Stem Cell Clinic

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

By Stem Cell Medical Center

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

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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

By Stem Cell Medical Center

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

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

By Stem Cell Medical Center

(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

Safety and efficacy of co-administration of CD19 and CD22 CAR-T … – Journal of Translational Medicine

By Stem Cell Medical Center

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Safety and efficacy of co-administration of CD19 and CD22 CAR-T ... - Journal of Translational Medicine

NKY community helping raise money for mother and teacher in need of lifesaving surgery – WKRC TV Cincinnati

By Stem Cell Medical Center

NKY community helping raise money for mother and teacher in need of lifesaving surgery

NKY community helping raise money for mother and teacher in need of lifesaving surgery (Lindsey Hughes)

FORT MITCHELL, Ky. (WKRC) - A Northern Kentucky mother and teacher needs help covering the cost of a highly-expensive, but lifesaving medical procedure.

NKY community helping raise money for mother and teacher in need of lifesaving surgery (WKRC, Lindsey Hughes)

A fundraiser was held Sunday afternoon at The Braxton Barrel House for Lindsey Hughes. She's battlingsystemic scleroderma, a rare autoimmune disease.

Hughes is a teacher at Beechwood High School, and a new mother.

NKY community helping raise money for mother and teacher in need of lifesaving surgery (Lindsey Hughes)

In October 2022, after years of suffering, doctors diagnosed her with the disease. It affects her skin and internal organs.

"I went up to the University of Michigan. There's a scleroderma center and the doctors there told me if I want to be able to see my daughter grow up and live a functional life again, I need a stem cell transplant, said Hughes.

Hughes says both the University of Michigan and the Mayo Clinic have approved her for the transplant. She's currently going through pre-transplant testing.

NKY community helping raise money for mother and teacher in need of lifesaving surgery (Lindsey Hughes)

With the price of the procedure starting at $250,000, it's unclear what, if any, help insurance will be.

Thanks to donations and fundraisers, Hughes is getting closer to covering the cost that she hopes will give her future quality time with her family and friends.

"I feel great today. Physically, Im exhausted, but its been so amazing to see friends and family come out to give support, she said.

For more information about Hughes and how you can help, check out the Facebook page about her journey and her GoFundMe campaign.

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NKY community helping raise money for mother and teacher in need of lifesaving surgery - WKRC TV Cincinnati

New Insights on Treating Neurodegeneretive Diseases Could Lead … – MarketScale

By Stem Cell Medical Center

Scientists have been stumped for years on how to awaken stem cells to make new neurons in the human brain; a new study out of the journal Science Advances may have just unlocked critical insight into this neurogenerative puzzle through a roadmap of metabolic pathways. The study, which was conducted on adult and elderly mice, found that a unique gene in their genetically-mutated mice activated dormant neural stem cells, in effect generating new neurons in the brain. This discovery to awaken stem cells may lead to new clinical trials for treating people with neurodegenerative diseases, including an estimated 6.5 million Americans ages 65 and older who are living with Alzheimers in 2022.

With the increasing number of people developing these diseases, will there be many more discoveries down the road? Overall, clinical trials for Alzheimers disease medications are giving new options to patients.

Alzheimers research is getting to a place where cancer research was maybe 30, 40 years ago, says Anton Porsteinsson, MD, director of the Alzheimers Disease Care, Research and Education Program at the University of Rochester Medical Center in New York, as quoted in the Association of American Medical Colleges News. I think were at a point where were going to see a logarithmic increase in discovery.

Dr. Dung Trinh, MD, Chief Medical Officer of the Healthy Brain Clinic, which provides individualized plans for brain health with coaching and support including memory testing and brain health exams, gives his perspective on this new research and helps track the implications of this research for neurobiologists and for patients with neurodegenerative diseases.

Dungs Thoughts

Neural degeneration, otherwise known as the loss of brain cells, is a very common thread among pretty much all the neural degenerative diseases we have in the brain that includes Alzheimers disease and other dementias such as vascular dementia. It includes multiple sclerosis and Parkinsons disease. The one underlying thread is the loss of brain cells, otherwise known as neurodegeneration.

So, this research actually is very exciting. We have not found a strategy to reproduce successfully more brain cells that have been less with these neurodegenerative diseases. And the best weve had so far is to hopefully try to slow down neurodegeneration, but the ability to create more brain cells, especially from stem cells that have been inactive in the brain, is a very exciting new revelation.

And this will lead to new classes of clinical trials and studies that will revolutionize this field. The field of neurodegeneration unfortunately have not caught up as far as finding new treatments and finding new medications due to the fact that we have not been able to successfully create or find a way to make new brain cells consistently.

Article written by Sonya Young.

Continued here:
New Insights on Treating Neurodegeneretive Diseases Could Lead ... - MarketScale

Hospital Acquired Disease Testing Market, Size is estimated to be US$ 14.91 billion by 2030 with a CAGR of – EIN News

By Stem Cell Medical Center

Hospital Acquired Disease Testing Market - PMI

The report "Hospital Acquired Disease Testing Market, By Test Type - Trends, Analysis and Forecast till 2029.

Key Highlights:

In December 2021, the healthians and QRX launch rapid PCR covid test with turnaround time of 30 minutes.

Analyst View:

The rise of hospital acquired diseases is fueled by poor infection control techniques and procedures at healthcare facilities, as well as filthy and non-sterile environmental surfaces, which is propelling the hospital acquired disease testing market forward. Furthermore, rising antibiotic resistance as a result of enhanced medical treatment leads to the development of hospital-acquired infections, which fuels market expansion. Furthermore, the market is being driven by the rising occurrence of nosocomial infections such as surgical wounds, urinary tract infections, and lower respiratory tract infections in intensive care units, orthopedics, and acute surgical wards.

