The walls of the hyperbaric chamber room are lined with under-the-sea wallpaper, providing an aquarium-like sensory experience to the children, and televisions hang above as a distraction if needed.

As Peterson discussed the benefits of hyperbaric oxygen therapy (HBOT) removes bacteria, increases stem cell generation her elderly parents were placed in nearby chambers for their daily dives.

HBOT involves breathing pure oxygen in a pressurized chamber, pumping 350 liters of oxygen per minute inside to create double the air pressure from outside. Its been a well-established treatment for decompression sickness, more commonly known as the bends, that occurs when a scuba diver ascends too quickly. Other major uses include treatment for wounds that won't heal, anemia, radiation burns and vision or hearing loss.

On its various social media channels, Oxford advertises HBOT can be used to reverse aging, improve general wellness and even to potentially treat individuals with long-haul COVID-19 symptoms.

Andrew Kistner, marketing director for Oxford, moved his family from Toledo in June 2021 to be close to the center. His daughter, Grace, has cerebral palsy and the family was desperate for a treatment.

We had tried everything, Kistner said, whose daughter had been in therapybetween nine months and a year old."She was making some progress but it was so slow. We didnt have anything to lose. Wed rather lose a little bit of money and time than later say we should have done it.

Kistners daughter did four sets of 40-round dives in the chamber and said positive results started early on.

We noticed cognitive improvements pretty quickly, along with improvement in problem solving, Kistner said.

His daughter was later diagnosed with an autism spectrum disorder and she continues the therapy today. Oxford even hired his wife as a nurse and later Kistner as its marketing director.

The center told Crain's in early August that about three-quarters of the roughly80 pediatric patients at Oxford Recovery receive HBOT therapy. After this story was published, the center said that figure was inaccurateand it has eight pediatric patients now. Peterson first discovered HBOT after her daughter JeAnnah was diagnosed with viral encephalitis at 9 years old, leaving her unable to speak and nearly blind. Through her own research, Peterson sought out HBOT for her daughter, who eventually recovered from the brain infection.

All the doctors said it wouldnt work, Peterson said. I had to have a $72,000 down payment to get that treatment. They only treated her after a foreign doctor said they used HBOT back home. We dont treat neurological disorders like we should in the U.S.

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At Oxford Recovery Center, autism treatment on the fringes of science - Crain's Detroit Business

Brea Lipe, MD: Hello and welcome to this OncLive My Treatment Approach program titled, "Recent Advances in the Treatment of Multiple Myeloma at First Relapse." I am Brea Lipe, and I'm the associate professor at the department of medicine at the University of Rochester in New York, and the director of the multiple myeloma program. I am joined today by my colleague, Dr Peter Forsberg, and I would like to welcome him to introduce himself.

Peter Forsberg, MD: Hi, Dr Lipe. I'm Peter Forsberg, I'm associate professor at the University of Colorado and the director of our myeloma program. So happy to participate in the conversation today. So welcome and thanks for joining us. And today we're going to discuss recent updates in the treatment of relapse/refractory multiple myeloma, and its impact on clinical practice. So, we'll be doing that by presenting two hypothetical patient cases, and then discussing our treatment approach to illustrate how we incorporate recent data in our clinical practice. So, let's go ahead and get started. So as Dr. Lipe said, our- the name of our presentation today is my treatment approach, recent advances in the treatment of multiple myeloma and early relapse specifically. And this is a patient profile to start with. So, this is a patient who was diagnosis, a 63-year-old female. This was in January 2017 when she presented with anemia, hypercalcemia, and after being evaluated by her primary care physician was found to have acute onset severe rib pain. And then radiographs had evidence of non-displaced rib fractures, bilaterally. Workup showed an IgG kappa multiple myeloma, and subsequent bone marrow biopsy demonstrated 35% clonal plasma cells. And cytogenetics included FISH, which showed a gain of chromosome 1q. So, she underwent a PET CT, which confirmed lytic disease throughout the spine and multiple rib lesions, and was treated initially with RVD, or lenalidomide, revlimid, bortezomib, Velcade, and dexamethasone starting in February 2017. Completed five cycles, achieved a very good partial response and then proceeded with autologous stem cell transplant with melphalan 200 milligrams meter squared conditioning, and after recovery was started on lenalidomide maintenance. So unfortunately, at follow up, on four years follow up state reevaluation was found to have progressive disease and at that time was started on isatuximab, carfilzomib, dexamethasone as second line therapy in May of 2021. So as of last follow up, the patient continues on the isatuximab, carfilzomib and dexamethasone in a very good partial response and is tolerating therapy well without issue. So, I believe, I think that brings us into discussion. In terms of my initial impressions of this case, I think it's a pretty standard consideration. A patient in 2017 diagnosed with new myeloma in their early to mid-60s. Treated with RVD induction, has long been a standard of care initial combination. And then followed by an autologous stem cell transplant and lenalidomide maintenance. And we know that based on recent data that patients with this combination of induction followed by transplant, followed by maintenance can have really stable long-lasting remissions potentially. So, patient experiencing relapse several years in- following the initiation of their induction, is pretty common. So, I think this is a pretty common scenario for us to be dealing with. And I think that the main consideration that's sort of become more prominent in the last couple of years is, do we start still with RVD or would we think about using a four-drug combination in this patient for initial induction, incorporating a CD38 monoclonal antibody like daratumumab plus RVD. So, I think that's probably the biggest practice change that might inform how we treat this patient that'd be a little different than what we might have been doing in 2017. Certainly, something that's does not uniform necessarily across myeloma providers, but is appropriate consideration, I think. And I- but otherwise I think still considering stem cell transplant and often lenalidomide based maintenance remains our kind of primary standard of care. I guess, I'd ask you if you had any additional thoughts. And then, I know the question of defining relapse, how we identify a progressive event. Defining with biochemical versus clinical relapse and sort of characteristics and standard criteria that define those. Maybe sort of delineating how you define progressive disease for [myeloma] in your practice.

