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Author｜Sindy He Layout Designer｜Cecilia Qin Introduction The development of lymphoma occurs when one of the white blood cells called lymphocytes grows uncontrollably. The lymphocytes in our body help our immune system fight infections by traveling around in our lymphatic system. The lymphocytes are divided into two types: T lymphocytes (T cells) and B lymphocytes (B cells). With all types of lymphoma, diffuse large B-cell lymphoma (DLBCL) constitutes almost one-third of all clinical cases of non-Hodgkin's lymphoma (NHL). Since its discovery, this type of lymphoma has been labeled "aggressive" or "moderately to highly malignant" lymphoma. Because DLBCL is heterogeneous, it has different subtypes with different clinical characteristics, genetic changes, and treatment responses. Is Lymphoma common? What is the rate? Non-Hodgkin's lymphoma (NHL) is one of the most common cancers worldwide, accounting for approximately 4% of all cancers. Especially in recent years, the incidence rate of lymphoma has shown a more obvious rising trend. According to the China Anti-Cancer Association (CACA), “ the annual incidence of lymphoma in China is about 75,400, with an incidence rate of 4.75/100,000, and the number of deaths is about 40,500, with a mortality rate of 2.64/100,000.” The Development of DLBCL Treatment /r-CHOP Regimen/ r-CHOP (rituximab + cyclophosphamide + adriamycin + vincristine/vincristine + prednisone) is the current standard of care for the treatment of DLBCL, but resistance and relapse are still a problem for up to 30%-40% of patients. /Stem Cell Transplantation/ DLBCL patients who experience refractory or relapsed results following chemotherapy often undergo stem cell transplantation. In most cases, stem cell transplants are autologous, meaning the patient receives his or her own stem cells prior to the procedure. In other cases, patients will receive an allogeneic transplant in which they receive stem cells from another donor. Similar to r-CHOP Regimen, clinical trials show a high rate of relapsed or refractory large B-cell lymphomas even after finishing treatment. /Glofitamab-gxbm（Columvi, Genentech, Inc.)/ On June 15, 2023, the Food and Drug Administration granted accelerated approval to Glofitamab-gxbm (Columvi, Genentech, Inc.) for relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) or large B-cell lymphoma (LBCL) arising from follicular lymphoma, after two or more lines of systemic therapy. The study showed that patients treated with Columvi had an overall remission rate (the sum of complete and partial remissions) of 56%, with a complete remission rate of 43% and a median duration of remission of 1.5 years. On March 25 of this year, the drug was authorized by Health Canada for conditional use in adult patients with R/R DLBCL (relapsed or refractory diffuse large B-cell lymphoma), follicular lymphoma-transformed diffuse large B-cell lymphoma (DLBCL), or primary mediastinal B-cell lymphoma (PMBCL), who are subject to second-line or higher systemic systemic therapy and who are not candidates for receive or cannot receive CAR-T cell therapy or have received prior CAR-T cell therapy. In February of this year, the National Medicines Control Administration (NMPA) approved the drug's marketing application for Mainland of China. The drug is intended for adult patients who have received at least two lines of systemic therapy for diffuse large B-cell lymphoma (RDLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) with relapsed or refractory lymphoma. Glofitamab in Refractory Diffuse Large B-Cell Lymphoma Glofitamab is a bispecific antibody capable of targeting both CD3 and CD20 in a 2:1 fashion. It contains a protein domain that targets CD3 protein on the surface of T cells (1 Fab arm for binding CD3 on T cells) and two protein domains that bind to CD20 protein on the surface of B cells (2 Fab arms for binding CD20 on B cells). As a result of this dual-targeting strategy, T cells are able to target and kill tumor cells with greater specificity. Medical researchers are testing many treatments that may do more to help people with DLBCL. If you have this condition and want information about newer treatments, ask your healthcare provider about participating in a clinical trial.

Writer｜Katherine Yang Layout Designer｜Cecilia Qin Organ Preservation A new breakthrough in organ preservation, safe transplantation is not a dream! Most people must hear about transplant surgery before. Commonly known organ transplants include the liver, kidney, and cornea. However, contemporary transplant procedures frequently encounter two significant challenges. First, the demand for organs is far greater than the amount of donations. In addition to the crime problems arising from the imbalance between supply and demand, it is also necessary to compare the degree of fit between the donor and the patient. The second problem is that organ preservation could be better. The importance of organ preservation is not only because of the need for organ transfer but also because the operation cannot be completed in a short period of time, so maintaining the activity of organs during this period is also extremely important. So today we will introduce to you the development of organ transplantation and organ preservation. Introduction to Organ Transplatation In a comprehensive context, organ transplantation can be classified into two primary categories: organs and tissues. The category of organs encompasses vital structures such as the heart, lungs, kidneys, liver, pancreas, and small intestine. On the other hand, tissues consist of diverse elements such as solid bones, cartilage, ligaments, tendons, corneas, amniotic membranes, blood vessels, heart valves, peripheral blood stem cells, umbilical cord blood, skin, and bone marrow. Organ transplants can be further categorized based on their sources into two primary types: living donor organ donation transplants and cadaveric organ donation transplants. Living organ donation and transplantation pertain to the act of a healthy adult voluntarily offering a portion of their own organs or tissues for transplantation, without compromising their own overall health and physiological functions. Among these cases, liver and kidney donations are the most prevalent. In the case of organ donation and transplantation from cadavers, the process involves obtaining consent for organ donation from the deceased individual prior to their passing. Subsequently, the organs are retrieved after the donor has been declared brain-dead or has passed away. It's important to highlight that in numerous countries, the sources of "legitimate" organs are procured without financial transactions. Organ Preservation Moving forward, let us delve into the central theme of this article - organ preservation. The pivotal prerequisite for the triumphant accomplishment of organ transplantation lies in the imperative need to sustain the viability of the organ. This viability must be maintained starting from the moment the organ is detached from the donor until the primary blood vessels are interconnected with the recipient. Within this critical interval, any loss of organ functionality is irreversible and leads to a forfeiture of its initial purpose. To illustrate, let's consider the cases of kidney and liver. Following the cessation of their blood supply, these organs face deprivation of essential oxygen and nutrients. Once outside the body, kidneys can sustain their functionality for a duration of 45 to 60 minutes at room temperature. On the other hand, the liver's capability to retain its activity is