very steep learning curve in the beginning, when base editing just wasnt working, said McAuley, who is now pursuing an M.D.-Ph.D. at UC San Diego and is the studys co-first author. But I kept pushing forward. My goal was help get this therapy to the clinic as fast as was safely possible.

McAuley reached out to the Broad Institutes David Liu,the inventor of base editing, for advice on how to evaluate the techniques safety for thisparticular use. Eventually, McAuley identified a base editor that was highly efficient at correcting the disease-causing genetic mutation.

UCLA Broad Stem Cell Research Center

Dr. Gloria Yiu and Grace McAuley

Because the disease is extremely rare, obtaining patient stem cells for the UCLA study was a significant challenge. The project got a boost when Wright provided the researchers with blood stem cells donated by a CD3 delta SCID patient who was undergoing a bone marrow transplant.

The base editor corrected an average of almost 71% of the patients stem cells across three laboratory experiments.

Next, McAuley worked with Dr. Gloria Yiu, a UCLA clinical instructor in rheumatology, to test whether the corrected cells could give rise to T cells. Yiu used artificial thymic organoids,which are stem cell-derived tissue models developed by Crooks lab that mimic the environment of the human thymus the organ where blood stem cells become T cells.

When the corrected blood stem cells were introduced into the artificial thymic organoids, they produced fully functional and mature T cells.

Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients stem cells could fix the defect seen in this disease, said Yiu, who is also a co-first author of the study.

As a final step, McAuley studied the longevity of the corrected stem cells by transplanting them into a mouse. The corrected cells remained four months after transplant, indicating that base editing had corrected the mutation in true, self-renewing blood stem cells. The findings suggest that corrected blood stem cells could persist long-term and produce the T cells patients would need to live healthy lives.

This project was a beautiful picture of team science, with clinical need and scientific expertise aligned, said Crooks, a professor of pathology and laboratory medicine. Every team member played a vital role in making this work successful.

The research team is now working with Wright on how to bring the new approach to a clinical trial for infants with CD3 delta SCID from Canada, Mexico and the U.S.

This research was funded by theJeffrey Modell Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the V Foundation and the A.P. GianniniFoundation.

The therapeutic approach described in this article has been used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The technique is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Kohn and McAuley listed as co-inventors.

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UCLA-led study uses base editing to correct mutation that causes ... - UCLA Newsroom

Chimera research opens new doors to understanding and treating … – Drug Discovery News

When I was in college, my mother needed a heart transplant, said Mary Garry, a cell biologist at the University of Minnesota. Even though she was only in her fifties, Garrys mother was told that she was too old to receive a transplant; there simply were not enough hearts available.

My mother died in 1980, said Garry. The number of donor hearts that are available today is really not much more than the number that was available later on in the 1980s.

The need for organs, especially kidneys, livers, and hearts, far outstrips availability. Today, more than 100,000 people in the United States alone are on the national transplant waiting list (1). Many will die while waiting.

As scientific understanding of stem cells, gene editing, and organism development improved, Garry felt that her career path was clear. When the technologies became available to solve this problem, it seemed very much like the right thing to do.

Today, Garry and her husband Dan, a transplant cardiologist, are pioneers in the field of interspecies chimera research, the study of organisms containing cells from two different species. Their team focuses on using human induced pluripotent stem cells to grow human tissues inside pigs.

Other scientists, including Jun Wu, a stem cell biologist at the University of Texas Southwestern Medical Center, are also studying chimeras with the ultimate goal of one day being able to grow enough human organs to meet the enormous need for transplants, potentially saving hundreds of thousands of lives. Human pluripotent stem cells harbor the potential to provide an inexhaustible supply of donor cells or tissues or organs for transplantation, Wu wrote in an email.

In Greek mythology, the chimera was a fire-breathing monster part goat, part snake, part lion that terrorized the people of Lycia before being slain by the hero Bellerophon. In biology, a chimera is much less monstrous; it is any organism that contains two or more sets of DNA. This can range from the relatively pedestrian, such as a person who received a bone marrow transplant, to creatures that seem more at home in science fiction, such as animals containing cells or tissues belonging to other species.

Lab-created interspecies chimeras are not especially new. Scientists at the ARC Institute of Animal Physiology announced their creation of sheep-goat hybrids known as geeps in 1984 (2). Early chimera research was difficult and inexact. Scientists painstakingly removed tissue from one embryo and grafted it into another embryo (3). However, advances in stem cell research in the 2000s revolutionized the field, opening up new possibilities and new applications for multispecies organism research.

In 2007, a team at Kyoto University created pluripotent stem cells from adult human somatic cells (4). Researchers began to dream of a future in which a patients own cells, perhaps from the blood or the skin, could be converted into these induced pluripotent stem cells and grown into whatever organ the patient needed. Not only would this provide an adequate supply of organs, but it would also eliminate the need for patients to take potentially dangerous immunosuppressant drugs; since the new organs would be made from their own cells, they wouldnt have to worry about organ rejection.

Jun Wu helped create rat-mouse chimeras like those pictured above. The brown fur was generated from rat cells.

credit: Carlos Pinzon Arteaga, UT Southwestern

Some researchers are attempting to use stem cells to bioengineer human organs in the lab in vitro, rather than inside another species (5). While Garry readily acknowledges the importance of multiple approaches, she said that there are important advantages to growing organs in developing animals rather than in vitro.