Brea Lipe, MD: So, I always think it's fun to kind of look back and we see these patients in our practice, and they were started on therapy in 2017 or whenever that might have been, and to think about how our practice has changed. And I would agree that quads are something that I use a lot more frequently now, pretty much uniformly for induction in patients who are able. The only other thing that I thought was different about this case, that I might have done something different about even back in 2017 was the gain of 1q and that portending some higher risk features. And I often even back then used a more combination maintenance approach for those patients with higher risk cytogenetics. But regardless the patient did really well after transplant with just lenalidomide maintenance, which is great. And so, I think that it does come to this interesting question of what biochemical versus clinical relapse is and how those are defined. And so, the goal in my practice is to always have biochemical relapses because by the time we have clinical relapses, that's really defined by those CRAB criteria or symptomatic myeloma. So, my goal is to avoid symptoms because those can be compounding over time and can increase the toxicities of our therapy. So, my goal is always to catch it before it gets to the point where the patients are beginning to have suffering and side effects. And what we know is that biochemical relapse, so that's defined by the International Myeloma Working Group, the relapse criteria, and it's a biochemical relapse when we don't have those classic myeloma symptoms. And that's pretty much the standard IMWG relapse criteria, which includes changes of 25% to the paraprotein, as long as it's at least a rise of 0.5 and changes to the involved versus uninvolved light chains of at least 10. And so, there are pretty standard criteria for that, that you can follow over time for patients who achieve a CR, which this patient might not have. But anytime you start to see the reemergence of a paraprotein that's also a biochemical relapse. And so, I think that it's important to keep close track of our patients. I like to follow my patients in their labs, even when they're several years out closely, just so that I know that when they're starting to have these biochemical relapses, so I can intervene before they get a clinical relapse. We know that on average patients with biochemical relapses will have symptomatic development of myeloma defining events within about five months. So, I think that just highlights the need to identify those biochemical relapses. When you intervene on that is- can be up for debate but constitutes a biochemical relapse it's relevant for treatment versus those patients who will just kind of slowly progress biochemically and might be- might not progress within five months symptomatically. So, I think it's just important to keep an idea on.

See the article here:
Patient Profile 1: A 63-Year-Old Female with Relapsed Multiple Myeloma - OncLive

Melanin-producing cells of the skin

Melanocytes are melanin-producing neural crest-derived[3] cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),[4] the inner ear,[5] vaginal epithelium,[6] meninges,[7] bones,[8] and heart.[9] Melanin is a dark pigment primarily responsible for skin color. Once synthesized, melanin is contained in special organelles called melanosomes which can be transported to nearby keratinocytes to induce pigmentation. Thus darker skin tones have more melanosomes present than lighter skin tones. Functionally, melanin serves as protection against UV radiation. Melanocytes also have a role in the immune system.

Through a process called melanogenesis, melanocytes produce melanin, which is a pigment found in the skin, eyes, hair, nasal cavity, and inner ear. This melanogenesis leads to a long-lasting pigmentation, which is in contrast to the pigmentation that originates from oxidation of already-existing melanin.

There are both basal and activated levels of melanogenesis; in general, lighter-skinned people have low basal levels of melanogenesis. Exposure to UV-B radiation causes increased melanogenesis. The purpose of melanogenesis is to protect the hypodermis, the layer under the skin, from damage by UV radiation. The color of the melanin is black, allowing it to absorb a majority of the UV light and block it from passing through the epidermis.[10]

Since the action spectrum of sunburn and melanogenesis are virtually identical, they are assumed to be induced by the same mechanism.[11] The agreement of the action spectrum with the absorption spectrum of DNA points towards the formation of cyclobutane pyrimidine dimers (CPDs) - direct DNA damage.

Typically, between 1000 and 2000 melanocytes are found per square millimeter of skin or approximately 5% to 10% of the cells in the basal layer of epidermis. Although their size can vary, melanocytes are typically 7 m in length.

The difference in skin color between lightly and darkly pigmented individuals is due not to the number (quantity) of melanocytes in their skin, but to the melanocytes' level of activity (quantity and relative amounts of eumelanin and pheomelanin). This process is under hormonal control, including the MSH and ACTH peptides that are produced from the precursor proopiomelanocortin.

Vitiligo is a skin disease where people lack melanin in certain areas in the skin.

People with oculocutaneous albinism typically have a very low level of melanin production. Albinism is often but not always related to the TYR gene coding the tyrosinase enzyme. Tyrosinase is required for melanocytes to produce melanin from the amino acid tyrosine.[12] Albinism may be caused by a number of other genes as well, like OCA2,[13] SLC45A2,[14] TYRP1,[15] and HPS1[16] to name some. In all, already 17 types of oculocutaneous albinism have been recognized.[17]Each gene is related to different protein having a role in pigment production.

People with ChdiakHigashi syndrome have a buildup of melanin granules due to abnormal function of microtubules.

In addition to their role as UV radical scavengers, melanocytes are also part of the immune system, and are considered to be immune cells.[18] Although the full role of melanocytes in immune response is not fully understood, melanocytes share many characteristics with dendritic cells: branched morphology; phagocytic capabilities; presentation of antigens to T-cells; and production and release of cytokines.[18][19][20] Although melanocytes are dendritic in form and share many characteristics with dendritic cells, they are derived from two different cell lineages. Dendritic cells are derived from hematopoietic stem cells in the bone marrow. Melanocytes on the other hand originate from neural crest cells. As such, although morphologically and functionally similar, melanocytes and dendritic cells are not the same.

Melanocytes are capable of expressing MHC Class II,[19] a type of MHC expressed only by certain antigen presenting cells of the immune system, when stimulated by interactions with antigen or cytokines. All cells in any given vertebrate express MHC, but most cells only express MHC class I. The other class of MHC, Class II, is found only on "professional" antigen presenting cells such as dendritic cells, macrophages, B cells, and melanocytes. Importantly, melanocytes stimulated by cytokines express surface proteins such as CD40 and ICAM1 in addition to MHC class II, allowing for co-stimulation of T cells.[18]

In addition to presenting antigen, one of the roles of melanocytes in the immune response is cytokine production.[21] Melanocytes express many proinflammatory cytokines including IL-1, IL-3, IL-6, IL-8, TNF-, and TGF-.[18][19] Like other immune cells, melanocytes secrete these cytokines in response to activation of Pattern Recognition Receptors (PRRs) such as Toll Like Receptor 4 (TLR4) which recognize MAMPs. MAMPs, also known as PAMPs, are microbial associated molecular patterns, small molecular elements such as proteins, carbohydrates, and lipids present on or in a given pathogen. In addition, cytokine production by melanocytes can be triggered by cytokines secreted by other nearby immune cells.[18]

Melanocytes are ideally positioned in the epidermis to be sentinels against harmful pathogens. Melanocytes reside in the stratum basale,[21] the lowest layer of the epidermis, but they use their dendrites to interact with cells in other layers,[22] and to capture pathogens that enter the epidermis.[19] Melanocytes likely work in concert with both keratinocytes and Langerhans cells,[18][19] both of which are also actively phagocytic,[21] to contribute to the immune response.