confined to a mere 10 to 15 minutes. Therefore, in clinical practice, the shorter the ischemic time of an organ, the better. However, this time is extremely limited, and doctors barely have enough time to complete the surgery. As a result, humans have been continuously working to extend organ viability. Currently, there are two methods used in clinical practice to achieve this goal. Firstly, organs are either immersed in an organ preservation solution or continuously perfused with such a solution. This method primarily relies on the organ preservation solution to provide the minimum required nutrients for maintaining cellular viability and protecting the cells. Secondly, low-temperature preservation is utilized to reduce cellular metabolism. Current techniques often combine both methods in application, but they are researched separately in the scientific field. Therefore, the following discussion will also be divided into two parts: organ preservation solutions and organ preservation techniques. Organ Preservation Solution The concept of "organ preservation solution" first emerged in the manuscript of the French internist César Julien Jean Legallois in the year 1812. He boldly hypothesized that the injection of fluids could sustain the activity of the heart. With this, he officially initiated the beginning of organ preservation techniques. Initially, there was an idea to utilize blood from the same species to maintain organ activity. However, this concept proved entirely impractical for human application due to the large demand for blood. Consequently, scientists embarked on further research to explore the possibility of using blood from species A to sustain the organs of species B. However, the results unveiled that cross-species blood infusion was toxic and led to a rapid deterioration of the organs. Currently, the organ preservation solutions available in the market can primarily be categorized into three types: intracellular fluid (ICF)-type solutions, extracellular fluid (ECF)-type solutions, and amino acid-type solutions. ICF-type solutions Compared to other types of preservation solutions, ICF-type solutions mainly consist of low Na+ and high K+ concentrations. The first ICF-type solutions was the Collins solution, developed by Collins and colleagues in 1969. This marked the world's first cell preservation solution. However, the Collins solution had a significant drawback: the presence of magnesium phosphate precipitates, which could lead to crystal residues in the kidneys, adversely affecting renal function. To address this concern, a team modified the Collins solution in 1980, giving rise to the Euro-Collins solution, which has been in use since. Shortly after, the University of Wisconsin solution, with similarly low sodium and high potassium content, was introduced and is also still in use today. ECF-type solutions Differing from intracellular preservation solutions, extracellular preservation solutions primarily consist of low potassium and high sodium compositions. The most common examples of these solutions include EP4 (or EP-TU) solution, LPDG solution, and ET-K solution. Amino acid-type solutions In addition to the ICF-type solutions or ECF-type solutions, this category of solutions incorporates amino acids and histidine buffer systems. This addition has also proven to yield favorable preservation outcomes. Common examples of amino acid preservation solutions include HTK solution, Custodiol-N solution, and Celsior solution. In addition to the three categories of organ preservation solutions mentioned above, numerous biotechnology companies are continually researching solutions with different compositions. For instance, Renfang (Beijing) Biomedical Research Institute Co., Ltd. has developed a novel oxygen-carrying organ preservation solution. This solution employs hemoglobin, a biomaterial known for its efficient oxygen-carrying capabilities, as a key component. This technology has already obtained a patent in China and demonstrates the potential to significantly enhance organ utilization rates, surgical success rates, and patient survival rates. Organ Preservation Technology Currently, the most prevalent organ preservation technique is cold storage, where for every 10°C decrease in temperature, the metabolic rate decreases by a factor of two. While cold storage is the most cost-effective preservation method, it presents potential challenges such as the formation of ice crystals within the organs and the possibility of uneven cooling, both of which can lead to organ damage. Apart from cold storage techniques, there is ongoing research into the vitrification freezing technique. Vitrification freezing employs highly concentrated cryoprotectants to dehydrate cells, followed by rapid cooling, preventing the formation of ice crystals within the cytoplasm. This technique has been applied to embryo freezing, but its application to organs still faces certain challenges. For instance, cryoprotectants in sufficient doses are toxic and can induce additional cell damage, so determining the appropriate dosage remains a subject of investigation. Additionally, uneven thawing rates can also harm organs. However, addressing the latter concern, a new solution was presented in the June issue of "Nature" this year - nanowarming. This technique successfully thawed a mouse kidney that had been frozen for 100 days, and the kidney exhibited good post-thaw condition, successfully enabling transplantation. The last technique to be introduced is the commercially available normothermic preservation. In 2008, a research team from the University of Oxford established the OrganOx Medical company, which sought to closely replicate the in vivo environment, including factors such as temperature, blood perfusion rates, and pulsatile blood pressure. This technique has been adopted for clinical use in the United States; however, the device's cost is considerably high, and its usage requires the agreement to provide organ data to the research team, contributing to its relatively low market adoption. Beyond the University of Oxford team, another group from Switzerland has been researching normothermic preservation techniques. They published their results in May of last year in "Nature." This Swiss team comprises professionals from the engineering, biochemistry, and medical fields. Notably, the donor, in this case, had a history of abdominal desmoid fibromatosis and had suffered from long-term infection and sepsis. Such organs with such medical histories are generally not considered for donation. Nonetheless, the research team preserved the organ in the device for three days while simultaneously administering antibiotic treatment. Ultimately, they successfully restored the organ's health and performed a successful transplantation, highlighting the advantages of normothermic preservation. Conclusion Currently, there exists a severe global imbalance between the supply and demand of organs, with this issue being particularly pronounced in Eastern societies. The primary cause stems from the belief in Eastern cultures that post-death preservation of bodily integrity is essential. However, in practice, whether it's through living or deceased donation, surgeries are conducted to the standards of surgical procedures. In cases of deceased donation, substitutes are employed to fill and suture, restoring the appearance, and making it indistinguishable from standard surgical procedures. Overall, it’s important to emphasize that as scientists diligently work on developing these technologies, more sustainable organs can be left in the world and more lives can be saved.