We think that the developmental cues that exist in the pig will help to guide the human cells inside the porcine embryo. In the in vitro approach, there is a physical scaffold that exists, but the biological cues like the growth factors or the sheer force of blood flow or other things of that nature that are present in the living organism are missing, she said. Scientists may not yet know enough to accurately mimic all of the developmental cues that instruct the cells to become a specific organ. Nature knows more than we do because we can't reinvent all those things in vitro, said Garry.

One method for growing an organ from one animal inside of a different species is blastocyst complementation. Researchers knock out a gene that drives the development of a specific organ in the host blastocyst and implant pluripotent stem cells from a donor species.

Early studies demonstrated that this technique worked, at least in some closely related species. In 2010, stem cell biologist Hiromitsu Nakauchi and his team at the University of Tokyo deleted a gene that drives pancreas formation in mouse embryos and injected rat pluripotent stem cells to fill the empty niche. The resulting mice were born with functional pancreases made of mostly rat cells (6).

Since then, Nakauchi and others have created chimeric organisms with replacement livers, lungs, and kidneys (79). Despite these successes in rodent models, translating these findings to human organs is proving to be much more challenging.

How closely animals are related seems to be an important factor in determining how easily an interspecies chimera can be created. In this sense, it might be easiest to grow human organs in closely related nonhuman primates. However, many scientists believe that logistically, pigs are the most suitable species for large-scale production of human organs: Pigs mature quickly, have large litters, and their physiologies are similar to humans in many ways (10). At 90 to 200 pounds, a miniature pigs body size is more similar to a humans than a typical research monkeys; male rhesus macaques are only about 17 pounds on average, which could present difficulties when trying to grow human-sized organs (11).

Even though pigs are optimal for growing human organs in some respects, their evolutionary distance from humans creates some difficulties. During his postdoctoral research at the Salk Institute for Biological Studies, Wu explored strategies for making human stem cells more suitable for this task.

Jun Wu studies the barriers to interspecies chimerism.

credit: UT Southwestern

By coaxing human pluripotent stem cells into an intermediate form, somewhere in between a nave stem cell and a primed stem cell, Wu, along with other researchers at the Salk Institute, produced the first human-pig chimeric embryos in 2017 (12). Although this was a major step forward, it was a far cry from pigs with fully human organs. Researchers estimated that the embryos contained about one human cell for every 100,000 pig cells (12,13).

Deleting pig genes that drive development of specific organs, as Nakauchi did in mice and rats, can help more human stem cells grow in pig embryos, but its still not enough to produce a fully human organ or tissue type. The Garrys knew that the human cells needed an extra boost, so they used human cells that overexpressed BCL2, an antiapoptotic factor. By combining these boosted human cells with pig blastocysts that lacked the master regulator gene ETV2, the Garrys successfully produced a pig embryo with a fully human endothelium, the tissue that lines the vascular system, including the heart and blood vessels (14).

While endothelium transplants arent feasible, Garry said that this is still an important step forward. In other models, the kidney or pancreas may be made of cells from another species, but the endothelium was still made of host cells, which play a large role in organ rejection by the transplant recipient.

The endothelium is so important that it's possible that just knocking out the vasculature with a single gene deletion ETV2 may be enough to make every porcine organ compatible to transplant into humans. The site of rejection is primarily the endothelium that lines the vasculature, Garry said.

The Garrys also created pig embryos with human skeletal muscle tissue, this time deleting the p53protein in the human cells to boost growth (15). While these studies show that growing human tissues in pigs is possible, these growth-boosting strategies arent necessarily appropriate for creating organs for transplant into humans, as both genetic alterations also come with an increased risk of cancer growth.

Garrys team is currently working on understanding the relationship between the human stem cells and the pig cells of the host embryo, which may lead to strategies to increase the growth of the human cells that are more suitable for organs destined for transplantation.

We think that the efficiency of the chimerism really comes down to immunological barriers, she said. So, were working with various other groups that are really experts in immunobiology, including David Sachs group at Columbia University, who are helping us to understand all these factors that present hurdles for advancement.

Garry estimated that organs grown in pigs could be ready for trials in humans in as little as five years.

Other researchers are exploring alternative strategies to increase efficiency even in evolutionarily distant animals (16,17).

Wu hopes to make progress in this area by exploring differences in chimerism between closely and more distantly related organisms. Comparing differences of human extended pluripotent stem cells in mouse and monkey blastocysts in culture will help us understand species barriers during early development due to genomic evolution and develop better strategies to overcome these barriers to enable more robust contribution of human chimerism in evolutionarily more distant species, e.g. pigs, wrote Wu.

To this end, Wu, along with a team of researchers from the Salk Institute for Biological Studies and the Kunming University of Science and Technology, created the first human-monkey chimeric embryos in 2021 (18).

Wu also identified cell competition between animal and human cells during development as an important factor in chimerism failure (19). Cell competition is known to serve as a quality control mechanism to selectively remove unfit cells from a developing embryo. Human pluripotent stem cells are thus treated as unfit cells in a growing animal embryo and are targeted for elimination," wrote Wu.