Improper infection control practices and procedures at healthcare center Improper infection control practices and procedures at healthcare center and unclean and non-sterile environmental surfaces lead to development of hospital acquired diseases, which is driving growth of the hospital acquired disease testing market. Furthermore, increasing antibiotic resistance due to adoption of advanced medical care results into development of hospital acquired diseases, which in turn is fueling growth of the market. Moreover, increasing prevalence of nosocomial infections such as surgical wounds, urinary tract infections, and lower respiratory tract infections in intensive care units, orthopedic, and acute surgical ward are driving growth of the market. Hospital acquired infection is a major burden for society, patients, and healthcare management. Increasing awareness among population regarding hospital acquired infections, adoption of infection control programs by healthcare facilities, maintaining personal hygiene by the hospital staff, complete sterilization of medical equipment, and a clean sanitary environment in the health care facilities may restrain growth of the hospital acquired disease testing market.

Get a Sample Copy of the Hospital Acquired Disease Testing Market: https://www.prophecymarketinsights.com/market_insight/Insight/request-sample/98

Key Market Insights from the report:

Hospital Acquired Disease Testing Market accounted for US$ 7.2 billion in 2020 and is estimated to be US$ 14.91 billion by 2030 and is anticipated to register a CAGR of 7.6%. Global Hospital Acquired Disease testing market is segmented into test type and region. Based on Test Type, the Global Hospital Acquired Disease Testing Market is segmented into Urinary Tract Infection, Surgical Site Infection, Pneumonia, Blood Stream Infection, Methicillin-resistant Staphylococcus Aureus, and others. By Region, the Global Hospital Acquired Disease Testing Market is segmented into North America, Europe, Asia Pacific, Latin America, and Middle East & Africa.

Competitive Landscape & their strategies of Hospital Acquired Disease Testing Market:

The key players in the global Hospital Acquired Disease Testing market includes; Diatherix laboratories Life technologies Cantel Medical Corporation Meridian Biosciences Qiagen GmbH Nordion Roche Cepheid

The market provides detailed information regarding the industrial base, productivity, strengths, manufacturers, and recent trends which will help companies enlarge the businesses and promote financial growth. Furthermore, the report exhibits dynamic factors including segments, sub-segments, regional marketplaces, competition, dominant key players, and market forecasts. In addition, the market includes recent collaborations, mergers, acquisitions, and partnerships along with regulatory frameworks across different regions impacting the market trajectory. Recent technological advances and innovations influencing the global market are included in the report.

Some Important Points Answered in this Market Report Are Given Below: Explains an overview of the product portfolio, including product development, planning, and positioning Explains details about key operational strategies with a focus on R&D strategies, corporate structure, localization strategies, production capabilities, and financial performance of various companies. Detailed analysis of the market revenue over the forecasted period. Examining various outlooks of the market with the help of Porters five forces analysis, PEST & SWOT Analysis. Study on the segments that are anticipated to dominate the market. Study on the regional analysis that is expected to register the highest growth over the forecast period

Get Free PDF Download of Hospital Acquired Disease Testing Market: https://www.prophecymarketinsights.com/market_insight/Insight/request-pdf/98

Market Segmentation:

This report forecasts revenue growth at global, regional, and country levels and provides an analysis of the latest industry trends and opportunities in each of the sub-segments from 2019 to 2029. For the purpose of this study, has segmented the Global Hospital Acquired Disease Testing Market report based on Test Type and Region.

By Test Type - Urinary Tract Infection, Surgical Site Infection, Pneumonia, Blood Stream Infection, Methicillin-resistant Staphylococcus Aureus, and others

Regional Insights:

On the basis of region, the global plant stem cells market finds its scope in North America, Europe, Latin America, Asia Pacific, Middle East and Africa. India hospital acquired infection diagnostics market is predicted to rise significantly due to rising occurrence of nosocomial illnesses such as surgical site infections and bloodstream infections. After completing a study on 10,835 patients in diverse clinical settings, India observed a 4.4 percent overall growth rate for hospital acquired illnesses, according to the Indian Journal of Basic and Applied Medical Research.

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Prophecy Market Insights is specialized market research, analytics, marketing/business strategy, and solutions that offers strategic and tactical support to clients for making well-informed business decisions and to identify and achieve high-value opportunities in the target business area. We also help our clients to address business challenges and provide the best possible solutions to overcome them and transform their business.

Topics Related:

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Influenza Diagnostics Market, By Type (RT-PCR, Viral Culture, Antigen Detection Tests, Serological Assays, Simple Amplification-based Assays, Molecular Assays, and Others) By End-Users (Hospitals, Clinics, Diagnostic Laboratories and Others) and By Region (North America, Europe, Asia Pacific, Latin America, and Middle East & Africa) - Trends, Analysis and Forecast till 2032

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Hospital Acquired Disease Testing Market, Size is estimated to be US$ 14.91 billion by 2030 with a CAGR of - EIN News

Hearing loss research: 5 advancements in the past year – Labiotech.eu

By Stell Cell Research

At present, more than 1.4 billion people live with hearing loss globally. Hearing disorders are often caused by aging, frequent exposure to loud noises and even hereditary factors. In this article, we will look at some of the latest advancements in hearing disorders research which could broaden the scope for treatments and other measures to curb auditory loss.

Hearing loss research was first documented in 1550 BC in an Ancient Egyptian medical text Ebers Papyrus, which contained a remedy for Ear that Hears Badly; an outlandish concoction of liquids like olive oil, red lead, goat urine and ant eggs, to be injected into the ear.

Then, in the 16th century, the first school to teach sign language to pupils who were deaf, was established in Spain. And, in a major breakthrough in scientific research, the first-ever pair of hearing aids, ear trumpets were developed in the 1610s, which resembled a horn.