Writer｜Asteria Xu Layout Designer｜Cecilia Qin Pheochromocytomas /tumors found in the adrenal glands/ Pheochromocytomas are tumors found in the adrenal glands and are composed of chromaffin cells. Chromaffin cells produce catecholamine, hormones typically released when someone is under physical or emotional stress. The overproduction of catecholamine in pheochromocytoma can cause numerous symptoms, and the most commonly seen ones are high blood pressure, headache, heavy sweating, strong and irregular heartbeat and fatigue. /Clusters/ Pheochromocytomas are categorized into three clusters based on their germline or somatic mutations, and these three clusters are pseudohypoxic signaling, kinase signaling and Wnt signaling. Cluster 1: Pseudohypoxic Cluster When the oxygen levels are low, cells will trigger a series of reactions called hypoxia response. Cells that activate hypoxia responses under normal oxygen levels are said to exhibit a pseudohypoxic response. Pseudohypoxic responses are commonly seen in tumors, leading to heightened glycolytic metabolism and angiogenesis, the formation of new capillaries. Cluster 1 is divided into two subclusters: cluster 1A, which involves the Krebs Cycle and cluster 1B, which pertains hypoxia signaling. Mutations in the Krebs cycle result in the accumulation of oncometabolites, which are metabolites that are significantly elevated in tumor cells compared to normal cells. The accumulation of oncometabolite, together with mutations in the hypoxia signaling, lead to the stabilization of Hypoxia Induced Factor 1α (HIF-1α). Hypoxia Induced Factor 1 (HIF-1)is a heterodimeric transcription factor, which means that it consists of two subunits, HIF-1α and HIF-1β. Under normal circumstances, HIF-1α undergoes continuous degradation. However, when the concentration of oxygen decreases, the degradation of HIF-α is retarded, leading to its increased expression under hypoxic conditions. In cancer, HIF-1α activates the transcription of genes that promotes angiogenesis, metastasis and other cellular processes. Cluster 2: Tyrosine Kinase-Linked Signaling Pathway Activated mutations in genes such as RET, NF1, HRAS, TMEM127, MAX, FGFR1, Met, MERTK, BRAF and NGFR lead to overactivation of PI3K/AKT, RAS/RAF/ERK, and mTORC1/p70S6 pathways. Similar to cluster 1, these pathways eventually result in the synthesis of HIF-α, leading to cell proliferation and angiogenesis. Cluster 2 tumors show the adrenergic phenotype, which means that the quantity of epinephrine is greater than 5% of the total amount of catecholamines present. Cluster 2 tumors are generally less aggressive than cluster 1 and cluster 3 tumors. Cluster 3: Wnt signaling Compared to cluster 1 and cluster 2, cluster 3 remains relatively unexplored. Two mutations hold significance within the Wnt cluster. First, the mutation of MAML3 results in the overactivation of Wnt/Hedgehog signaling. Second, the mutation of CSDE1 leads to the overactivation of ß-catenin, a target of Wnt signaling. Consequently, these two mutations result in angiogenesis and cell proliferation. Treatment For locoregional diseases, the primary option for patients is the surgical removal of tumors. In the case of metastatic disease, alleviating symptoms by reducing catecholamine production can also result from removing primary tumors. Preoperative treatments Before surgery, patients’ blood pressure and heart rate must be brought under control to prevent the occurrence of cardiovascular emergencies and other catecholamine-associated side effects. Alpha-adrenoceptor blockers are usually employed to control high blood pressure. They prevent norepinephrine, a type of catecholamine, from tightening the walls of blood vessels. Phenoxybenzamine, a type of alpha-adrenoceptor blocker, is the most frequently used. Surgery Typically, doctors perform a procedure called adrenalectomy to remove the primary tumor, thereby reducing catecholamine levels by excising the adrenal glands. There are various approaches to adrenalectomy. One approach is open adrenalectomy involving a large abdominal incision. Although once the standard for tumor removal, open adrenalectomy is being supplanted by a newer technique, laparoscopic adrenalectomy. Laparoscopic adrenalectomy has become the golden standard of surgical treatment for benign tumors. In this approach, doctors make three or four small incisions and put laparoscopes, which are small cameras, through these incisions. The laparoscopes allow the surgeons to see the internal organs and guide them through the surgery. This approach is less invasive, resulting in reduced patient discomfort and faster recovery. After an overnight stay in the hospital, patients typically recover at home over a few weeks. There are two distinct approaches to laparoscopic adrenalectomy. The first is lateral transperitoneal adrenalectomy (LTA) involving incisions on the side, and the adrenal glands are exposed by detaching adjacent organs. Another approach is the posterior retroperitoneal adrenalectomy (PRA), which is minimally invasive and is commonly used to remove benign tumors. In PRA, incisions are made on the back rather than the through the abdomen, offering advantages for patients with previous abdominal incisions (because it doesn’t enter the abdomen, so is preferred by patients who have had incisions on the abdomen before). This approach, however, is only effective for tumors that are smaller than 6cm. Chemotherapy Metastatic pheochromocytoma can be treated by chemotherapy. Chemotherapy targets rapidly dividing cells, which is a feature of cancer. Unfortunately, hair cells and cells in the stomach are also rapidly dividing, resulting in chemotherapy-related side effects such as hair loss and loss of appetite. CVD (cyclophosphamide, vincristine, and dacarbazine） can also be used for the treatment of malignant pheochromocytomas. Studies have shown that a partial response to tumor volume can be seen in 37% of patients and a partial response to catecholamine excess can be seen in 40% of patients. Conclusion Although in recent years, many studies have been done on pheochromocytoma that provide valuable insights into the causes and treatments, many details regarding the mechanism of pheochromocytoma remain unclear. Further research is needed to enhance our understanding of the disease and to develop more efficient treatment methods for this form of cancer.