By investigating the mechanisms underlying this process, Wus team identified ways to help human cells survive in animal embryos. When growing mouse-human embryos, they found upregulation of genes related to the NF-B signaling pathway in the human cells. This pathway controls many different cellular functions, including response to stress and apoptosis, a type of cell death. By genetically altering this pathway, the researchers improved the survival of human cells in the mouse embryos (19).

Jian Feng develops mouse-human chimeric embryos, like the above mouse embryo at embryonic day 17, with human cells labeled with green fluorescent protein.

credit: Zhixing Hu

Jian Feng, a stem cell researcher at the University at Buffalo, is developing another technique to encourage human cells to grow in mouse embryos. Unlike Garry and Wu, Fengs goal is not to grow human organs, but to improve our understanding of neurodegenerative disease.

Feng was originally trained as a molecular biologist, but early on, he became interested in studying Parkinsons disease, especially the early-onset form of the disease caused by a mutation in the PRKN gene. I felt that I could use the full power of molecular biology to study a complex human disease, he said.

Feng soon encountered the difficulties of studying human diseases in mice. When he knocked out the PRKN gene in the mice, they didnt seem affected at all. So, when he read about the creation of mouse induced pluripotent stem cells, followed shortly by the generation of the human versions in the 2000s, he knew immediately that he wanted to use these human cells to study this human disease.

Studying the cells in culture wasnt necessarily the answer though. If we want to study human CNS problems, we have to have a circuit, said Feng. Furthermore, the dopaminergic neurons of the substantia nigra, which degenerate in Parkinsons disease, cant be easily re-created in a dish. These are very unique cells. They have extremely complicated axon arborization, said Feng. We needed to find a surrogate that could allow us to make these cells in vivo.

Like other researchers, Feng has been working on strategies to improve the efficiency of human-animal chimerism. By temporarily inhibiting the signaling protein mTOR, Feng converted human pluripotent stem cells into a form that displayed improved growth when transplanted into mouse embryos; after 17 days, some of the mouse embryos had as many as four percent human cells (16).

Jian Feng studies mouse-human chimeric embryos with the goal of building better models of Parkinsons disease.

credit: Sandra Kicman

Eventually, Feng wants to use chimera technology to create better models of Parkinsons disease, such as mice with human dopaminergic neurons in the substantia nigra. However, he noted that there are still many technical issues to overcome.

While creating rodents with human brain cells is a daunting task, it isnt completely without precedent. In 2017, a group at the University of Rochester created chimeric mice with glial cells, the non-neuronal cells of the central nervous system, frominduced pluripotent stem cells derived from human patients with schizophrenia (19). The glial cells developed abnormally, and the mice displayed anxiety, impaired social behavior, and disrupted sleep patterns, suggesting that glial cells likely play a role in the development of schizophrenia, and that these mice could be used as improved models for developing new therapies.

More recently in the fall of 2022, researchers at Stanford University transplanted a human stem cell derived cortical organoid into the brain of a newborn rat (20). The human neurons integrated into the rat brain; activating them sufficiently provoked certain behaviors.

While researchers still have lots of work ahead of them, they hope that one day their efforts will provide organs for transplants and a deeper understanding of neuropsychiatric diseases, saving lives and alleviating suffering around the world.

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Chimera research opens new doors to understanding and treating ... - Drug Discovery News

Grandmother on mission to find bone marrow match for grandson … – KSTP

A Minnesota grandmother is traveling hundreds of miles across two states in the hopes of finding a bone marrow donor for her grandson.

Ari Chambers-Baltz, 22 months old, is diagnosed with hyper IgM, a rare immune disorder.

One out of a million boys get this. All will pass away by the age of 30 if they dont get a transplant, said Sharon Chambers, Aris grandmother.

Chambers said so far, there is no perfect match for Ari through Be the Match, the national marrow registry.

Thirty-nine million people, and theres no match for Ari yet, Chambers said. But it just takes one. Im looking for that one person out there.

The family is now hosting sign-up drives at malls, churches and colleges across Minnesota and Wisconsin.

5 EYEWITNESS NEWS was there as dozens of college students stepped up to swab their cheeks Friday at Bethel University, which is Aris parents alma mater.

Its just an easy thing that means nothing to me but can mean a lot to somebody else, said Aiden St. George, who signed up for the registry during Fridays drive.

Ari and his parents currently live in Illinois, although much of their family is in Minnesota.

If Ari finds a match, his stem cell transplant will take place at M Health Fairview Masonic Childrens Hospital in Minneapolis.

His doctor told 5 EYEWITNESS NEWS a transplant would represent a cure for Ari, and he would likely go on to lead a full, healthy life.

Masonic Childrens Hospital has already done five stem cell transplants for kids with hyper IgM and all have been successful.

If there is a match, 90% of the time, we would collect stem cells through your blood, similar to donating plasma. It takes about four to six hours to donate. In 10% of cases, we take the marrow out of your hip bone, which is a surgical procedure, said Keesha Mason, account manager for Be the Match.

Mason said 500 people have stepped up to join the registry after hearing Aris story.

All those people that have registered for Ari, the masses of people, they might not be a match for Ari, but they could be a match for someone along the road, Mason said. Theres something about believing in miracles and being a part of something bigger than you know.