In 1898, the first portable hearing aid which used a carbon transmitter to convert weak signals to strong ones, was developed by American electrical engineer Miller Rees Hutchinson.

However, the mass production of hearing aids only began in the early 1900s, with the devices getting more compact and convenient to use as technology progressed. Soon enough, the invention of the cochlear implant (CI) transformed therapeutic research when the first one was successfully implanted by two doctors in California, in the U.S..

Currently, there are various studies being conducted to determine how the factors contributing to hearing loss could be altered to potentially cure hearing disorders. Here are five of the latest studies on hearing disorders, which could possibly influence therapeutic research in the field.

A new research has revealed a link between hearing loss and dementia in older adults.

The research, which was published by Johns Hopkins Bloomberg School of Public Health in Maryland, U.S.A in January 2023, showed that people, specifically older adults who have been diagnosed with hearing disorders, are more likely to have dementia a condition that is associated with the decline in brain functioning where symptoms affect memory, attention and other mental abilities.

However, the greater discovery is that the likelihood of dementia was lower among those who wore hearing aids.

This study refines what weve observed about the link between hearing loss and dementia, and builds support for public health action to improve hearing care access, said Alison Huang, who is the lead author of the research paper and a senior research associate in the Bloomberg Schools Department of Epidemiology and at the Cochlear Center for Hearing and Public Health.

The medical trials studied 2,413 individuals, nearly 50% of them being over the age of 80, where the prevalence of dementia was 61% higher among those participants with moderate to severe hearing loss when compared to participants who had normal hearing. Moreover, the use of hearing aids exhibited a decrease in the prevalence of dementia by 32% in 853 participants who had moderate and severe hearing loss, indicating that treating hearing disorders could lower the risk of dementia.

The research is part of a larger investigative analysis National Health and Aging Trends Study (NHATS) which began in 2011, and is funded by the National Institute on Aging in the U.S..

Although the reason why people with hearing loss have a greater possibility of being diagnosed with dementia is yet to be determined through further clinical studies which will take place this year this breakthrough drives the need for more hearing loss therapies.

A step forward in hearing disorders research, studies have shown that there could be a potential for the reversal of hearing loss.

The research, which was conducted by Del Monte Institute for Neuroscience at the University of Rochester in New York, in the U.S., has found that although cochlear hair cells (sensory cells for hearing) cannot be repaired in human beings with hearing loss, the cells can be regenerated in birds and fish, influencing research in cell regeneration in mammals.

Previously, it was discovered that the expression of ERBB2 an active growth gene was able to activate the development of new hair cells in mammals, but the mechanism behind it was not fully understood initially, according to Patricia White, a professor of Neuroscience and Otolaryngology at the University of Rochester Medical Center. Eventually, it was found that the activation of ERBB2 triggered a cascade of cellular events where the cells began to multiply to become new sensory hair cells.

The study, published in January 2023, examined the process of regeneration of hair cells in mice using single-cell RNA sequencing, where the overactive ERBB2 was observed. It was determined that this signaling promoted stem cell-like development with the expression of proteins through the CD44 receptor which are present in the hair cells.

This discovery has made it clear that regeneration is not only restricted to the early stages of development. We believe we can use these findings to drive regeneration in adults, said Dorota Piekna-Przybylska, scientist and an author of the study.

Data from 3.5 million Danes were gathered to determine a link between traffic noise and the risk of tinnitus a condition which causes a ringing in the ears.

The study was conducted by the University of Southern Denmark (SDU) and published in Environmental Health Perspectives in February 2023, to recognize whether varying degrees of noise can result in being diagnosed with tinnitus. The research established that with an increase in every ten decibels, the risk of developing tinnitus increases by six percent, according to Manuella Lech Cantuaria, researcher and assistant professor at the Maersk Mc-Kinney-Moller Institute at SDU.

This followed a study in 2021 that found a correlation between traffic noise and dementia, particularly Alzheimers disease.

These findings contribute to the growing evidence of sounds of traffic being a detrimental pollutant affecting health, particularly of city-dwellers in congested areas.

We want to increase the focus on the health risks associated with being exposed to noise, which is not only an annoyance but also harmful to your health. Hopefully, our results can help influence urban development, said Cantuaria, who believes that noise regulation programs such as highway shielding and noise-reducing asphalt should be considered.

The efficacy of cochlear implants could be improved, according to a new study that targets the locus coeruleus a region in the brainstem that produces the hormone noradrenaline which is a neurotransmitter.

The study used rat models that were fitted with cochlear implants to determine the performance of the devices. It was observed that the stimulation of the locus coeruleus through its production of noradrenaline led to improved effectiveness of the implants.

Researchers monitored two groups of rats one set with a stimulated locus coeruleus and the other without, after training them to respond to auditory stimuli. The ones which had an activated brainstem learned faster and responded to the tasks quicker. These rats completed the auditory task within three days while those that did not receive the boost took up to 16 days, indicating the role of the locus coeruleus in reviving hearing.

Researchers of the study have pointed out the relevance of the locus coeruleus in mirroring the rat models ability and have stated the need for noninvasive mechanisms to trigger regions of the brain for further studies for hearing disorders.

Aminoglycosides, a class of antibiotics which are used as prophylactics treatments to prevent diseases and to treat infections in the urinary tract and abdomen, have been found to cause the dysfunction of autophagy the recycling of old cells in hair cells, leading to permanent hearing loss.

These findings have given rise to the research potential for therapeutic autophagy components to target aminoglycosides ototoxicity (drug-induced hearing loss), according to the research which was conducted by Indiana University School of Medicine in the U.S..

According to Bo Zhao, researcher and assistant professor at the Indiana University School of Medicine, the translocation of RIPOR2 a protein required for auditory perception caused by the binding of the aminoglycosides to the protein, affects autophagy activation, resulting in hair cell death.