Writer｜Sindy He Layout Designer｜Cecilia Qin Why is sleep a luxury now? Have you ever had insomnia, or have you been plagued by it? An ongoing survey finds out that people under 18 have a high level of sleep procrastination rate; this group of people tends to stay on their phones for hours before going to bed, and consequently past the time when they should go to bed. On the other hand, people over 18 affected by work and school pressure, mental anxiety, and family reasons, develop a feeling that sleep is a waste of life, so take the initiative to sleep late, by extending the night to pretend to seize the time, to resist the "life wasted" feeling of emptiness. This is the implementation of their own "sleep deprivation", in self-punishment, and self-torture. According to statistics from the Chinese Sleep Research Society (CSRS), more than 300 million Chinese people suffered from some kind of sleep disorder in 2021, and the incidence of insomnia among adults is as high as 38.2%. The 2022 China National Healthy Sleep White Paper shows that nearly three-quarters of respondents said they had sleep problems, including 33.1% of difficulty falling asleep, 25.8% of easy waking, 23.5% of insomnia, 21.8% of snoring, and 20.5% of excessive dreaming. With these sky-rocketing morbidities, people need to acknowledge this is indeed a problem. So, what exactly is insomnia and what are some criteria for it? The National Institutes of Health answered this question by explaining that "Three main components are required to diagnose insomnia: persistent sleep difficulties, adequate sleep opportunities, and associated daytime dysfunction" (nih.gov, 2022). Insomnia might be a minor annoyance for some people. Others may have severe disruptions from sleeplessness. For numerous reasons, your body needs sleep and we should try our best to rest and keep you from functioning at your best. We should put this issue under the spotlight: Insomnia is a prevalent sleep disorder that often goes undiagnosed by physicians. However, its effect on the human body is massive. As Dr. Michael Twery, a sleep expert at NIH points out, "Almost every tissue in our bodies is affected by sleep;" and he furthers, "It has an impact on our immune system, appetite, breathing, blood pressure, and cardiovascular health." Among the most common treatments are relaxation techniques and deep breathing exercises. In some cases, medication is also prescribed. But consult your doctor before trying over-the-counter sleep medications, as they may leave you feeling a sense of drowsiness in the morning. How does daridorexant work to treat insomnia? The more widely used treatments today are pharmacotherapy, including those approved by regulatory agencies for the treatment of insomnia, off-label prescription drugs for insomnia, over-the-counter (OTC) sleep aids, and dietary supplements (e.g., melatonin). All of these medications have more serious side effects, including nightmares while sleeping, short-term feelings of depression, stomach cramps, and sleep-related behaviors such as driving while not fully awake. The US Food and Drug Administration authorized daridorexant (Quviviq) for the treatment of adult insomnia in January 2022. Unlike other insomnia medications on the market, daridorexant has very few common side effects. Adult patients with insomnia may use the oral pill daridorexant. It comes from the class of medications known as orexin receptor antagonists. The Orexin receptor antagonist (ORA) is the most recent class of insomnia medications. Every day, your brain produces a protein called orexin that helps you wake up. During the wake-up process, orexin attaches itself to certain nerve cells. In the hours before sleep, orexin is typically less active so you feel sleepy. At that time, other proteins that promote sleep are more active. Daridorexant functions as an ORA by inhibiting orexin from attaching to those nerve cells. As a result, your brain enters sleep mode and remains there for as long as possible. It will take a while for daridorexant to wear off, and then you will feel a natural urge to wake up again. In three phases of clinical studies, most people tolerated Daridorexant well. Headache and sleepiness were the most common side effects. Because of the risk of addiction, Daridorexant has been requested by the FDA to be classified under controlled prescription drugs. How should I take care of myself? March 17th is World Sleep Day, and this year's theme is "Good Sleep, Source of Health". One-third of a person's life is spent in sleep, and a good night's sleep is related to one's the mental outlook and physical health. Here are some techniques you should practice to improve your sleeping quality. Establish healthy sleep habits: Maintain a routine, go to bed regularly at night, and avoid staying on cell phones or TV too long before going to bed. Regulate emotions Face the stresses and challenges in life positively, find relaxation methods that suit you, such as yoga, meditation, and deep breathing, etc. Dietary regulation Avoid drinking large amounts of coffee, tea, and cola, and be careful to eat a light and regular diet. Face insomnia If it is short-term insomnia, there is no need to over panic, you can first self-adjust by the above methods, if self-adjustment is difficult, insomnia persists, or combined with emotional problems, you should seek professional medical help.

Writer｜Rachel Du Layout Designer｜Cecilia Qin Molecular Mechanism of Gastric Progenitor Cell Differentiation That Can Lead to Various Gastric Diseases Defective gastric progenitor cell differentiation is associated with several gastric diseases such as atrophic gastritis, intestinal chemosis and gastric cancer. The gastric body is the major part of the mouse and human glandular stomach and contains functional epithelial cells that secrete mural cell acids, main cell proteases, and pit and neck cell mucus. These cells are continuously replenished by stem/progenitor cell populations in the gastric unit, thus defects in differentiation of gastric epithelial cells are associated with gastric diseases. For example, chronic H. pylori infection can lead to pseudopyloric chemosis, in which proliferating progenitor and premature cells express increased neck and principal cell markers, while the number of mural cells is reduced. Through ultrastructural evidence, we know that in healthy gastric body tissues, highly proliferating isthmus progenitor cells in the upper middle part of the gastric unit differentiate into a variety of epithelial cell lineages, including concave, cervical, mural, and endocrine cells. In the past, the progenitor cells were thought to differentiate from the neck cells, but recent studies have shown that the progenitor cells possesses a stem cell-like self-renewal capacity for maintaining their own numbers. Currently, researchers do not have a clear understanding of the mechanism by which the close coordination between progenitor cell self-renewal and differentiation to maintain tissue integrity. To investigate this process, scientists used Quartz-Seq2, a single-cell RNA sequencing technology, to analyze the gene expression dynamics of progenitor cell differentiation into depressed cell, neck cell and wall cell lineages in healthy adult mouse somatic tissues. The results showed that the EGFR-ERK signaling pathway plays an important role in promoting the differentiation of depressed cells, while NF-κB signaling maintains the undifferentiated state of gastric progenitor cells. Furthermore, inhibition of EGFR in vivo by pharmacology revealed a decrease in the number of recessed cells. This finding was surprising because in previous studies, EGFR signaling was considered to be one of the major predisposing factors for the development of gastric cancer. However, the researchers' findings suggest that in normal gastric homeostasis, EGFR signaling acts as a promotee of differentiation rather than cell mitosis. Gastric gland cell differentiation and signaling studies: The researchers performed a detailed single-cell analysis of the differentiation process of gastric gland cells and explored the regulatory mechanisms involving signaling pathways. EGFR signaling: EGFR is a receptor tyrosine kinase that is associated with overexpression of these receptors in gastric cancer by HER2 (Erbb2) and EGFR. However, this study found that in healthy gastric glands, EGFR signaling acts as a promoter of differentiation rather than cell division. TGFα-EGFR-ERK signaling: TGFα promotes sunken cell differentiation but inhibits sunken cell proliferation via the EGFR-ERK signaling pathway in healthy gastric glands at steady state. TNFSF12-NF-κB signaling: TNFSF12-NF-κB signaling plays a role in isthmic progenitor cell maintenance, maintaining these cells in an undifferentiated state. Limitations of the study are that while computer analysis inferred signaling networks, the study has not validated signaling pathways involved in neck and wall cell differentiation. And, some cellular markers were not detected in their gastric-like organs. Overall, this study broadens the understanding of gastric progenitor cell differentiation in the academic community. activation of EGFR-ERK signaling plays an active role in the differentiation of gastric progenitor cells and contributes to the formation of recessed cells. This finding contributes to further understanding of the mechanisms underlying gastric diseases and provides new ideas for the development of therapeutic approaches for related diseases. However, further studies are still needed to reveal the complete mechanism of gastric progenitor cell differentiation and its relationship with the disease.