Aris family hopes his match is out there.

We know we need help, and were not afraid to ask because it is a life-and-death situation, Chambers said. Were choosing to hope. And we need Minnesota and Wisconsin to help us the rest of the way.

If you would like to join the Be the Match Registry on behalf of Ari, text AriMN to 61474.

There are in-person sign-up drives happening on these days as well:

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Grandmother on mission to find bone marrow match for grandson ... - KSTP

Doctors: Live or cadaver donors can now save the life of a Rockton … – Rockford Register Star

Five years after being diagnosed with a rare autoimmune disease and told he would need a triple transplant to survive; Rockton resident Joe Beard has some positive news to share.

Beard, 42, a husband and father of two young daughters, suffers from STAT3 gain of function, a multiorgan autoimmune disease that is actually attacking his own body.

He is on home dialysis and is in need of a liver, kidney and bone marrow transplant.

More:'This is going to kill me': Rockton man with rare genetic disorder in need of 2 live donors

Outside of a recent stint in the hospital to stop internal bleeding in his abdomen, not much has changed physically in the past year for Beard. But emotionally? His spirits are as high as ever.

Earlier this year, Beard learned that Dr. Andres Duarte, a liver specialist at the University of Pittsburgh Medical Center who was working on Beard's case, is now based in Chicago serving as director of the Northwestern Medicine Organ Transplantation Center.

Having Duarte located in Chicago is significant for several reasons:

Beard and his wife, Hayley, have already met with Duarte and other doctors in Chicago.

"The head guy was almost giddy with excitement," Beard said. "I mean it was just like, 'Wow! Maybe this is God's plan. Meet Dr. Duarte and then two years later, follow him out here to Chicago.'"

At the time of Beard's diagnosis in 2018 there were only 28 known cases of STAT3 gain of function.

Hayley, Beard's wife of nine years, has already agreed to donate up to 60% of her liver, the only organ in the human body capable of re-growing.Liver regeneration after donation takes six to eight weeks.

What is still needed is a kidney donor. If the kidney comes from a live donor, that person also will likely be asked to be the bone marrow donor, too.

"So,right now, the plan is to proceed with my care at Northwestern," Beard said, "and we're just asking people to sign up to be a donor for a kidney or stem cell and to share the story."

To register to be a donor, you can do so at nmlivingdonor.org.

To help the family with travel and expenses, donations can be sent to:

Roscoe United Methodist Church, C/O Joseph Beard Transplant Fund, 10816 Main St., Roscoe, Illinois, 61073

Chris Green: 815-987-1241; cgreen@rrstar.com; @chrisfgreen

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Doctors: Live or cadaver donors can now save the life of a Rockton ... - Rockford Register Star

What Is Hyperbaric Oxygen Therapy (HBOT)? Forbes Health – Forbes

The use of hyperbaric medical therapy can be traced back to the late 1600s in Britain, but HBOT was not used widely until after World War II, when it was utilized to treat decompression sickness in divers. Since that time, scientific research into the methods and uses of HBOT has been ongoing, with hundreds of facilities providing this therapy since the early 2000s.

Fundamentally, HBOT [delivers] oxygen at greater concentrations than those naturally available in the atmosphere, explains Ahmet Ergin, M.D., an endocrinologist at Heart & Family Health Institute in Florida. Increasing the atmospheric pressure during an HBOT treatment session allows more oxygen to dissolve into the bloodstream, enabling the healing and regeneration of damaged or injured tissues, according to Ergin.

Through this process, HBOT not only increases oxygen concentration, but also reduces inflammation, speeds recovery time and lessens pain, according to Dr. Ergin.

During hyperbaric oxygen therapy, a patient breathes 100% oxygen intermittently while the whole body is pressurized within a hyperbaric chamber to at least 1.4 atmospheres absolute (ATA), explains Dr. Renie Guilliod, a rehabilitation specialist at UT Southwestern Medical Center in Texas and director of the Hyperbaric Medicine Program at the Institute for Exercise and Environmental Medicine. ATA is a unit of measurement used to describe the sum of barometric (air) and hydrostatic (fluid) pressures used in hyperbaric oxygen therapy.

With HBOT, we deliver higher amounts of oxygen to the body by increasing the driving pressure of O2 from the lungs through the blood to the tissues, says Dr. Guilliod.

This oxygen delivery results in intermittent hyperoxygenation, which means ones oxygen levels in the blood are higher for a short period. The increase in blood oxygen levels has been demonstrated to promote the healing of injured tissues and can be used for several conditions.

HBOT is part of the Undersea and Hyperbaric Medicine Society (UHMS). The American Board of Medical Specialties recognizes it under the umbrella of the American Board of Preventive Medicine (ABPM) and the American Board of Emergency Medicine (ABEM).

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What Is Hyperbaric Oxygen Therapy (HBOT)? Forbes Health - Forbes

Moorfields Eye Hospital surgeon saves the vision and the career … – Ophthalmology Times

(Image Credit: AdobeStock/Fukume)

A Moorfields Eye Hospital ophthalmologist has performed a life-changing surgery on a 23-year-old patient after diagnosing him with a progressive eye disease that is prevalent in Middle Eastern communities.