The scientists found that reducing the expression of RIPOR2 prevented the death of hair cells in mice.

The proteins which were identified in the research could be significant drug targets for hearing loss which is caused by medicines like antibiotics.

New technologies related to hearing loss:

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Hearing loss research: 5 advancements in the past year - Labiotech.eu

MAGENTA THERAPEUTICS, INC. MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) – Marketscreener.com

By Stell Cell Research

The following discussion and analysis of our financial condition and results ofoperations should be read in conjunction with our consolidated financialstatements and related notes appearing at the end of this Annual Report on Form10-K. Some of the information contained in this discussion and analysis or setforth elsewhere in this Annual Report on Form 10-K, including information withrespect to our plans and strategy for our business, includes forward-lookingstatements that involve risks and uncertainties. As a result of many factors,including those factors set forth in the "Risk Factors" section of this AnnualReport on Form 10-K, our actual results could differ materially from the resultsdescribed in, or implied by, the forward-looking statements contained in thefollowing discussion and analysis.

Overview

Magenta Therapeutics, Inc. is a biotechnology company focused on improving stemcell transplantation.

In February 2023, after a review of Magenta's programs, resources andcapabilities, including anticipated costs and timelines, we announced thedecision to halt further development of our programs. Specifically, wediscontinued the MGTA-117 Phase 1/2 clinical trial in patients withrelapsed/refractory acute myeloid leukemia, or R/R AML, and myelodysplasticsyndromes, or MDS. We discontinued the MGTA-145 Phase 2 stem cell mobilizationclinical trial in patients with sickle cell disease, or SCD. Lastly, we stoppedincurring certain costs relating to MGTA-45, including manufacturing and costsrelating to certain other activities that were intended to support aninvestigative new drug application, or IND, for MGTA-45 (previously namedCD45-ADC). As a result of these decisions, we conducted a corporaterestructuring that resulted in a reduction in our workforce by 84%.

Coinciding with the decisions related to the programs and across the portfolio,we announced that we intended to conduct a comprehensive review of strategicalternatives for the company and its assets. As part of our strategic reviewprocess, we are exploring potential strategic alternatives that include, withoutlimitation, an acquisition, merger, business combination or other transaction.We are also exploring strategic transactions regarding our product candidatesand related assets, including, without limitation, licensing transactions andasset sales. There can be no assurance that the strategic review process or anytransaction relating to a specific asset, will result in Magenta pursuing such atransaction(s), or that any transaction(s), if pursued, will be completed onterms favorable to Magenta and its stockholders in the existing Magenta entityor any possible entity that results from a combination of entities. If thestrategic review process is unsuccessful, our board of directors may decide topursue a dissolution and liquidation of Magenta.

Our product candidates have been designed to improve the patient experience whenpreparing for stem cell transplant or gene therapy. Our MGTA-117 productcandidate was designed as an antibody drug conjugate, or ADC, designed todeplete CD117-expressing stem cells in the bone marrow in order to make room forsubsequently transplanted stem cells or ex vivo gene therapy products. Theprocess of making room in the bone marrow is known as conditioning, and thecurrent standard of care for conditioning utilizes chemotoxic agents. Our secondtargeted conditioning product candidate, MGTA-45, is an ADC designed toselectively target and deplete both stem cells and immune cells, and it isintended to replace the use of chemotherapy-based conditioning prior to stemcell transplant in patients with blood cancers and autoimmune diseases. Lastly,our MGTA-145 product candidate, in combination with plerixafor, is designed toimprove the stem cell mobilization process by which stem cells are mobilized outof the bone marrow and into the bloodstream to facilitate their collection forsubsequent transplant back into the body for the purpose of resetting the immunesystem.

In January 2023, we voluntarily paused dosing in our MGTA-117 Phase 1/2 clinicaltrial for MGTA-117 in patients with R/R AML and MDS after the last participantdosed in Cohort 3 in the clinical trial experienced a Grade 5 serious adverseevent, or SAE (respiratory failure and cardiac arrest resulting in death) deemedto be possibly related to MGTA-117. This safety event was reported to the FDA asthe study's third safety event which is of a type referred to as a "Suspected,Unexpected, Serious Adverse Reaction," or SUSAR. The FDA subsequently placed thestudy on partial clinical hold in February 2023.

In April 2022, we announced a plan to more narrowly focus our capital allocationon the MGTA-117 targeted conditioning program, the MGTA-45 IND-enablingactivities and the MGTA-145 stem cell mobilization efforts in sickle celldisease while also de-prioritizing other portfolio investments. We made certainreductions in our planned spending related to research platform-relatedinvestments in new disease targets, paused certain MGTA-145 investments,including the program's planned MGTA-145 dosing and administration optimizationclinical trial in healthy subjects and reduced planned general andadministrative expenses. In connection with these reductions to our plannedspending, we also reduced our workforce by 14%.

Since our inception in 2015, we have focused substantially all of our effortsand financial resources on organizing and staffing our company, businessplanning, raising capital, acquiring and developing our technology, identifyingpotential product candidates

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and undertaking preclinical studies and clinical trials, including MGTA-117,MGTA-45 and MGTA-145. We do not have any products approved for sale and have notgenerated any revenue from product sales.

Since our inception, we have incurred significant operating losses. Net losseswere $76.5 million and $71.1 million for the years ended December 31, 2022 and2021, respectively. As of December 31, 2022, we had an accumulated deficit of$402.0 million.