Writer | Cylina Wang Layout Designer | Cecilia Qin Artificial Intelligence in drug discovery Artificial intelligence (AI) is revolutionizing the field of drug discovery by enabling researchers to design and test new drugs more speedily and accurately than ever before. This article explores the latest developments in AI-based drug discovery, including its potential applications and implications for society and the pharmaceutical industry. 01 INTRODUCTION The process of developing new drugs is lengthy, complex, and expensive. Trial-and-error experimentation, which is one of the past’s typical methods for drug discovery can take years and cost billions of dollars. On the other hand, technological advancements recently have enabled researchers to use AI algorithms to design new drugs with greater efficiency and accuracy. In this article, we will explore the cutting-edge field of AI-based drug discovery and explore how it is transforming the world of medicine. 02 How AI is Used in Drug Discovery AI is being used in drug discovery in a number of ways. These include predicting the properties of molecules, identifying potential drug targets, and designing new compounds. For instance, using deep learning neural networks to predict the effectiveness of potential drug candidates based on their chemical structures is one of the most promising applications of AI in this field . From this application, researchers can be enabled to identify promising compounds much more quickly than traditional methods. Virtual screening, which is another key application of AI in drug discovery, where people use computer simulations to screen large databases of molecules and predict which ones are most likely to be effective against a particular disease. By using AI, researchers can easliy filter out molecules that are unlikely to be effective, so that they can focus their efforts on a smaller set of compounds, saving time and resources. 03 Benefits of AI in Drug Discovery There are many potential benefits of using AI in drug discovery. First, AI can greatly reduce the time and cost, like bringing new drugs to market. Just to take an example, identify promising compounds more quickly is a great benefit and proved to us that AI has the potential to accelerate the drug development process and bring life-saving treatments to patients faster. In addition, AI-based drug discovery has the potential to improve the safety and efficacy of new drugs. By using computer simulations to predict the behavior of molecules in the body, researchers can identify potential safety concerns early on in the drug development process. This can help prevent costly and potentially dangerous setbacks in the future. 04 Challenges and Future Directions Despite the many benefits of AI-based drug discovery, there are also significant challenges that must be addressed. For example, AI algorithms are only as good as the data they are trained on, and there are concerns about bias and the quality of the data used to develop these algorithms. Looking to the future, AI’s potential in this field is continuing to boost and it could continue transforming the field of drug discovery. As AI algorithms become more sophisticated and data becomes more abundant, researchers may be able to design entirely new classes of drugs that were previously impossible to develop using traditional methods. 05 Conclusion In conclusion, the use of AI in drug discovery is an exciting area of research with enormous potential for improving human health and wellbeing. By enabling researchers to design and test new drugs more efficiently and accurately than ever before, AI has the potential to revolutionize the pharmaceutical industry and bring life-saving treatments to patients faster. However, it is important to address the challenges associated with AI-based drug discovery and ensure that these technologies are used responsibly and ethically.