Mogemad Osama, an Ajman University student from Palestine who plans to become a dentist, struggled for years with devastating vision loss which caused him to change his prescription glasses multiple times. After deciding that he needed to seek help, Osama was referred to Esmaeil Arbabi, MD, at MoorfieldsEye Hospital, a Mubadala Health partner.

According to a Moorfields Eye Hospital news release, Osama feared he would not be able to realize his dream of practicing dentistry.

My career depends on two things: my eyes and my hands, he said in the news release. When I first started having problems with my vision, it was a huge disappointment for me. But I never give up.

Osama was soon diagnosed with keratoconus, which affects the structure of the cornea and gradually causes blurred vision that cannot be corrected with glasses. The eye hospital noted in the news release a recent study found while the disease affects only one in 2,000 people worldwide, the prevalence of the disease in the United Arab Emirates (UAE) is 2.7 percent, which is 54 percent higher than the global average, according to the hospitals news release. The condition also impacts both men and women and typically stabilizes by the time people reach their 30s, although by then serious damage could have been caused.

Mogemad Osama and Esmaeil Arbabi, MD. (Image courtesy of Moorfields Eye Hospital)

According to Arbabi, who has treated a number of cases of keratoconus, the cause of the disease is unknown, but genetics and environmental factors could play a role. Osamas father had surgery several years ago for the same condition.

Instead of opting for a corneal transplant, Arbabi performed cross-linking, combined with a sophisticated laser treatment on Osamas left eye. The advanced laser reshapes the cornea and smoothens the irregularities caused by keratoconus. This will then be immediately followed by the application of Vitamin B eyedrops and shining of an ultraviolet light on the eye. The procedure only takes just 15 minutes to complete and has a 95 percent chance in stopping the progression of the disease.

Early diagnosis and early treatment are absolutely essential, Arbabi in the news release. If we catch this early enough, we can treat it so that its like nothing has happened at all. But if you delay, theres a risk of a lifetime wearing hard, rigid contact lenses, or ultimately requiring a corneal transplant. It could lead to a poor quality of life for the rest of your life.

Before the procedure I was experiencing double vision; it wasnt clear at all, said Osama. But 10 days after, everything in my left eye was back to normal. I even returned to university and started to work again. It would be fair to say that my career has been saved by Dr. Arbabi and the great staff at Moorfields.

The disease will be the focus of the 1st Annual International Keratoconus Academy (IKA) of Eye Care Professionals Keratoconus Symposium will take place April 22-23, 2023, at the Scottsdale Marriott at McDowell Mountains in Scottsdale, Arizona.

This new hybrid, interactive conference for optometrists, ophthalmologists, and other eye care professionals involved in keratoconus management will promote ongoing professional education and scientific development in keratoconus and other forms of corneal ectasia. The topics covered will include using new diagnostic technologies, maximizing keratoconus management in clinical practice, and amplifying clinician voices on keratoconus best practices.

The co-chairs of the event are IKA CEO and cofounder S. Barry Eiden, OD, FAAO, FSLS, North Suburban Vision Consultants, Deerfield, Illinois; IKA president and cofounder Andrew S. Morgenstern, OD, FAAO, FNAP, Walter Reed National Military Medical Center, Bethesda, Maryland; and IKA executive board member Elizabeth Yeu, MD, Virginia Eye Consultants, Norfolk.

The 1st annual IKA Keratoconus Symposium will be [a gathering] of some of the greatest minds in the field of keratoconus who will share their extensive knowledge and experience regarding the most current information available and their visions toward the future,Eiden commented.

Registration is free for students, residents, fellows, active duty service members, and veterans.

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Moorfields Eye Hospital surgeon saves the vision and the career ... - Ophthalmology Times

Clinical Commentary: Addressing Treatment Tactics in Blastic … – Targeted Oncology

Gary J. Schiller, MD

Director, Bone Marrow/Stem Cell Transplantation

Professor, Hematology-Oncology

David Geffen School of Medicine at UCLA

Los Angeles, CA

I have a lot of patients in my clinic with [BPDCN], but in general, it is a rare disease [that clinicians] may not see for many years in their practice. Its true epidemiology is not known because [clinicians] didnt know how to identify it, so it is historically rare. To make it even more difficult, there was a change in nomenclature by the [World Health Organization] back in 2016.1 A lot of older practitionersand Im one of those older practitionerswould call this [disease] some sort of lymphoid leukemia with cutaneous manifestations.

There is a lot of difficulty in recognizing this disease clinically and pathologically, and its more recent that [the targets of] CD4, CD56, and CD123 expression [were] all identified as pathognomonic.2 Right now, we think this constitutes less than half a percent of all hematologic malignancies and less than a percent of [patients with] cutaneous lymphoma.

We believe there are [approximately] 4 cases per 10 million population, so that gives you an idea of rarity, but I think that we dont know because we havent had a strong diagnostic bed of criteria until [approximately] 2016. Weve been doing this for [approximately] 5 or 6 years, and knowledge will increase when weve gone past a decade with homogeneous diagnostic criteria.