Tyrosine is the non-essential amino acid precursor of melanin. Tyrosine is converted to dihydroxyphenylalanine (DOPA) via the enzyme tyrosinase. Then DOPA is polymerized into melanin. The copper-ion based enzyme-catalyzed oxidative transformation of catechol derivative dopa to light absorbingdopaquinone to indole-5,6-qionone is clearly seen following the polymerization to melanin, the color of the pigment ranges from red to dark brown.

Numerous stimuli are able to alter melanogenesis, or the production of melanin by cultured melanocytes, although the method by which it works is not fully understood. Certain melanocortins have been shown in laboratory testing to have effect on appetite and sexual activity in mice.[23] Eicosanoids, retinoids, oestrogens, melanocyte-stimulating hormone, endothelins, psoralens, hydantoin, forskolin, cholera toxin, isobutylmethylxanthine, diacylglycerol analogues, and UV irradiation all trigger melanogenesis and, in turn, pigmentation.[24] Increased melanin production is seen in conditions where adrenocorticotropic hormone (ACTH) is elevated, such as Addison's and Cushing's disease. This is mainly a consequence of alpha-MSH being secreted along with the hormone associated with reproductive tendencies in primates. Alpha-MSH is a cleavage product of ACTH that has an equal affinity for the MC1 receptor on melanocytes as ACTH.[25]

Melanosomes are vesicles that package the chemical inside a plasma membrane. The melanosomes are organized as a cap protecting the nucleus of the keratinocyte.When ultraviolet rays penetrate the skin and damage DNA, thymidine dinucleotide (pTpT) fragments from damaged DNA will trigger melanogenesis[26] and cause the melanocyte to produce melanosomes, which are then transferred by dendrites to the top layer of keratinocytes.

The precursor of the melanocyte is the melanoblast. In adults, stem cells are contained in the bulge area of the outer root sheath of hair follicles. When a hair is lost and the hair follicle regenerates, the stem cells are activated. These stem cells develop into both keratinocyte precursors and melanoblasts - and these melanoblasts supply both hair and skin (moving into the basal layer of the epidermis). There is additionally evidence that melanocyte stem cells are present in cutaneous nerves, with nerve signals causing these cells to differentiate into melanocytes for the skin.[27]

Visit link:
Melanocyte - Wikipedia

Friday, August 12, 2022

A Purdue University chemical engineer has improved upon traditional methods to produce off-the-shelf human immune cells that show strong antitumor activity, according to a paper published in the peer-reviewed journal Cell Reports. And future research plans include clinical trials involving the Purdue University College of Veterinary Medicine.

Dr. Xiaoping Bao, a Purdue University assistant professor in the Davidson School of Chemical Engineering, said CAR-neutrophils, or chimeric antigen receptor neutrophils, and engraftable HSCs, or hematopoietic stem cells, are effective types of therapies for blood diseases and cancer. Neutrophils are the most abundant white cell blood type and effectively cross physiological barriers to infiltrate solid tumors. HSCs are specific progenitor cells that will replenish all blood lineages, including neutrophils, throughout life.

These cells are not readily available for broad clinical or research use because of the difficulty to expand ex vivo to a sufficient number required for infusion after isolation from donors, Dr. Bao said. Primary neutrophils especially are resistant to genetic modification and have a short half-life.

Dr. Bao has developed a patent-pending method to mass-produce CAR-neutrophils from human pluripotent stem cells (hPSCs), that is, cells that self-renew and are able to become any type of human cell. The chimeric antigen receptor constructs were engineered to express on the surface of the hPSCs, which were directed into functional CAR-neutrophils through a novel, chemically defined protocol.

The method was created in collaboration with Dr. Qing Deng in Purdues Department of Biological Sciences; Dr. Hal E. Broxmeyer, now deceased, at the Indiana University School of Medicine; and Dr. Xiaojun Lian at Pennsylvania State University.

We developed a robust protocol for massive production of de novo neutrophils from human pluripotent stem cells, Dr. Bao said. These hPSC-derived neutrophils displayed superior and specific antitumor activities against glioblastoma after engineering with chimeric antigen receptors.

Dr. Bao disclosed the innovation to the Purdue Research Foundation Office of Technology Commercialization, which has applied for an international patent under the Patent Cooperation Treaty system of the World Intellectual Property Organization. The innovation has been optioned to an Indiana-headquartered life sciences company.

We will also work with Dr. Timothy Bentley and his team at the Purdue College of Veterinary Medicine to run clinical trials in pet dogs with spontaneous glioma, Dr. Bao explained. Dr. Bentley is professor of neurology and neurosurgery in the College of Veterinary Medicines Department of Veterinary Clinical Sciences.

This research project was partially supported by the Davidson School of Chemical Engineering and College of Engineering Startup Funds, Purdue Center for Cancer Research, Showalter Research Trust and federal grants from the National Science Foundation and National Institute of General Medical Sciences.

Click here to view a complete news release.

Writer(s): Steve Martin | pvmnews@purdue.edu

Read more:
PVM to Play Role in Research on New Patent-pending Method to Mass-produce Antitumor Cells to Treat Blood Diseases and Cancer - Purdue University

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Stem cell-based therapy for human diseases | Signal Transduction and Targeted Therapy - Nature.com

If a tree falls in a forest and nobody is around to hear it, does it make a sound? Similarly, if the U.S. Food and Drug Administration ultimately votes to approve Eli Lillys donanemab or Eisais lecanemab both anti-amyloid beta (A) antibodies will it make an impact on Alzheimers disease (AD)?

The stupid question is: if I have Alzheimer's disease and my plaque is gone, but I still have Alzheimer's disease, do I care? Maria Maccecchini, Ph.D., founder, president and CEO of Annovis Bio asked during an interview with BioSpace.

On Thursday, Maccecchini participated in a panel discussion, Integrative Systems Biology of Alzheimers Disease, at the Alzheimers Association International Conference (AAIC), addressing this very question. The panel, hosted by renowned AD researcher Dr. Jeffrey Cummings, M.D., and KristaLanctt,Ph.D. of Sunnybrook Research Institute, also looked at integrative approaches being taken to treat the disease.