Writer｜Jessie Liao Layout Designer｜Cecilia Qin Introduction If you see someone sitting in front of you twitching and spasming non-stoppablely, hold back for a few seconds before criticizing them because they may not be able to control it. This is what's known as Tourette syndrome, a neurological disorder that is characterized by sudden unwanted and uncontrolled rapid and repeated movements or vocal sounds called tics. This passage will delve further into this  enigmatic condition that affects approximately 1% individuals of the human population . Potential Cause Tourette syndrome is a heterogeneous disorder in which the phenotypic expression may be affected by environmental factors, such as immune responses. Several studies have indicated that genetic factors play a significant role in the development of Tourette syndrome and its co-occurrence with other disorders, such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). The syndrome has a complex inheritance pattern and, according to various genetic studies, several genes and loci have been correlated with it , including dopamine, serotonin, and norepinephrine, which are neurotransmitters that facilitate communication between nerve cells, or help nerve cells talk to one another. However, all current studies require further confirmation due to lack of consistent results. On the other hand, copy number variations, which are polymorphisms, result from changes in the number of gene copies due to chromosomal deletions or duplications, are also considered significant contributors of mutations for Tourette syndrome. In the past decade, researchers have made exciting discoveries regarding genetic mutations in individuals with Tourette syndrome through whole genome/exome sequencing. Hence, more studies are needed to reveal the exact mechanisms of the underlying syndrome, which may help to provide more information on the prognosis and therapeutic plans. Learning to suppress symptoms, even for brief moments, can significantly improve the quality of life for patients experiencing severe symptoms. This could be a precious experience for those who struggle with managing their condition . Symptoms The defining characteristic of Tourette syndrome is the presence of tics, which are sudden, brief, and intermittent movements or sounds, ranging from mild to severe. Tics are similar to hiccups in that they are involuntary actions of the body, regardless of whether or not one wants to experience them , you just simply can't control them. Symptoms of Tourette syndrome typically start between ages 5 and 10, with the first symptoms often being motor tics, one of the two types apart from vocal tics, in the head and neck area. When dealing with mild symptoms, it is likely for patients to maintain a normal daily routine. However, severe symptoms can severely hamper communication, daily activities, and overall quality of life. Firstly, motor tics, which commonly involve frequent eye blinking, head jerking, shoulder shrugging, darting eyes, nose twitching and even mouth movements. More complex motor tics, which resulted from distinct and coordinated patterns of movements instead of simple and brief ones, include touching or smelling objects, obscene gesturing, bending or twisting and hopping. On the other hand, vocal tics, which produce sounds, are often expressed through grunting, coughing, throat clearing and barking. Complex ones include repeating others' words and phrases or their own, or sometimes even using swear words. These tics show variations among individuals, such as differences in type, frequency, and severity, thus it should be noted that patients may exhibit varying behaviors during an onset, as each individual's response to the situation may differ. Diagnosis Well, not just anyone who makes noises or does something baffling or repetitive is considered to   have Tourette syndrome, often the diagnosis of Tourette syndrome requires a person to have both  motor and vocal tics for at least one year. This diagnosis method relies solely on the judgement of health professionals, unlike other diseases which are diagnosed through methods such as blood tests. Treatment While Tourette Syndrome has no cure, there are treatments available to manage the tics associated with it. For individuals experiencing disruptive tics that cause pain, injury, interfere with daily life or create stress, medication and behavioral treatments like Comprehensive Behavioral Intervention for Tics (CBIT) are available. While CBIT is an acronym for a highly structured therapy that typically takes place in an office on a weekly basis. The process includes habit reversal and education about tics, along with relaxation techniques. It's effective in reducing tic symptoms and related impairment. A therapist works with the person to identify triggers and change surroundings if possible. The person also learns new behaviors to replace tics through habit-reversal techniques. CBIT skills can be learned with the help of an experienced therapist  and support from those close to the person with tic disorders. Behavioral therapy can effectively manage Tourette syndrome symptoms. However, few clinicians are trained in this  approach for tic disorders. The CDC and The Tourette Association of America are working to educate more health professionals in this area. Educating others about Tourette syndrome can reduce teasing and stress for those with the condition. When people understand that tics are involuntary and not purposely made disruptive behavior, they can provide more support which may help lessen symptoms . Medications can help reduce disruptive tics and related symptoms of ADHD or OCD, but they cannot eliminate tics completely. Finding the most suitable medication and dosage may take time, and the presence of side effects should be carefully considered. Medications do not yield the same results for everyone, and side effects or lack of effectiveness may be reasons to avoid their use. Conclusion There is still much to learn about Tourette syndrome, which we know little about. The main reason that we should discover more is that there are still people suffering from it. "These are things you would never notice if you're just having a conversation with me but, for me, they're very exhausting.", is what Billie Eilish, the singer, says about her experience. While the movie "Front  of the Class" depicts the struggles of the main character to become the teacher he always wanted to be, despite his symptoms. Understanding more about this syndrome and showing respect to those who have it is the least we can do before seeking a cure .

Author | Rachelle Wu Editor丨Valuri Yang The secret of neurons regeneration As many people know, almost all the people’s brain stop growing after they finish their adolescence, which mean the ability of nerve regeneration is greatly reduced, and even the regeneration of neurons is stopped. Therefore, when people suffered severe neurological damage after the age of 18, it will be hard for them to recover from the damage and go back to the normal function. For example, Alzheimer's disease (AD) is a degenerative disease of the central nervous system that typically occurs in old age and or pre-old age. This disease is caused by the irreversible cranial nerve death, it is still one of the incurable diseases. If there is a way to regenerate neurons in the brain, this could be a new opportunity for many patients, including those with Alzheimer's disease. Fortunately, neuronal regeneration is not completely impossible, and scientists have found a type of resting or dormant cell called neural stem cells (NSC) in certain areas of the adult brain. These stem cells can be activated and regrown to differentiate into a variety of cell lineages, including astrocytes, neurons, and more. Despite this, little is known about the activation of these dormant cells. How do we activate them? Can NSC be activated in the elderly? How can these NSC be harvested and used effectively? What diseases could this technology be used to treat? A team led by scientists from the Universities of Lausanne and Geneva has discovered that cellular metabolism is important in the activation of NSC and has found a way to activate these stem cells. Scientists have found NSC in parts of the adult brain that can give rise to new neurons over the course of a lifetime. This biological phenomenon is known as adult neurogenesis. The scientists then successfully increased the number of new neurons in the brains of adult and even old mice in the laboratory. However, adult neurogenesis decreases significantly with age. The laboratory led by professor Jean-Claude Martinou ( Emeritus Professor in the Department of Molecular and Cellular Biology at the UN IGE Faculty of Science) and Marlen Knobloch (Associate Professor in the Department of Bio medical Sciences at the UNIL Faculty of Biology and Medicine) discovered a special metabolic mechanism through which NSCs can be activated. They found that mitochondria, organelles that produce energy within cells, are involved in regulating the level of adult NSC activation. Eleven years ago, Professor Martinou’s group found a protein called mitochondrial pyruvate transporter (MPC). MPC plays a special role in this regulation. Its activity affects the metabolic choices available to the cell. By understanding the metabolic pathways that distinguish active and dormant cells, dormant cells can be waken up by modifying mitochondrial metabolism. Professor Jean-Claude Martinou concludes:"These results shed new light on the role of c ell metabolism in the regulation of neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases." Due to the low number of NSC in the adult human brain, stem cell transplants are necessary when large numbers of neural stem cells are required for treatment. The number of cells required for NSC transplantation is huge, and the source of cells has become the primary problem that must be solved in clinical treatment and scientific research. Research has shown that NSC with the ability to self-renew can be isolated from rodent embryonic tissue and human brain tissue. Nowadays, it is clear that there are three sources to get NSC, including direct extraction from primary tissues, differentiation from pluripotent stem cells, and trans differentiation from somatic cells. Currently, NSC transplant technology has the potential to cure many diseases, such as Alzheimer's disease, stroke, spinal cord injury (SCI), traumatic brain injury (TBI), Parkinson's syndrome (PD) and other diseases caused by the reduced or damaged neurons.  At present, patients with these diseases are rarely able to get effective treatment, which troubles many people, and more people will benefit from NSC transplant technology after it is more perfect and popularized.