How BPDCN Presents

[This disease] is characterized by production of clonal plasmacytoid dendritic cells. These cells are characteristic with their expression pattern and are a little more common in the older population, even [for patients older than] 70 years.3

Many of the patients are older men, but not exclusively, as Im taking care of a young [woman] right now [who is] in her 30s, so this epidemiology is also bound to change if they have an antecedent hematologic disorder that is rare.

The primary sits of involvement are skin, bone marrow, peripheral blood, lymph nodes, leptomeninges, and extramedullary sites such as in the muscle behind the retroperitoneum also occur. Early recognition is challenging, as the clinical features are also challenging and can overlap with other diseases, and there are delays between the onset of the skin rash and the diagnosis.

[Those] who see this in the field are internists, dermatologists, and hematologists and oncologists after a while, [and they can miss] this diagnosis unfortunately. The typical journey for a patient with this condition is that they start having continuous lesions and are then examined by a primary care physician for a while, and they may or may not be identified as having something that requires immediate biopsy evaluation. When the patient develops pancytopenia, thats when the referral occurs, and the median time to final diagnosis is often 6 months.

However, this disease is highly aggressive when its not treated with specific agents, and the survival is 6 to 18 months.4 [Clinicians] have tried all kinds of treatments, such as vincristine, steroids, treating it like its acute lymphocytic leukemia, or treating it now like one would acute myeloid leukemiawith venetoclax [Venclexta] and azacitidine [Onureg]. But without specific therapy, the survival is short.

Cutaneous Features of BPDCN

The cutaneous features vary a little, but most patients present with some nodule that is described as dark purple, brown, or [bruised]. Sometimes they can have plaques, but I view them as basically little hemorrhages that are in the form of nodules or plaques that are often disseminated, typically sparing the dermis.

Skin biopsies that include the deep dermis and subcutaneous fat are very important to making a diagnosis, but as I say, usually the disease involves the peripheral blood and bone marrow, so there are easier ways to make a diagnosis than taking a deep tissue biopsy.4

Some of our patients do have localized manifestations and a localized geography. The other differential diagnoses include extramedullary hematopoiesis and some malignant neoplasms. This disease can spread broadly like a leukemia, and its not unusual for patients to have splenomegaly. What Im dealing with right now with a patient of mine is leptomeningeal involvement with cranial neuropathy. That is not a rare thing, [its a] typical kind of leptomeningeal leukemia in that patients have cranial nerve findings at the base of the brain.5

Other sites of the disease include sinus, tongue, breast tissue, gallbladder, [and] muscle, so this disease can spread broadly. Initial evaluationof course, besides the usual history, physical, and blood countwould be an assessment of the skin lesions in terms of how disparate they are and [whether] there are any hints of blood involvement, cytopenias, leukocytosis with blasts, or bone marrow aspirate biopsy, because it would be the easiest way to make a diagnosis.

Evaluations of BPDCN

The molecular analysis by sequencing frequently identifies mutations in the typical older personkind of clonal hematopoiesis ASXL1 but also U2AF1 [and] things like TP53 [are] quite adverse, as well as occasionally IDH or IKZF1.

A PET CT is a good idea if [the clinician] suspects there is extensive extramedullary disease or adenopathy [theyd] like to follow. [There is also a recommendation for] diagnostic lumbar puncture at the time of diagnosis, but we typically do it at the time of relapse.

The [National Comprehensive Cancer Networks] set of guidelines for the evaluation and workup drives home the characteristic findings on histopathology, immunohistochemistry, and flow cytometry.6 Of course, if [someone is] in a center where this disease is uncommon, its certainly worthwhile to speak to [clinicians] who have experience with it and have participated in some of the trials or used the licensed medication.

In the peripheral blood, these cells look a little [like] lymphoid. Its common to find peripheral blood involvement in this disease, although maybe not quite in the leukemic phase. As Ive described before, these blasts are large, nuclear chromatin is open, nuclei are typically present, and the cytoplasm is not granular, so it doesnt look like myeloid leukemia. [However], monocytic leukemia can look similar and typically doesnt have much in the way of granulesand there are no vacuoles, so its not like Burkitt lymphoma.

There is no particular characteristic of a cytogenetic abnormality in BPDCN, but there are abnormalities [such as] deletions of the monosomy 5 and 6 or 13 and 15. The molecular abnormalities are also varied, and findings in a common older patient [can include] TET2 and ASXL1. But TP53, the adverse finding, is also common, as well as occasionally NPM1.

CD123 is a perfect marker because its present in over 95% of patients cells in the malignant neoplasm, and it is not so heavily expressed on healthy cells.7 This also has constituted a target for therapy because of the relative distribution of that marker on neoplastic cells, but there arent typical T-cell or B-cell markers.8

Treatment Paradigm in BPDCN

Tagraxofusp [Elzonris] is a typical immunotoxin and a CD123-directed antibody. That CD123 is the IL-3 alpha receptor, and attached to it is a payload of truncated diphtheria toxin, which is delivered into the cell that has this receptor. Its a first-in-class CD123-targeted immunotherapeutic and is FDA approved for [the] treatment of [patients with] BPDCN.9

Patients who have impaired performance status can get other treatments like localized treatment [such as] radiation or venetoclax-based therapy. Somebody who is protein malnourished would not be a candidate for tagraxofusp because this drug causes capillary leak, so there is a warning in the label, and patients with serum albumin less than 3.2 g/dL are not eligible for treatment. [However], on that treatment with steroids, they can get their albumin to improve by improving their performance status [and] increasing their appetite and food intake.