The Battered Anti-Amyloid Theory

As anti-A therapeutics continue to fail, allegations recently broke calling into question seminal research behind the hypothesis. While looking into claims of misconduct by AD drug developer Cassava Sciences, Vanderbilt neuroscientist and physician Matthew Schrag made a discovery: It appeared to Schrag that the pioneering research of Sylvain Lesn and Karen Ashe possibly contained tampered images of Western blots, a laboratory technique used to visualize proteins. This data formed the backbone of the argument that A*56 - an oligomer of amyloid- proteins - is responsible for the AD hallmark of memory loss. The 2006 paper has been cited by some 2,300 other studies over the past 16 years.

Despite the failure of these drugs (Biogens Aduhelm is a possible though highly-scrutinized exception), the pharmaceutical industry continues to cling to the theory. Its no wonder why, given the astronomical resources that have been devoted to it. In 2021 alone, anti-amyloid research received nearly $300 million in support from the National Institutes of Health.

I had thought that amyloid was dying 10 years ago, Maccecchini said. It does not die. Maccecchini was perusing the booths at AAIC when she came across an Eli Lilly representative. She asked the individual why, with all of the failures in the space, she was still working in it. Her response? Because Lilly is the only employer in town.

When you have put billions into something, unless that person resigns or dies, they're not going to admit being wrong, Maccecchini said.

She was unwavering in her position on anti-A antibodies. I would not use an antibody in an elderly person with an impaired brain if my life depended on it. It's toxic. You're killing these people earlier. She also noted the perils of PET scans, which she said kills nerve cells.

The RNA-based Approach

Instead, Berwyn, PA-based Annovis is developing buntanetap, a small molecule that inhibits multiple neurotoxic proteins tau, aSynuclein, TDP-43 and amyloid beta at once. These proteins, she explained, are regulated by the same homologous region in messenger RNA (mRNA). This region, and only this region, binds to iron regulatory protein 1, a storage protein in the cytoplasm.

When it's bound, the mRNA is not translated; when it's free, the mRNA is translated, Maccecchini said. When the mRNA gets over-translated, (leading to the aggregation of these proteins), our drug stops it because it keeps it bound.

Buntanetap is currently being assessed in Phase III trials for Parkinsons disease, and Annovis plans to kick off a Phase II/III trial in AD this Fall. The company also intends to file a grant to study the drug in Lewy body dementia, with potential grants for both Huntingtons disease and amyotrophic lateral sclerosis (ALS) also under consideration.

While Maccecchini believes buntanetap will be effective in stopping the progression of AD, shes aiming higher.

If you already have dementia, stopping it is nice, but you would like to get better, right? she said. Eventually, while it is not possible today, Maccecchini envisions buntanetap being combined with stem cell therapy. Even if we figure out how to make (stem cells) become neurons, they'll diebecause the brain has Alzheimers. But if our drug stops them from getting Alzheimer's, then we can actually improve cognition.

The HGF-MET Approach

In Bothell, Washington, Athira Pharma is developing fosgonimeton, a small molecule designed to enhance the activity of hepatocyte growth factor (HGF) and its receptor, Met, with the aim of impacting neurodegeneration and regenerating brain tissue.

Athira Chief Medical Officer Hans Moebius, M.D., Ph.D. explained that the origin of plaques is inside of neurons and that this is why anti-A antibodies havent been effective to date.

This is a lysosomal overload with amyloid fibrils and it originates inside neurons, he told BioSpace. These monoclonal antibodiesare entering the brain only to a minuscule fraction, about one percent. From this percent of monoclonal antibodies, I maintain that zero percent enter neurons. You cannot rescue neurons by hoping you can get your monoclonal antibody into the neuron.

He shared that this mechanistic consideration has long led him to be critical of the amyloid hypothesis.

It is amazing to me to see that we are following Einsteins bon mot that repeating an experiment and hoping for a different outcome is the definition of stupidity, he said. At least what we should do is open our eyes a little bit and look with a different view on the disease. In Moebius view, Alzheimers is probably a family of diseasesand there are many pathophysiological processes ongoing.

Moebius referred to HGF-Met as being a key neurotrophic system to maintain homeostasis in the brain. First discovered in the liver, HGF is now known to be ubiquitous.

In Alzheimer's disease, we know that in predilection areas like the frontal cortex and the hippocampus, we have a depletion of Met expression, he said.

So, Athira is developing a pipeline of small molecules that aim to enter the brain and positively modulate the HGF-Met system. Importantly, these small molecules are not agonists; they are modulators. We are not overruling the natural regulation; we can only boost the natural signal. That, Moebius said, is a key point for safety.

Last week, Athira presented data from the Phase II proof-of-concept trial of fosgonimeton in mild-to-moderate AD. While the primary analysis did not meet statistical significance in the primary endpoint (event related potential (ERP) P300 latency), the company said the data gave meaningful insights into the drugs potential effects. These include a statistically significant reduction in plasma levels of the validated neurodegeneration biomarker neurofilament light chain (NfL) in a pre-specified subgroup of monotherapy patients. This data will inform the larger LIFT-AD study, which has already enrolled 300 patients.

The Metabolic Hypothesis

For John Didsbury,Ph.D., president and CEO of T3D Therapeutics, amyloid could be part of the answer but only part of it.

North Carolina-based T3D approaches AD as a brain-specific form of diabetes type 3 diabetes where aberrant metabolism is causing brain starvation, leading to loss of brain functions such as cognition. But, Didsbury said, The metabolic hypothesis is not antithetical to the amyloid hypothesis. They're highly interrelated and they perpetuate each other.

Didsbury told BioSpace that three main causes of AD are interconnected in a massive positive feedback loop. These causes are metabolic changes, structural change (plaques and tangles) and stress.

Insulin, Didsbury said, is the single most important regulator of brain functions, including cognitive function. Resistance to insulin precedes seeing Alzheimer's symptoms, he noted.

T3D set out to find a potential drug target that can bypass or correct the dysfunctional insulin signaling pathways causing this resistance. The companys research culminated in T3D-959, which aims to break this positive feedback cycle by correcting these metabolic defects.

The drug acts to correct dysfunctional glucose energy metabolism and dysfunctional lipid metabolism found in the brains of Alzheimers patients. It targets multiple abnormalities, as opposed to just plaques and tangles. T3D-959 is currently being assessed in a Phase II clinical trial of mild-to-moderate AD patients.

While the company is currently blinded to the data, We have encouraging results that are pointing to potential improvement, not just a slowing of decline, but potential improvement in cognitive performance and function and in executive function, Didsbury shared. T3D anticipates reporting top-line results in early April 2023.

He added that these results seem to go against the "recently perpetuated mantra that you can never treat AD effectively if you're at a mild-to-moderate stage.