Author | Olivia Qian Editor丨Valuri Yang 01  Abstract Recently, in a study, scientists at Harvard Medical School discovered a new molecule, CUDC-907, in the fight against aging and age-related diseases. It selectively destroys senescent cells in a zombie state without affecting healthy cells. Not only can this delay aging and improve quality of life and longevity, but the molecule can also effectively eliminate senescent cells that remain in the body after cancer treatment. 02   Keywords Aging, Mitochondria, Cancer, DNA, NCC system 03   Experiment process In this study, the researchers explored molecules capable of simultaneously reversing cellular aging and restoring vitality to human cells. They developed a cell-based assay, known as NCC, to distinguish between young and senescent cells. The team used advanced cell-based assays to identify six chemical mixtures, some of which are used to treat a variety of physical and mental illnesses. These drugs can be used to treat epilepsy, depression, or Parkinson's disease. In addition, the research team conducted experiments and studies on mice and monkeys and found that the chemical mixture can rejuvenate mouse and monkey cells, improve vision and prolong life. It turns out that these chemical combinations can restore genes to a youthful state, reversing transcriptome age in less than a week, and studies of various organs and tissues such as the optic nerve, brain tissue, kidneys, and muscles in animals have yielded encouraging results. 04   Result Using a signature known as aging-related secretion phenotype (SASP), the scientists found that aging is related to cell morphology, chromatin structure, and the release of inflammatory factors, and found that Yamanaka factors OCT4, SOX2, and KLF4 (OSK) can restore the initial form and function of senescent cells. The researchers are now planning human clinical trials to test the safety and effectiveness of the chemical mixture. The implications of this new discovery are far-reaching, and by developing chemical alternatives to reverse aging, this research could revolutionize the treatment of aging, injury, and age-related diseases, with enough potential to save money and time. 05   Risks and difficulties Although scientists have developed new chemical molecules that can reverse aging, there may be unintended consequences and side effects. Another risk is human complexity. Although it has achieved great success in animal experiments, there can be surprises when it is translated into the human body. In addition, aging can raise ethical issues, and these interventions may affect social class inequality, leading to social chaos. 06 A natural compound that can fight aging 1. Vitamin A compounds, such as retinol and retinoic acid, can make crow's feet and dark spots fade and improve photoaging. 2. Vitamin C is an antioxidant that protects the skin from sun damage and reduces fine lines and wrinkles 3. Peptides, these molecules are natural components of living organisms that stimulate collagen production and make skin glow. 4. Grape seed extract, the anti-aging effect mainly comes from proanthocyanidins, which can remove toxic free radicals in the human body and protect cell tissues from free radical oxidation.

Author｜Penny Pang Layout Designer｜Cecilia Qin Breast Cancer IGFBP2 protein/breast cells/adipocytes According to the latest data from the World Health Organization, breast cancer has surpassed lung cancer to become the world's leading tumor. This long-latent and deeply hidden "female killer" has been gradually gaining attention. Various methods for treating different types of breast cancer have emerged in recent years. This article will explain the latest research findings in the field of breast cancer – healthy human breast and normal tissue fat cells secrete IGFBP2, which can effectively prevent the spread of breast cancer cells. Introduction Breast cancer (BC) is a disease characterized by the uncontrolled growth of abnormal breast cells, leading to the formation of tumors. Breast cancer cells originate in the milk ducts and/or lobules within the breast. The earliest form (in situ) does not pose a life-threatening risk. However, as the growth becomes uncontrolled, cancer cells spread to nearby breast tissues (invasive), ultimately forming tumors with the appearance of lumps or thickening and causing life-threatening [1]. According to pathological classification, breast cancer is typically categorized as non-invasive carcinoma, early-stage invasive carcinoma, or invasive carcinoma, etc. As the global incidence of breast cancer continues to rise, the development of metastatic disease remains a major cause of death. For breast cancer patients, the progression from non-invasive ductal carcinoma in situ (ductal carcinoma in situ DCIS) to invasive ductal carcinoma (IDC) leads to a significantly worse prognosis and is a precursor to metastatic disease. Latest Research The tissue composition of the human breast is unique, healthy breast stroma has sparse extracellular matrix (ECM) and a significant number of fat cells capable of secreting insulin-like growth factor-binding protein 2 (IGFBP2). In contrast, breasts of breast cancer patients exhibit high fibrosis (increased ECM deposition) and a reduction in the size and quantity of fat cells near the tumor. Changes in breast stroma are crucial factors in the progression of breast cancer, leading research teams to stain slices of healthy breast tissue with IGFBP2 to assess the physiological relevance of this discovery. Unexpectedly, the stain displayed a strong positive IGFBP2 signal in fat cells (as shown in Figure 1). To further explore the clinical significance of these, researchers stained slices of healthy breast tissue, DCIS, and IDC patient samples and found a significant decrease in the number of IGFBP2-positive cells in breast cancer patients compared to the healthy state. Moreover, compared to DCIS and healthy samples, the expression of IGFBP2 in fat cells was significantly reduced in IDC samples, with a further decrease in fat cells at the tumor boundary compared to the pre-invasive cancer stage (Figure 2). The study found that co-culturing cancer cells with fat cells that secrete IGFBP2 significantly reduced cancer cell invasion into the fibrous collagen I matrix (Figure 3). Adding fat cells to the co-culture system also significantly reduced cancer cell multiplication, suggesting that apart from IGFBP2, fat-secreted factors play an additional role in cancer suppression. Overall, these findings reveal the role of healthy breast fat cells in restraining cancer invasion. However, further research on the question of how IGFBP2 exerts its anti-invasive function is needed. Conclusion