[The approval for the therapy came from the] multicenter, 4-stage, single arm, phase 1/2 trial [NCT02113982] evaluating this drug as monotherapy in patients with first-line or relapsed/refractory BPDCN, administered via intravenous infusion daily from day 1 through 5 for a 21-day cycle.10

The key eligibility criteria for the trial included albumin greater than or equal to 3.2 g/dL, age greater than or equal to 18 [years], a reasonably good performance status of less than or equal to 2, and adequate organ function. The primary end point was a combined rate of complete remission [CR] and CR with residual skin abnormality [CRc] in first-line patients.

The secondary end point was the duration or response [of treatment] and CR with residual skin abnormality not indicative of active disease. Some of these patients will have resolution of the nodule, but pigmentation that might remain, which didnt exclude them from being complete remitters.

Twenty-nine patients were previously untreated in the first line, the overall response rate [ORR] was 90% in stages 1 to 3, and the CR and CRc rate was 72%. Of those previously treated, many had more than 1 line of therapy, [with] some even having more than 4 lines of therapy.

Overall, the ORR was 75%, and many of these patients went on to stem cell transplant, but the impact of the drug on survival is harder to assess when you use allogeneic stem cell transplant as a consolidated maneuver.

[However], the overall likelihood of remaining in remission at 2 years was [approximately] 50% of those who went into remission. The median duration of CR and CRc was less than 3 years, and the median overall survival for all patients [was 8.2 months (95% CI, 4.1-11.9)].

Adverse Events With Tagraxofusp

The adverse event [AE] profile is important [with this therapy], and AEs occurring in at least 20% of patients included transaminase elevations [64%], peripheral edema [42%], weight increase [35%], hypokalemia [20%], and hypocalcemia [20%].

AEs that led to discontinuation were predominantly the capillary leak syndrome type, an increase in weight, and a decrease in albumin. [However], AST [aspartate aminotransferase] and ALT [alanine aminotransferase] increase also led to discontinuations.

Fortunately, discontinuations were not common on the trial, with only 6 of 89 [patients]. Again, however, to point out for those who had at least 1 grade greater than or equal to grade 3, treatment-emergent AEs were identified in 75 of 89 patients, with the most common grade 3 or great AEs [being] thrombocytopenia and [fewer] AST and ALT increases.

The overall incidence of capillary leak syndrome was high, over 50%. Most were grade 1 to 2 and resolved but some were not, including 2 fatal events, so you need to watch this. The first cycle must be given in the hospital. Common signs and symptoms include hypoalbuminemia, edema, weight gain, and hypotension.

Before initiating therapy, make sure the patient has adequate cardiac function and that the serum albumin is over 3.2 g/dL. During treatment, ensure that serum albumin levels stay above 3.5 g/dL and have not dropped by more than half an albumin level prior to initiation of each dose. Assess for signs and symptoms of capillary leaks, such as weight gain, new onset or worsening edema, pulmonary edema, hypotension, [and] hemodynamic instability. Seek medical advice if you see any of these things.

REFERENCES

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544

Deconinck E, Petrella T, Garnache Ottou F. Blastic plasmacytoid dendritic cell neoplasm: clinical presentation and diagnosis. Hematol Oncol Clin North Am. 2020;34(3):491-500. doi:10.1016/j.hoc.2020.01.010

Pemmaraju N. Blastic plasmacytoid dendritic cell neoplasm. Clin Adv Hematol Oncol. 2016;14(4):220-222.

Julia F, Petrella T, Beylot-Barry M, et al. Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients. Br J Dermatol. 2013;169(3):579-586. doi:10.1111/bjd.12412

Pemmaraju N, Wilson NR, Khoury JD, et al. Central nervous system involvement in blastic plasmacytoid dendritic cell neoplasm. Blood. 2021;138(15):1373-1377. doi:10.1182/blood.2021011817

NCCN. Clinical Practice Guidelines in Oncology. Blastic plasmacytoid dendritic cell neoplasm, version 2.2022. Accessed February 22, 2023. https:// bit.ly/3ZgDzbM

Molina Castro D, Perilla Surez O, Cuervo-Sierra J, Moreno A. Blastic plasmacytoid dendritic cell neoplasm with central nervous system involvement: a case report. Cureus. 2022;14(4):e23888. doi:10.7759/cureus.23888

Pemmaraju N, Lane AA, Sweet KL, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm. N Engl J Med. 2019;380(17):1628-1637. doi:10.1056/ NEJMoa1815105

FDA approves tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. FDA. December 26, 2018. Accessed February 22, 2023. https:// bit.ly/3YWJ5Rb

Pemmaraju N, Sweet KL, Stein AS, et al. Long-term benefits of tagraxofusp for patients with blastic plasmacytoid dendritic cell neoplasm. J Clin Oncol. 2022;40(26):3032-3036. doi:10.1200/JCO.22.00034

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Clinical Commentary: Addressing Treatment Tactics in Blastic ... - Targeted Oncology

Expert Tips on Alopecia Management From AAD 2023 – Dermatology Times

Scarring alopecia, stem cells, exosomes, and frontal fibrosing alopecia (FFA) were all hot topics of discussion during Ronda Farahs, MD,FAAD, multiple alopecia sessions at the 2023 American Academy of Dermatology (AAD) Annual Meeting in New Orleans, Louisiana.