We vehemently disagree with that, he continued. Coming from large pharma, I believe that this new mantra that you have to go early before symptoms to treatwas brought on by large pharma as [a way of] rationalizing their failures.

With anti-A antibodies, Didsbury said, at best, you are seeing just a slowing in decline.

Is there still hope that anti-amyloid is the answer? Are we just targeting it the wrong way? More likely, it seems, Alzheimers is a complex disease process that requires an integrative approach.

See the original post here:
A Referendum on Anti-Amyloid and Promising New Therapeutic Targets at AAIC - BioSpace

The RCMP is asking the public's help to locate a person of interest after a woman was assaulted with a crow bar in Nerepis, N.B.

Members of the Grand Bay-Westfield RCMP and Ambulance New Brunswick responded to a report Tuesday afternoon of an assault with a weapon at a residence on Birch Street, according to Cpl. Jullie Rogers-Marsh.A 33-year-old woman had been struck over the head with a crow bar in the front yard of the residence, Rogers-Marsh said. She was transported to hospital and treated for injuries that were not considered life-threatening. RCMP said Thursday that the woman has since been released from hospital.

In the course of their investigation, police learned that a man fled the scene in a vehicle before police arrived. The man is considered a person of interest in the investigation.

The suspect is described as 58 tall (173 centimeters) with a skinny build. He is believed to be between 25 and 28 years old with short buzzed dirty blond hair. At the time of the alleged attack, the man was wearing a black hooded sweatshirt, jeans and white sunglasses, Rogers-Marsh said.

The vehicle of interest is described as a black four-door car with a tinted back window and tinted rear windows. Through the investigation, police obtained surveillance video footage of the vehicle and believe it to be a 2016-2020 model Honda Civic. It appears to have a spoiler on the back.

The RCMP hopes that information from the public may help provide additional clues to further their investigation. Police are looking to speak with anyone who was around Britain Road, Crandall Road or Birch Crescent in Nerepis between 2:00 and 2:45 p.m. on Tuesday, July 26.

Anyone who may have witnessed the incident, seen the vehicle of interest, or has any information about the incident, is asked to contact the Grand Bay-Westfield RCMP at (506) 757-1020. Information can also be provided anonymously through New Brunswick Crime Stoppers online or by calling 1-800-222-TIPS (8477).

To prepare yourself for a potential incident, always keep your vet's phone number handy, along with an after-hours clinic you can call in an emergency. The ASPCA Animal Poison Control Center also has a hotline you can call at (888) 426-4435 for advice.

Even with all of these resources, however, the best cure for food poisoning is preventing it in the first place. To give you an idea of what human foods can be dangerous, Stacker has put together a slideshow of 30 common foods to avoid. Take a look to see if there are any that surprise you.

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RCMP Investigating After Woman Attacked With Crow Bar - q961.com

CASE SUMMARY

A 54-year-oldwoman presented with Revised International Staging System stage II multiple myeloma, based on evaluations that showed a hemoglobin level of 7.0 g/dL, 2-microglobulin of 6 mg/dl, albumin 3.2 g/dL, calcium 11.3 mg/dL, lactate dehydrogenase of 200 U/L, and creatinine clearance of 45 mL/min. Bone marrow showed 22% clonal plasma cells. Serum kappa free light chains were 24 mg/dL. She had no cytogenetic abnormalities and an ECOG performance score of 1. A PET/CT scan showed multiple bone lesions in the vertebrae. She had no extramedullary disease. She was diagnosed with IgG-kappa myeloma and was considered transplant eligible.

Daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (Dara-VRd) induction therapy was initiated. She achieved a very good partial response (VGPR) post induction therapy. She underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT). Her post-ASCT response was a VGPR.

DISCUSSION QUESTIONS

CAITLIN COSTELLO, MD: This patient did get a quadruplet regimen with dara-VRd. She achieved a VGPR post-induction, had stem cells mobilized, underwent her transplant, and post-transplant her response is a VGPR. What would you do next?

THOMAS DEKKER, MD: Consolidation with CAR [chimeric antigen receptor] T-cell therapy.

COSTELLO: With CAR T cell, sure. Youre going for it; I like it. This patient is post-transplant, they have a VGPR. The GRIFFIN study [NCT02874742] would give these patients consolidation with dara-VRd.

PREETI CHAUDHARY, MD: I would not do CAR T-cell therapy.

COSTELLO: What would you do?

CHAUDHARY: In my opinion, in multiple myeloma, patients do a maximum of 11 months with CAR T-cell therapy. It has a good response, but I dont think thats sustainable.

COSTELLO: I appreciate throwing ideas out there. That is not something we have an option to do right now. Its an interesting option, and something we can talk about; but yes, I agree with you. I think for the meantime, short of trials that are looking at doing CAR T-cell therapyparticularly for those patients who have not had an adequate response to transplant or consolidation, or patients who relapse shortly after their transplantI think the standard of care as it stands now is doing consolidation or trying to find a maintenance regimen to get them to minimal residual disease [MRD] negativity.

With all that being said, what are we going to do now for these patients? Weve talked about what these transplant eligible patients are getting consolidation and maintenance; weve talked about maintenance approaches for these patients who get quadruplets, to put them on doublets. Seeing all those deep response rates, is anyone getting cold on transplants? If we are going to get 90% remission rates, does anyone reconsider the role of transplant here?

PAMELA MIEL, MD: I dont make that call, meaning I still send patients to the transplant doctors to see if theyre going to proceed with the transplant or not. But, if theyre transplant eligible, they get referred.

COSTELLO: As a transplanter, I thank you for that. We want to see these patients, make the decisions, have the discussion with the patients so we can look at their risk/benefit profile, and understand their responses to their current therapy. So, please still send them in their third cycle, if not earlier, so we can have those discussions and make plans.

There are a lot of maintenance regimens that are out there, and different things to choose from; a whole other conversation in and of itself. Lenalidomide is the mainstay where we have an overall survival benefit, where we dont have it in any other maintenance regimens.1 But it does allow for the option of continued doublets. I think we will soon see daratumumab and lenalidomide as a doublet get added on to that maintenance therapy once we have some of these randomized trials that are going on that show the continued benefit of patients to get daratumumab in the maintenance setting if they did not receive it in the up-front setting.

DISCUSSION QUESTION

How likely are you to change your practice with respect to management of transplant eligible newly diagnosed myeloma?

DEKKER: I already use quadruplet.