We expect to continue to incur costs and expenditures in connection with theprocess of evaluating our strategic alternatives. There can be no assurance,however, that we will be able to successfully consummate any particularstrategic transaction. The process of continuing to evaluate these strategicoptions may be very costly, time-consuming and complex and we have incurred, andmay in the future incur, significant costs related to this continued evaluation,such as legal, accounting and advisory fees and expenses and other relatedcharges. A considerable portion of these costs will be incurred regardless ofwhether any such course of action is implemented or transaction is completed.Any such expenses will decrease the remaining cash available for use in ourbusiness. In addition, any strategic business combination or other transactionsthat we may consummate in the future could have a variety of negativeconsequences and we may implement a course of action or consummate a transactionthat yields unexpected results that adversely affects our business and decreasesthe remaining cash available for use in our business or the execution of ourstrategic plan. There can be no assurances that any particular course of action,business arrangement or transaction, or series of transactions, will be pursued,successfully consummated, lead to increased stockholder value, or achieve theanticipated results. Any failure of such potential transaction to achieve theanticipated results could significantly impair our ability to enter into anyfuture strategic transactions and may significantly diminish or delay any futuredistributions to our stockholders.

Should we resume development of our product candidates, our ability to generateproduct revenue sufficient to achieve profitability will depend heavily on thesuccessful development and eventual commercialization of one or more of ourproduct candidates. In addition, we will incur substantial research anddevelopments costs and other expenditures to develop such product candidatesparticularly as we:

enroll and conduct clinical trials for our product candidates;

initiate and conduct preclinical studies and clinical trials of our otherproduct candidates;

develop any other future product candidates we may choose to pursue;

seek marketing approval for any of our product candidates that successfullycomplete clinical development, if any;

maintain compliance with applicable regulatory requirements;

develop and scale up our capabilities to support our ongoing preclinicalactivities and clinical trials for our product candidates and commercializationof any of our product candidates for which we obtain marketing approval, if any;

maintain, expand, protect and enforce our intellectual property portfolio;

develop and expand our sales, marketing and distribution capabilities for ourproduct candidates for which we obtain marketing approval, if any; and

expand our operational, financial and management systems and increase personnel,including to support our clinical development and commercialization efforts andour operations as a public company.

If we resume development of our product candidates, we will not generate revenuefrom product sales unless and until we successfully complete clinicaldevelopment and obtain regulatory approval for our product candidates. If weobtain regulatory approval for any of our product candidates, we expect to incursignificant expenses related to developing our commercialization capability tosupport product sales, marketing and distribution. Further, we expect to incuradditional costs associated with operating as a public company.

Should we resume development of our product candidates, we will need substantialadditional funding to support our continuing operations. Until such time as wecan generate significant revenue from product sales, if ever, we expect tofinance our operations through a combination of equity offerings, debtfinancings, collaborations, strategic alliances and marketing and distributionor licensing arrangements. We may be unable to raise additional funds or enterinto such other agreements or arrangements when needed on favorable terms, or atall. Additionally, because of the numerous risks and uncertainties associatedwith pharmaceutical product development, we are unable to accurately predict thetiming or amount of increased expenses or when or if we will be able to achieveor maintain profitability. Even if we are able to generate product sales, we maynot become profitable. Accordingly, if we fail to raise capital or enter intonecessary strategic agreements, or fail to ever become profitable, we may haveto significantly delay, scale back or discontinue the development andcommercialization of one or more of our product candidates, and we may also beforced to reduce or terminate our operations.

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As of December 31, 2022, we had cash, cash equivalents and marketable securitiesof $112.0 million. Based on our current operating plan, we believe that ourexisting cash, cash equivalents and marketable securities will enable us to fundour operating expenses and capital expenditure requirements for the next twelvemonths from the issuance date of this Annual Report on Form 10-K. See "Item 2.Management's Discussion and Analysis of Financial Condition and Results ofOperations - Liquidity and Capital Resources."

Impact of the COVID-19 Pandemic

The COVID-19 pandemic, including the emergence of various variants, has causedand could continue to cause significant disruptions to the U.S., regional andglobal economies and has contributed to significant volatility and negativepressure in financial markets.

We have been carefully monitoring the COVID-19 pandemic and its potential impacton our business and have taken important steps to help ensure the safety of ouremployees and their families and to reduce the spread of COVID-19 in theCambridge community. We have established a hybrid work-from-home policy for allemployees, as well as safety measures for those using our offices and laboratoryfacilities that are designed to comply with applicable federal, state and localguidelines instituted in response to the COVID-19 pandemic. We will continue toassess those measures as COVID-19-related guidelines evolve.

The future impact of the COVID-19 pandemic on our industry, the healthcaresystem and our current and future operations and financial condition will dependon future developments, which are uncertain and cannot be predicted withconfidence. These developments may include, without limitation, changes in thescope, severity and duration of the pandemic, the actions taken to contain thepandemic or mitigate its impact, including the adoption, administration andeffectiveness of available vaccines, the effect of any relaxation of currentrestrictions within the Cambridge community or regions in which our partners arelocated and the direct and indirect economic effects of the pandemic andcontainment measures. See "Item 1A. Risk Factors" for a discussion of thepotential adverse impact of COVID-19 on our business, results of operations andfinancial condition.

Components of Our Results of Operations

Operating Expenses

Research and Development Expenses

Research and development expenses consist primarily of costs incurred for ourresearch activities, including our drug discovery efforts, and the developmentof our product candidates, which include:

employee-related expenses, including salaries and related costs, and stock-basedcompensation expense, for employees engaged in research and developmentfunctions;

expenses incurred in connection with the preclinical and clinical development ofour product candidates, including under agreements with contract researchorganizations, or CROs;

the cost of consultants and third-party contract development and manufacturingorganizations, or CDMOs, that manufacture drug products for use in ourpreclinical studies and clinical trials;

facilities, depreciation and other expenses, which include direct and allocatedexpenses for rent and maintenance of facilities, insurance and supplies; and

payments made under third-party licensing agreements.

We expense research and development costs to operations as incurred. Advancepayments for goods or services to be received in the future for use in researchand development activities are recorded as prepaid expenses. The prepaid amountsare expensed as the related goods are delivered or the services are performed.