Farah, associate professor of dermatology at the University of Minnesota, cosmetic lead at the University of Minnesota Health clinics, and director of medical dermatology at the University of Minnesota Health Maple Grove Medical Center, discussed alopecia in-depth at her AAD sessions: Cosmetic and Procedural Interventions for Scarring Alopecia, Stem Cells & Exosomes, and Cosmetics and FFA: Approach to Managing Facial Papules and Hyperpigmentation.

Transcript

Ronda Farah, MD, FAAD: Hi, I'm Dr. Ronda Farah. I'm a dermatologist at the University of Minnesota, associate professor. I'm also the University of Minnesota Health cosmetic lead and I'm the director of the Maple Grove Medical Center. I'm also working with the American Academy of Dermatology on social media.

Dermatology Times: What pearls did you share in your session, "Cosmetics and FAA: Approach to Managing Facial Papules and Hyperpigmentation?"

Farah: The cosmetics and frontal fibrosing alopecia talk is really focused for me on the forehead area. In the frontal fibrosing alopecia patient population, I try to keep the skin product away from the hair follicle as much as possible. I ask my patients not to apply that product directly on the hair follicle. Try to also keep sunscreens away unless they're non nanoparticle-based sunscreens, although we don't really know what the final verdict is going to be on sunscreens and I'm also leaning towards more physical-based sunscreens. And in addition to that, talking a little bit about the veins, the new article that came out in the JAAD and the utilization of this device on the forehead veins, which can become very prominent in frontal fibrosing alopecia and I think gently putting those out at the initial visit so that patients are aware those are typically there before they even start steroid injections. I am still utilizing some botulinumtoxin in frontal fibrosing alopecia. I do think that botulinumtoxin has been reported to cause depressions in the scalp so counseling patients on that, because knowing they can also have depressions from their scalp from frontal fibrosing alopecia is important. Also to limit that change in skin texture from the scalp at the front to lower down, I really work on removing seborrheic keratosis and sebaceous hyperplasia using topical tretinoin and oral isotretinoin, although that does have limited data to kind of help with that the facial papule appearance. Those are some of my big pearls for that talk.

Dermatology Times: What are the important takeaways from your session, "Cosmetic and Procedural Interventions for Scarring Alopecia?"

Farah: That session was great. We focused on scarring alopecia, we talked about using platelet rich plasma off-label which could be helpful, as there are case series and case reports. We talked a little bit about exosomes, which do not have strong medical evidence and will be marketed to you, including scalp serums. Lacking medical evidence, only one clinical study, I was able to identify to date that included a microneedle really muddying the waters, not FDA approved for injection, we are not using it. And then we also talked a little bit about photobiomodulation. That's off-label for darker skin types, but could be helpful in that population in our study.

Dermatology Times: What do you hope fellow physicians take away from your session, "Stem Cells & Exosomes?"

Farah: I'm passionate about exosomes because we performed a literature review. Two of the papers involved a human subject: one was just an abstract, the other one utilized a microneedle. That made it difficult in the second one to figure out if it was actually the microneedle or if it was the exosomes. All the other studies were pretty clinical. They were all in mice. They were promising, but they don't reach our level of evidence for evidence-based medicine. Exosomes are not FDA-approved to inject in the United States. There are reports of bacteremia, inflammation, blindness, neurologic issues, contamination with viruses, and concern for hepatitis C and HIV. People wonder if you can use exosomes topically, I wondered that too. From what I can make from my understanding, And again, I'm not a lawyer, but of these exposome products, they can be human. And if they're topical, they might get marketed to physicians and other clinicians as "Oh, well, it's topical, so you can use it." Well, maybe that is true. That seems like that might be true. Again, I'm not a lawyer, but those seem to not necessarily be regulated by the FDA. So, we're applying human product that's not necessarily regulated by the FDA. So, who's responsible for the product then? And from what I can understand, it appears to be the manufacturer. And so, if the manufacturer is not handling the human product correctly, or the manufacturer is outside the United States, that can make it difficult for a US patient. So, at this time, I do not recommend topical or injectable exosomes to my patients. I think it's a lot of items on the topical side that probably need some work, and my job is to discuss higher levels of medical evidence, although they do seem promising. We're working towards a study once we eventually have an investigational new drug application. So, I think exosomes could be exciting. But they're not something I would promote for hair growth. And you should also be aware as clinicians that the CDC has posted a "how-to" for patients on how to spot doctors or other types of clinicians who are telling you that they're doing a study on you with exosomes. So that is out there teaching the patient how to identify people who might be. And I'm not saying that this is happening. I just saw that the CDC had spent time developing that page. I'm not clear enough if that's happening. So, for me, it's about evidence-based medicine, and that's why I'm passionate about the exosomes topic.

[Transcript edited for clarity]

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Expert Tips on Alopecia Management From AAD 2023 - Dermatology Times