MILAN SHETH, MD: I feel that we still need a lot of long-term data to get a better sense of what it is that were achieving with the quadruplet therapy. Im still not convinced everybody needs quadruplet therapy. I think somebody else had already said that we know were going to get better responses because were using great drugs, but do we need to use everything up-front? I feel like theres still a lot of unanswered questions here.

MIEL: Ive been wanting to put patients on quadruplet treatment. I dont know if you know Nina Shah, MD, over at UC San Francisco, but Ive attended some of her talks, and shes pushing for the quadruplet treatment. The only thing that changed my mind was that when I spoke to the transplant doctor at UC San Diego, he said, If its not very high-risk disease, Id go with VRd [bortezomib, lenalidomide, and dexamethasone]. So, I put the patient on VRd. But I probably would want to put someone on dara-VRd, given the chance.

COSTELLO: Yes. I think that my takeaway from the data has been that we would, of course, love long-term data to come out, butwe have to wait a long time for it. While were waiting for some of these phase 3 studies to go on, which are happening now to look at real randomized data, to play out, I find that this is just too intriguing to not do quadruplets for everybody now.

Since [these data were presented at [the 2021 American Society of Hematology annual meeting], Ive transitioned just about everyone whos at least transplant eligible over to quadruplet regimens now.2 Any patients who are on the fence, where Im not sure if theyre going to be eligible for transplant, I still will try and give them the benefit of a quadruplet regimen, and very quickly drop the bortezomib if I get worried about them, and end up with dara-Vd [daratumumab, lenalidomide, dexamethasone]. But I think these MRD negativity rates are just too good, and if that is going to be the true surrogate end point that were all aiming for, dara-VRd has been my go-to for the last 6-plus months or so for these patients, until someone tells me otherwise.

References

1. Ho M, Zanwar S, Kapoor P, et al. The effect of duration of lenalidomide maintenance and outcomes of different salvage regimens in patients with multiple myeloma (MM).Blood Cancer J. 2021;11(9):158. doi:10.1038/s41408-021-00548-7

2. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(Suppl_1):79. doi:10.1182/blood-2021-149024

See more here:
Treating Multiple Myeloma Following Quadruplet Induction Therapy and ASCT - Targeted Oncology

Nearly twenty-five years ago, the scientific breakthrough of mammalian cloning marked a monumental moment in medicine and science. Anticipating the collision it would have with ethical decision making in medicine, I, the only physician-scientist in the U.S. Senate at the time, journeyed to the University of Edinburgh in Scotland to personally visit Sir Ian Wilmut at his research lab at the Roslin Institute.

My house call to Dolly in 1997: I stand with Dolly, the first ever mammal to be cloned from an adult ... [+] somatic cell, during my journey to visit her creator and caretaker, Sir Ian Wilmut.

Professor Wilmut just months before in 1996 had cloned a sheep from an adult somatic cell, shocking the world. This was the first successful attempt of its kind. All over the world people were wondering: would we be cloning a human being next? We talked science, we talked ethics, and we talked about his creations potential impact on altering the course of human history. I also met and examined the cloned sheep, Dolly, in her stall.

Dolly, named after Tennessees own Dolly Parton, was a Finnish Dorset sheep cloned from a single, adult mammary gland cell. Her creation, birth, and short life were scientific feats that immediately sparked global concern and discourse on the increasingly complex moral and ethical dilemmas posed by a sudden discovery of life-manipulating science.

Wilmut and colleagues published their achievement in February 1997, having kept Dolly secret for seven months. We, as a society, were quickly forced to answer difficult, probing questions. A few months later on the Senate floor, I borrowed a question that the Washington Post editorial board had posed a few years before: Is there a line that should not be crossed even for scientific or other gain, and if so where is it?

Here are my remarks in the Senate chamber in 1998:

So it is vital that our public debate and reflection on scientific developments keep pace, and even anticipate and prepare for new scientific knowledge. The moral and ethical dilemmas inherent in the cloning of human beings may well be our greatest test to date. We do not simply seek knowledge, but the wisdom to apply that knowledge. As with each of the mind-boggling scientific advances of the last century, we know that there is the potential for both good and evil in this technology. Congressional Record February 2, 1998

Years removed, I now reflect back on the confusion, questions, and status quo that Dolly challenged.

Dolly was the first mammal to be successfully cloned from an adult somatic cell, which is any type of bodily cell that is not a reproductive germ cell. The process Wilmut developed is technically called somatic cell nuclear transfer, colloquially known as cloning. It is the process of transferring the nuclear DNA of a donor somatic cell into an enucleated oocyte, followed by embryo development and then transfer to a surrogate recipient, followed by live birth.

Dollys creation in a test tube and eventual birth marked a major milestone in scientific research, suggesting that an animal could be cloned to create an exact replica using genetic material derived from theoretically any type of body cell. It opened the world to staggering new possibilities in reproductive cloning and therapeutic cloning.

Soon after Dollys birth, another parallel and similarly monumental finding was made: in 1998 embryonic stem cells were discovered. These cells are a highly unique type of unprogrammed somatic cell with the exceptional ability to both reproduce unlimited exact copies of themselves and develop into more specialized cell types, such as heart, lung, kidney or skin cells. And though seemingly miraculous in potential, these cells could not be created or programmed from any other type of cell and could only be collected from embryos an ethical dilemma because collection for research required destruction of the embryo itself.

Dolly changed this. Her successful creation paved the way for future scientists to develop a technique to independently produce equally powerful pluripotent stem cells by reprogramming other adult somatic cells, revolutionizing genetic therapy, and completely nullifying the ethical dilemma of collecting embryonic stem cells from embryos. Similarly, Dolly also highlighted the potential for scientists to create new tissues and organs for diseased patients, and to preserve the genetic material of endangered species.

But, along with these positive contributions came widespread concern about the ethics of cloning, especially around potential attempts to clone another human being. Many, including myself, feared this type of technology, if left unregulated, would be misused and abused. Indeed, cloning evoked great scientific power that demanded even greater ethical responsibility, and there were no established ethical guardrails at the time to monitor this duty.

In retrospect, these fears have diminished in part due to proactive measures and to the inherent complexities of the human genome (cloning an entire human being is, after all, a large jump from cloning a sheep). Importantly, legislative and scientific communities have been resolute and unified in their opposition to cloning human beings.

Though a human embryo was indeed successfully cloned in 2013, no known progress has been made when it comes to attempts to clone a human being. Yet the technique to create Dolly has been repurposed widely and has led to numerous scientific innovations.