Our direct research and development expenses are tracked on a program-by-programbasis and consist primarily of external costs, such as fees paid to consultants,central laboratories, contractors, CDMOs and CROs in connection with ourpreclinical and clinical development activities. We do not allocate employeecosts, costs associated with our platform technology or facility expenses,including depreciation or other indirect costs, to specific product developmentprograms because these costs are deployed across multiple product developmentprograms and, as such, are not separately classified.

Should we resume development of our product candidates, the successfuldevelopment and commercialization is highly uncertain. This is due to thenumerous risks and uncertainties, including the following:

successful completion of preclinical studies and clinical trials;

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receipt and related terms of marketing approvals from applicable regulatoryauthorities;

raising additional funds necessary to complete clinical development of andcommercialize our product candidates;

obtaining and maintaining patent, trade secret and other intellectual propertyprotection and regulatory exclusivity for our product candidates;

making arrangements with third-party manufacturers, or establishingmanufacturing capabilities, for both clinical and commercial supplies of ourproduct candidates;

developing and implementing marketing and reimbursement strategies;

establishing sales, marketing and distribution capabilities and launchingcommercial sales of our products, if and when approved, whether alone or incollaboration with others;

acceptance of our products, if and when approved, by patients, the medicalcommunity and third-party payors;

effectively competing with other therapies;

obtaining and maintaining third-party coverage and adequate reimbursement;

protecting and enforcing our rights in our intellectual property portfolio;

maintaining a continued acceptable safety profile of the products followingapproval; and

the continuing impact of the COVID-19 pandemic on our industry, the healthcaresystem, and our current and future operations.

A change in the outcome of any of these variables with respect to thedevelopment of any of our product candidates would significantly change thecosts and timing associated with the development of that product candidate. Wemay never succeed in obtaining regulatory approval for any of our productcandidates.

Research and development activities have historically been central to ourbusiness model. Product candidates in later stages of clinical developmentgenerally have higher development costs than those in earlier stages of clinicaldevelopment, primarily due to the increased size and duration of later-stageclinical trials. We expect our research and development expenses to decrease inthe near future as we halted the development of our product candidates while weexplore strategic alternatives. Should we resume development of our productcandidates, we expect research and development costs to increase significantlyfor the foreseeable future as our product candidate development programsprogress.

Inflation generally affected us by increasing our cost of labor and clinicaltrial costs. While we do not believe that inflation had a material effect on ourfinancial condition and results of operations during the periods presented, itmay result in increased costs in the foreseeable future.

General and Administrative Expenses

General and administrative expenses consist primarily of salaries and relatedcosts, and stock-based compensation, for personnel in executive, finance andadministrative functions. General and administrative expenses also includedirect and allocated facility-related costs and insurance costs, as well asprofessional fees for legal, patent, consulting, pre-commercialization,accounting and audit services. We expect our general and administrative expensesto decrease in the near future due to recent workforce reductions. We do expectto incur significant costs, however, related to our exploration of strategicalternatives, including legal, accounting and advisory expenses and otherrelated charges.

Interest and Other Income, Net

Interest and other income, net, consists of interest income and miscellaneousincome and expense unrelated to our core operations.

Income Taxes

Since our inception, we have not recorded any U.S. federal or state income taxbenefits for the net losses we have incurred in each year or for our earnedresearch and orphan drug tax credits, due to our uncertainty of realizing abenefit from those items. As of December 31, 2022, we had net operating losscarryforwards for federal income tax purposes of $272.9 million, of which $17.5million begin to expire in 2035 and $255.4 million can be carried forwardindefinitely. As of December 31, 2022, we had net operating loss carryforwardsfor state income tax purposes of $272.6 million which begin to expire in 2035.As of December 31, 2022,

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we also had available research and orphan drug tax credit carryforwards forfederal and state income tax purposes of $12.9 million and $3.4 million,respectively, which begin to expire in 2035 and 2030, respectively.

Critical Accounting Policies and Significant Judgments and Estimates

Excerpt from:
MAGENTA THERAPEUTICS, INC. MANAGEMENT'S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS (form 10-K) - Marketscreener.com

How ice hockey helped me to explain how unborn babies’ brains are … – Nature.com

By Stell Cell Research

Jean Mary Zarate: 00:04

Hello and welcome to Tales From the Synapse, a podcast brought to you by Nature Careers in partnership with Nature Neuroscience. Im Jean Mary Zarate, the senior editor at the journal Nature Neuroscience. And in this series, we speak to brain scientists all over the world about their life, their research, their collaborations, and the impact of their work. In episode six, we meet a researcher and author who was fascinated by the evolution of our brains and how they develop in the womb.

William Harris: 00:39

Hi, my name is William Harris, people generally call me Bill. I'm a professor emeritus at Cambridge University. Im a developmental neurobiologist, and Im the author of Zero to Birth, How the Human Brain is Built.

A developmental neurobiologist is basically someone who studies how brains develop. Its usually done in the laboratory. Its a field at the intersection of developmental biology and neuroscience.

Its carried out usually at the level of experimental animals and cells in petri dishes and things like that, rather than on human embryos.

So myself, you know I worked on fly embryos, I worked on salamander embryos, frog embryos, fish embryos. There are tons of fascinating questions about how the brain is made.

I myself got interested in it when I was a graduate student, and I was studying some mutant fruit flies. And these mutant fruit flies, they didn't see the world properly, they made visual errors. So lots of people had isolated, weird mutant flies that didn't see properly.

And when we traced the genes that were defective, mutated in those animals, we usually found that they operated at some point in the development of the visual system.

So that, you know, all these genes work to build the brain. And thats what really got me interested in it. And from that point, I just got more and more interested in how this most complicated organ develops.