In 2003, six years after her birth, Dolly became sick and was euthanized. Her decline in health was due to the development of tumors in her chest; some examinations of her cells suggested that she was also aging prematurely.

Despite her relatively short life (the average sheep lifespan is ~10-12 years), Dollys influence on the scientific community has been profound. Not only did she force scientists and researchers to redefine the ethics of their field, but she also laid the foundation for other significant scientific advancements in the fast-evolving new field we know today as regenerative medicine.

One powerful example is gene therapy and editing, where specific genes are targeted, edited, and repaired to protect against disease, cancer, autoimmune disorders, and even rewiring immune system cells for treatment-resistant cancer patients. This revolutionary innovation is made possible by CRISPR technology (the same technology that enabled rapid vaccine development for COVID-19), which is currently celebrating its 10-year anniversary.

Genetic cloning was also made possible thanks to Dolly. This is a type of cloning where scientists create copies of genes within DNA segments to combine with plasmid DNA, or self-replicating genetic material, and then place this new plasmid into a host organism, such as a bacterium, yeast, or mammal cell. This process is used to develop vaccines and antigen tests and is also used to identify useful genetic traits in plants, which can be replicated on a larger scale through the genetic modification of seeds.

Further, cloning techniques have also helped to advance agricultural practices. Farmers can use cloning technology to quickly introduce favored characteristics of prize livestock (such as the ability to produce large amounts of high-quality milk) into a herd by cloning and breeding. These livestock will then further reproduce using traditional breeding or assisted reproductive technology.

Despite advances in genetic cloning and agricultural practices, cloning especially the additional attempts at cloning whole organisms remains variable and highly inefficient.

Successful attempts have been made by companies like Sooam Biotech Research and ViaGen Pets to clone dogs and kittens for wealthy pet owners. But, even today, the success rate of animal cloning is estimated to be less than 30%. In fact, many animal rights activists oppose the practice citing animal welfare. In 2015, the European Union banned the practice of livestock cloning.

Overall interest in cloning slowed as advances in adult stem cell research gained traction in the 2000s. This resulted primarily from scientists newfound ability to take adult human cells, for example skin cells, and reprogram them back into an earlier, more primitive but more powerful embryonic-like, pluripotent cells.

This technique was pioneered by Japanese scientist Shinya Yamanaka in 2006, for which he was awarded the 2012 Nobel Prize in Physiology or Medicine. Yamanakas discovery of reprogramming already specialized adult cells to create induced pluripotent stem cells (IPS) took the ethical issue of destroying embryos for research off the table. Some scientists continue to look to cloning as a way to develop genetically unique stem cells that can be used to reduce the risk of triggering an immune response.

Notes taken shortly after my visit with Dolly.

We have come a long way since my exploratory journey from the Senate floor in Washington, DC, to the stall and research laboratory that housed Dolly in Edinburgh in 1997.

For all the controversy that Dolly sparked during her short life, her contributions to society have been nothing short of remarkable. She forced thought leaders, researchers, and policymakers around the world to confront the ethics of cloning. And, she encouraged us, as a society, to weigh in and engage on the ethical considerations of increasingly frequent scientific discoveries.

On all of these fronts, we worked tirelessly to instill and adhere to a strong scientific code, focusing on the bettering of science, innovation, and technology for societal good. Cloning gave us that first glimpse into the future.

As I said on the floor of the Senate on February 3, 1998:

This cloning debate, I think, maybe for the first time in the history of this body [the US Senate], forces us to address what is inevitable as we look to the future, and that is a rapid-fire, one-after-another onslaught of new scientific technological innovation that has to be assimilated into our ethical-social fabric. Congressional Record February 3, 1998

What I said then still holds true today, Science and ethics must march hand in hand. Congressional Record February 11, 1998

Read the rest here:
Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? - Forbes

IF you havent finalised your holiday plans, these ten top companies are your summer superheroes.

Theyre here to help with great holiday hacks and ideas, whether youre looking for a thrill-filled family trip or a chill-out break for two.

Surprising destinations, high-tech solutions to help you capture great memories, or simply a hay fever-free holiday: whatever you need, youll find it here.

10

The world of vlogging is highly competitive, so you need to grab any chance to stand out from the crowd.

Enter the Z 30, part of Nikons revolutionary Z series of mirrorless cameras and compatible with all NIKKOR Z lenses.

This innovative, compact and lightweight camera is packed with features to help ramp up your creativity and produce the kind of next-level content that simply isnt possible on a smartphone.

The Z 30 records up to 125 minutes of uninterrupted video in Full HD and approximately 35 minutes 4K UHD (ideal for tutorial vlogs) and lets you capture time-lapse movies or smooth slow motion in full HD.

The vari-angle touchscreen monitor makes shooting first-person vlogs or selfies a breeze, and exceptional vibration reduction ensures crystal-clear results every time.

There are 20 in-camera filters, all customisable in real time, and once youve created your content, you can upload it instantaneously, thanks to the Bluetooth and Wi-Fi functions.

Find out more about how to up your game with the impressive Z 30 at nikon.co.uk/en.

10

From a lagoon-view room at Hilton Garden Inn Snowdonia, you can enjoy the unlikely sight of people surfing or paddle boarding in the north Wales mountains.

The hotel is located in the heart of Adventure Parc Snowdonia, an outdoor playground filled with nature-inspired adventures, where the whole family can share thrilling activities in the great outdoors.

As well as testing yourself on the worlds first inland surf lagoon, you can go ziplining, whizz around on a bike on the pump track, try skate-bowl, or enjoy vigorous off-site experiences such as gorge walking and coasteering.

Even on rainy days, the fun doesnt stop: indoor adrenaline-pumping adventures include climbing walls, extreme slides, high ropes courses and caving.

Theres also a soft play zone for younger children.

After all the excitement, you can relax in the hotel, with its spa, modern, well-equipped rooms and relaxed bar/restaurant, or enjoy rustic outdoor living in a simple wooden camping pod.

Organise your family adventure now at adventureparcsnowdonia.com.

10

A magical family day out, this fairy tale theme park the largest in the Netherlands and third largest in Europe is open 365 days a year, packed with rides, attractions and shows, and surrounded by acres of natural woodland.

Theres something for every taste and age here, from high-adrenaline roller coasters such as Baron 1898 and water rides like Piraa, to a Fairytale Forest thats filled with characters from classic childrens stories, and a spectacular show of water, light and fire - Aquanura.

This year, expect even more fun as Efteling marks its 70th anniversary.

Special celebrations include Efteling Wonderland, a temporary fairytale that takes you through a rabbit hole into a scene inspired by Alices Adventures in Wonderland.

Easy to reach from the UK by ferry, train and air, the park offers a great choice of accommodation, from lakeside cabins and woodland cottages to fairy tale-themed hotel suites.

To experience a wonderful day at Efteling visit efteling.com.

10

If youve ever spent a summer suffering from hay fever, youll understand what a nuisance it can be.

However, there is a way that could help stop this all-too-common allergy from taking over your life: Allevia hay fever-relief tablets, now available over the counter.

Thanks to their key ingredient, fexofenadine (previously only available on prescription), Allevia has been designed to help provide relief from itchy, red, watery eyes, sneezing and a blocked or runny nose that hay fever sufferers know all too well.

Within an hour of taking a one-a-day tablet you can feel it taking effect, and the relief is reported to last for up to 24 hours.

Allevia are confident that no tablet is stronger for hay fever relief* and nothing works faster for 24-hour relief.

No wonder fexofenadine is the number one prescribed antihistamine by GPs in England*.

Live your life, not your allergy learn more at alleviaallergy.co.uk

Disclaimer: Allevia 120mg tablets contain fexofenadine. For the symptomatic relief of hay fever. Always read the label.

*For verification, email uk-medicalinformation@sanofi.com

10

Foreign travel can be a truly transformative experience. Thats certainly the case for hair loss sufferers who take a trip to Dr Karaaltin Hair Clinic in Istanbul.

This centre of excellence in hair restoration and hair transplantation treatments is in a well-equipped modern hospital and staffed by highly qualified professionals.

There are three staff anaesthesiologists and plastic surgeons who plan and manage your whole procedure, headed by plastic surgery professor Dr Mehmet Veli Karaaltin.

It claims to be the only clinic in the world that can combine hair transplantation with stem cell therapy, and provides an online lifestyle and aftercare programme of consultation.

It also invests in scientific research in its specialist field.

Treatments are carried out using the highest quality instruments and latest technology, and performed under local anaesthesia and intravenous sedation so that patients feel no discomfort.

The attention to patient comfort extends to providing VIP accommodation and transfer services.

While youre there, take the chance to explore the fascinating city of Istanbul the clinic is located close to Taksim Square, in the heart of the city.

Find out more and book an appointment at drkaraaltinhair.com.

10

If the mention of Wookey Hole conjures up images of the hairy Star Wars sidekick Chewbacca, think again.

This tiny Somerset village is famed for breathtakingly beautiful caves that were formed over millions of years.

Today, the magical world of Wookey Hole, rich in legends and adventures, is ideal for a family day out, with a host of attractions inside and out.

As well as exploring the spectacular caverns that once provided shelter for ancient hyenas, cave bears and Neanderthals, you can discover vintage penny arcades, museums, soft play zones and adventure golf, along with a cheese tunnel and dinosaur grove.

Oh, and keep an eye out for the famous witch of Wookey Hole.

Theres also a 4D cinema, the only place in the UK showing The Bear and The Squirrel, a new film from the Aardman group (Wallace and Gromit, Shaun the Sheep).

And, as the attraction is owned by the Cottle circus family you can enjoy summer performances by the Wookey Hole Circus School.

Plan your visit now at wookey.co.uk.

10

The best way to experience the Norfolk Broads National Park is by water.

So when you visit Britains largest protected wetland, make your first port of call Herbert Woods, a leader in the field of Norfolk Broads boat hire.

The regions largest independent hire boat marina, it has a fleet of more than 130 cruisers, with something to suit every budget and every type of holidaymaker, from romantic couples to groups of family and friends.

The cruisers sleep between two and 12 passengers and come in a variety of layouts, but all are light, airy and luxuriously kitted out with all the home comforts.

All are pet-friendly and self-drive, so you can explore at your own pace, completely in control of where you go maybe spotting otters and kingfishers along the River Ant, exploring the historic attractions of Norwich or venturing along the River Bure for some seaside fun in Great Yarmouth.

To book your Norfolk Broads boating holiday, visit herbertwoods.co.uk.

10

It may be one of the newer arrivals on the Cornish tourism scene, but Bodmin Jail has already clocked up awards, including Best Themed Entertainment and Attractions Project of the Year in the 2021 National AV Awards.

After a multimillion-pound investment, this immersive visitor experience opened in October 2020, using state-of-the-art technology and theatrical effects to bring the past vividly to life.

You can take a Dark Walk through Cornwalls murkier history, join a paranormal tour and get a feel for what it was like to live behind bars in this 18th-century prison on the edge of Bodmin Moor.

These days, an overnight stay is far more appealing.

Part of the handsome, Grade II listed building has been transformed into a boutique hotel, with 70 luxuriously styled rooms, a champagne bar and a fine-dining restaurant in the awe-inspiring surroundings of the former prison chapel.

For tickets, accommodation and restaurant reservations, visit bodminjail.org.

10

Banish any memories of the bad old days of self-tanning.

The trick to achieving a natural-looking sun-kissed glow without actually seeing any sun is to arm yourself with a bottle of Watermans Browned Off self-tanning foam.

Made in the UK (by a company that recently won a prestigious Queens Award for Enterprise), the mousse is easy to apply and quick to dry, and has a light, non-sticky formula.

Theres none of that odd biscuity smell you might associate with fake tans, just an appealingly tropical coconut scent, and its enriched with aloe vera and vitamin E, to aid absorption and hydration.

In just a few minutes, it delivers a flawless, streak-free finish and the more layers you apply, the deeper the tan.

Find out more, and shop for self-tanning products, at watermanshair.com.

10

If you have a fondness for heritage rail rides, youll love South Devon Railway, with its handsomely restored vintage locomotives and coaches.

This award-winning steam railway takes visitors on regular scenic trips along the beautiful valley of the River Dart between Buckfastleigh and Totnes, hugging the River Dart for much of the way.

If you fancy making a full day of it, take advantage of the 3 Great Attractions, 1 Amazing Day joint ticket.

This includes not just the return train trip but also admission to two other attractions: Dartmoor Otters and Buckfast Butterflies at one end of the line, and Totnes Rare Breeds Farm at the other.

Back on the tracks, there are some special attractions coming up later this year, including a Day Out With Thomas (every young childs favourite train) from 23-25 September and, from mid-November until Christmas, the chance to take a festive ride aboard the Polar Express.

Find out more at southdevonrailway.co.uk.

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Theyre here to save your travel plans this summer... - The Sun