And my main questions were, like, you know, wiring up, how does it get wired up? Thats what I spent most of my career doing.

I am a Canadian. I grew up in Canada, and played a lot of ice hockey. That's why there's a lot of ice hockey references in the book, analogies or metaphors in the book.

At the age when I went to university, I went to University of California at Berkeley. I was a graduate student at Caltech. My PhD supervisor was a famous guy named Seymour Benzer. And he worked on behavioural mutants of flies. I did postdoctoral work at Harvard Medical School, in the laboratories of David Hubel and Torsten Weisel, who studied the visual cortex of mammals, and how that developed.

And then I had my own career starting at the University of California, San Diego, in the biology department. And about 25 years ago, I moved to the University of Cambridge, where Ive been since.

I wrote the book because I wanted to do something useful with the perspective I had from 40 years of research and teaching of developmental neurobiology, teaching to university students.

I thought I could offer a glimpse into the field for people who wondered about such things, and have never, ever studied the subject.

I found it really difficult to make such a complicated scientific pursuit fascinating. But I tried to instill in the book some of the stories of the discoveries that have been made.

You know, how exactly were these discoveries made? And I added some colour, because I think people like to know this by trying to tie these discoveries to medical progress in neurology and psychiatry and psychology. Because so many of the things that go wrong during brain development lead to neurological or psychological syndromes.

William Harris: 05:14

Well, human brains are really different from those of every other species of animal. In fact, the brains of every species of animal are different from each other because theyve been tuned through millions of years of evolution to their particular lifestyle.

For example, an insects brain is geared to an insects world. And a human brain is geared to human affairs. But what we found out is that the instructions for making a human brain are written in the human genome, so it's largely genetic.

If you transferred a little bit of mouse embryonic brain tissue into a culture system and a human, then a brain into a culture system, theyd make, you know, a little bit of mouse brain or a little bit of human brain. Theyre genetically instructed to do that.

But what way, what way are the brains different? For example, our brains are about 10 times larger than expected for an animal of our size.

Human brains are about four times as large as chimpanzee brains, even though we weigh about the same as they do.

The architecture of human brains is different and human-specific. And the best example is the cerebral cortex, the covering of the brain where higher functions are. You know, in humans its 75% of the mass of our brain is cerebral cortex. Whereas in others, in monkeys, its only about 50%. And in most mammals, its, you know, 20% to 30%.

So its really taken over the dominant role in humans. So certain areas have enlarged, in comparison to other animals, and certain areas have not enlarged, may have shrunk.

So another key difference is the way brains develop. Just one of them, for example, is the fact that humans are born immature. Because their brains are getting bigger and bigger, they, you know, there, it seems that they constrict. Well, theres a squeezed point in evolution where, you know, in the embryo, you couldnt get an animal with a bigger brain and deliver it safely.

So, humans are born with a growing brain, and its gonna get bigger, but its as big as a mother can manage at that time. But it means that the brain is still immature when the human is born, compared to when a monkey is born. And it takes a longer time. And then it matures for a longer time postnatally too. So they spend a lot more time, humans, spend a lot more time than our closest relatives in, in learning about the world outside the womb, and that having an effect on the maturation of the brain.

We call the brain this collection of neurons thats in the head region. There are certain really circular symmetric animals like jellyfish, and they dont really have a front and a back.

And they dont have what we call a brain. They do have a nervous system, and neurons that connect to each other. But we call that a nerve net, because there isnt one centralized group where most of the neurons are.

So in evolutionary time, when bilaterally symmetric animals evolved 500-600 million years ago, and started to move in a forward direction, (you know, there was a front and a back end), it made sense to collect things at the front end that the animal was going to engage in first with the world.

So sensory apparatus, move there, smell, taste, vision, and the capacity to process the information that comes in through those senses was handled by a growing collection of neurons, which we ended up calling the brain.

If you wanted to break it down, what happens in what trimester, you could kind of think of it like this....

You start as a fertilized egg, and this egg divides and one cell becomes two, two four, four eight, eight 16 and so on. You get this ball of cells. Now, every one of those cells has the potential to make a whole human being, theyve got the genetic instructions to do everything to make a brain.

But at some point in early development, only about three weeks post-fertilization, some of the cells, some of those cells become committed to make the brain. They become the Adams and Eves, if you will, of the brain.

And they arrange themselves into groups that are the founders of different regions of the brain. There are hundreds of different regions of the brain. But these are the neural stem cells, theyre still dividing, theyre proliferating.

And theyre going to make a brain of the right size and proportions. Theyre going to make a brain with 100 billion neurons by birth.

William Harris: 11:08

Then in the second trimester, growth slows down a little bit, and some of the first neurons are generated from the neural stem cells. And connections start to be built between these first neurons. So for example, in the second trimester, you can already see some movements in the human embryo. And thats because muscle cells have connected.

Well, neurons in the spinal cord have connected with muscle cells. And neurons in the brain have connected with those motor neurons. So babies begin to kick their whole leg, move in slightly coordinated ways, bring their hands to their mouths, things like that.

You can see that connectivity is happening in the brain. I likened it to how a team is formed, and I give ice hockey analogies in the book, because thats my, that was a sport I had played and still coach.

So a coach will have tryouts and select the best players for different positions. The brain does the same thing. Maybe two neurons try out for every position, one makes it thats a little bit better at communicating, and the other one doesnt, and the one that doesnt has to commit suicide. So they go through a process called, in the business, apoptosis, where they break their own cells apart. But the survivors, once they survived, they have to last your whole life.

William Harris: 12:49

And then, in the last trimester, these neuron production grinds to a halt. The wiring up process is still going on. And this period of competition between neurons for survival, and then synaptic territory, that continues. And the neurons have to connect with each other in really precise ways and get fine tuned.

And this is still happening in the embryo, but it means that, you know, that when youre older, for example, and youre hungry, youve got neurons in your hypothalamus that will sense hunger, you know, sense the nutrition level in your brain, and neurons in your retina that can see a visual image and, you know, maybe its, this is kind of the example I give in the book, maybe its an English muffin, a picture of an English muffin that you can interpret, you learn to interpret.

And then you learn to, you know, the olfactory circuit in your nose has learned to interpret the smells received as melting butter on a freshly toasted muffin.

And then the neurons in your frontal cortex organize these pieces of information and integrate them, and send signals to the motor cortex. And the motor cortex then sends signals down the spinal cord to your motor neurons that organize a sequence of actions so that you can reach out and grab this muffin and bring it to your mouth and take a tasty bite. So a lot of that circuitry has been refined during the third trimester. Not all of it, but a lot of it.

We dont even really know how many types of neurons there are in the brain, but 1000s at least. Given that its the most complicated organ that we have, its not surprising that there are lots of different cell types. Its even been shown by recent science that every neuron in the brain has a distinct molecular identity from every other neuron in the brain. And it has a particular job.

Obvious for people are things like the rods and cones of our eyes, but the red, green, and blue-perceiving photoreceptors in the retina. So thats the three types of photoreceptors, the cone photoreceptors. And theres one type of rod cell. And then those four different photoreceptor types send their information to about 20 different next-order cell types. And they send their information to another 40 different next-order cell types, and so forth.

So by the time the image leaves the retina, the neural signal leaves the retina, its been seen by hundreds of different types of neurons, each doing a different kind of processing job.

There are lots of different types of neurons, some are numerous and tiny, and some are large, and few.

And one of the ones thats large and fewer are the dopaminergic neurons in the forebrain, whose degeneration is linked to Parkinsons disease. They're dopamine-secreting neurons. And they have exons that spread out across the cortex and many other areas of the brain. And they tone the brain, allowing people to initiate movements and things like that.

When they degenerate, then you develop Parkinsons disease. So different neurons, you can find out their function because when they when theyre gone, it reveals a defect, colour blindness, Parkinsons disease, and many other syndromes and neurological disorders are caused by defects in the formation of particular types of neurons.

William Harris: 17:03

Well, although the nervous system has started to fire up, its active before birth. And these prenatal activity patterns work, kind of like, test TV test patterns, if you remember those.

And theyre important to start to begin to tune brain function. But its only after a baby has been born that the outside world can have and does have such an influence on the activity patterns of the brain.

And so the outside world begins to fine tune the circuitry of the brain. The baby learns what its mother's face looks like, and many other things, the smell of coffee, or a muffin.

The babys brain, we say its over-wired. That means too many connections, there are too many connections. But its also under-connected because the connections arent very strong at the beginning.

And these connections need to continue to mature in the outside world. Synapses do continue to change to some extent throughout life, which is how people learn new things and forget other things.

William Harris: 18:28

Its interesting to think about the brain and the way the brain develops in two basic stages. One is building everything. And then the next stage is refining things. During the building phase youre constructing, adding more and more and more.

And during the refining phase, youre getting rid of stuff. For example, you might build a building, you might have scaffolding, and you put it up, and then you have to take it down at the end.

You may have brought in way too many bricks to build the building and have to discard some of those bricks at the end because they werent fit for purpose.

Well, the brain has a construction phase, and a destruction phase, or a decluttering phase. So first, you know, by the time a baby is born, it has more neurons than it will ever have in the rest of its life.

Neurons are dying at a faster rate than they are being born in a baby. In fact, neuronal birth has ground to a halt pretty much at the time of birth. But neurons are dying in vast numbers.

An adult human only has about half the neurons that it produced during its development. But once the brain has gone through this initial period of cell death, when its refined, got rid of the neurons that don't work so well, those neurons have to survive the rest of a lifetime because they dont divide anymore. And we dont have any neural stem cells left.

But what the survivors do is they continue to work against and with each other to gain or lose synaptic territory, and synaptic influence. And that continues on throughout life.

So, you know, a neuron might have a branch that goes to another area, and that branch might get pruned away, because someone else has taken over that territory. Those kinds of things happen, largely in childhood, but also, to a lesser extent, in an adult human.

William Harris: 20:45

My career, and particularly writing this book, has influenced the way I look at certain things, particularly my grandchildren, and one of my grandchildren features in the book a couple times.

One is about, you know, how people learn to be afraid of spiders, and whether epigenetics is involved or not.

And another is learning to speak. So babies are born with the potential to understand language. And their brains are already wired, so that they will be capable of getting it, but they cant speak yet.

So how does that happen? We talk about that in the book. But it wasnt my research so much, but it was really writing this book that changed my outlook, because I started to think about those things from a human perspective, instead of a fish brain perspective.

When I was researching, I was thinking about fish brains and fish retinas, writing a book starting to think more about human brains.

And I learned a lot about the connections between evolution and development in the brain. So how animal brains are like ours, and how theyre different from ours.

And the way its changed my outlook has, certainly, its increased my respect for what animals brains are and what animals are up, when I look at an animal.

And its also increased my respect for humans, because each one of us is born with a very unique brain. The developmental mechanisms that are used to make a brain ensures that your brain is going to be very different than my brain, its gonna be very different even if you had an identical twin brother, or sister that, you know, was grown in the same environment and had the same genes.

Theres a little bit of randomness thats thrown in. Probably our brains are the most unique things about us. We have unique faces, but our brains are even more unique. Just you cant see them.

23:06: Jean Mary Zarate

Now thats it for this episode of Tales From the Synapse. I'm Jean Mary Zarate, a senior editor at Nature Neuroscience. The producer was Don Byrne. Thanks again to Professor William Harris, and thank you for listening.

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How ice hockey helped me to explain how unborn babies' brains are ... - Nature.com

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