Writer | Katherine Yang Layout Designer | Cecilia Qin IMMUNOTHERAPY Cancer is also known as a malignant tumor. As the first of the top ten causes of death for human beings, it has always been a problem that has troubled us very much. Since the beginning of the development of medicine, human beings have been trying many ways to treat cancer. There are currently five major methods for cancer treatment: surgery, chemotherapy, radiation therapy, targeted drugs, and the latest immunotherapy. This article will focus on immunotherapy that drives human immune function, which can be subdivided into four primary methods: immune drugs, immune cell therapy, cancer vaccines, and bacterial therapy. How do cancer cells avoid the search of immune cells? As everyone knows, the occurrence of cancer is the continuous proliferation of cells caused by abnormal mutations in human genes, and it is extremely difficult for human immune cells to recognize cancer cells, which often leads to people finding it after seeking medical treatment due to discomfort. Normally, such abnormal cells should be discovered and killed by immune cells. However, cancer cells evade the search of immune cells by relying on his three tricks. Therefore, understanding the principle of cancer cell evasion is the key for humans to find corresponding treatment methods. Trick 1: Pretend to be a transparent person Almost all nucleated cells in vertebrates contain a very important protein—Major histocompatibility complex class I (MHC-I). MHC-I is the key for immune cells to distinguish between friend and enemy. When a cell is infected by a virus or becomes cancerous, it will present virus or tumor antigens through the MHC-I on the cell surface, allowing immune cells to kill the mutated cells. Cancer cells will reduce the concentration of their own MHC-I and turn themselves into "transparent people" to avoid the search of immune cells. Trick 2: I am a good person There is another protein on the surface of normal cells in the human body -- CD47. When CD47 binds to the signal regulatory protein α (SIRPα) on the surface of immune cells,  it will display a "don't eat me" signal to immune cells. Normally, CD47 is only present on the surface of normal cells, but the researchers found that cancer cells also have CD47 on the surface. In other words, when immune cells encounter cancer cells, they think the cancer cells are good people. Trick 3: Stop immune cells from attacking In order to prevent immune cells from being crazy and causing a cytokine storm in patients, immune cells have some unique "brake mechanisms" called "immune checkpoints". There are currently three known T cell immune checkpoints, namely PD-1, CTLA-4, and LAG-3; and there are also special proteins on the surface of cancer cells that can bind to immune checkpoints, reducing the ability of T cells to attack. The development of cancer treatment Humans can't understand cancer overnight. Actually, it takes us thousands of years. According to historical records, as early as 3000 BC, doctors at that time had used surgical resection to treat cancer, but it was not until 1891 AD that new treatments appeared. In 1891, American physician William Curley first used bacteriotherapy, which uses bacteria to treat cancer in the human body. However, at that time, Dr. Curley could not explain the principle of the therapy, so he was widely opposed by the academic community. Through time came the 20th century, when radiation therapy, chemotherapy, and targeted therapy appeared one after another. And at the beginning of the 21st century, was the time when immunotherapy (immune drugs, cell therapy, etc.) flourished. However, as scientists have understood the principles of bacterial therapy in recent years, perhaps bacterial therapy will become another new trend. Immunotherapy In 2007, Nature magazine published a paper confirming the connection between cancer cells and the immune system. And the paper further pointed out that T cells have the highest correlation with the occurrence of cancer. Therefore, humans have started research on T cells and cancer treatment. Immunological drugs The full name of immune drugs is commonly known as immune checkpoint inhibitors, which subdue cancer cells by using the third trick mentioned above. Taking PD-1 on the surface of T cells as an example, PD-1 will bind to PD-L1 on the surface of cancer cells, resulting in a decrease in the attacking ability of T cells. Immunopharmaceuticals use drug molecules to preempt cancer cells and bind to PD-1; however, this combination does not lead to a decrease in the attacking ability of T cells and only avoids the possibility of combining PD-1 and PD-L1. Immunopharmaceuticals can be applied to 17 types of cancer, including lung cancer, gastric cancer, esophageal cancer, head and neck cancer, cervical cancer, and hepatocellular carcinoma, with mild side effects, and the activation effect on the immune system can be preserved for 3 to 5 years after stopping the drug. However, with current technology, the success rate of this therapy is not high, and only 15% to 30% of solid tumor cancers respond to immune drugs. Doctors currently use three indicators to judge whether a patient is suitable for immunotherapy, namely the expression of PD-L1, microsatellite instability (MSI), and tumor mutation load (TMB). The expression of PD-L1 The higher the expression of PD-L1 on cancer cells, the higher the probability of effective immunotherapy. According to the latest ESMO Guidelines in 2019, when a patient's PD-L1 expression is ≥ 50%, immunotherapy is suitable for first-line treatment; if the patient's PD-L1 expression is < 50%, it is recommended to use Chemotherapy and immunological drugs together. Microsatellite instability (MSI) Microsatellites refer to DNA repeats in cancer cells. The higher a patient's MSI is, the more unstable his DNA is, making it easier for the immune system to identify abnormal cells. Tumor mutation load (TMB) The principle of TMB is similar to that of MSI. The more mutated a tumor is, the more likely it is to produce mutated proteins and trigger the body's immune response. Immune cell therapy At present, researchers have discovered two methods of immune cell therapy, CAR-T cell therapy invented in 2019, and TCR-T cell therapy invented at the end of 2022. Both of these cell therapies "strengthen" T cells in the body through gene editing. The following will introduce the two therapies separately. CAR-T cell therapy The secret weapon to strengthen T cells - CAR CAR is the abbreviation of Chimeric Antigen Receptor. As the name suggests, CAR-T cell therapy is to add chimeric antigen receptors on the surface of T cells through gene editing. The CAR can be regarded as a protein composed of three parts. The protein outside the T cell is an antibody molecule with high specificity and strong affinity for the surface antigen of the cancer cell; the middle block is responsible for maintaining the stability of the CAR so that it can maintain on the surface of T cells; and the block in T cells can be used to trigger intracellular signaling pathways. When a CAR antibody attached to the surface of a T cell comes into contact with a cancer cell, the CAR activates the T cell, causing it to kill the cancer cell. Therefore, in theory, as long as the antibody at the top of the CAR protein is replaced, various cancers can be attacked, which is also the biggest incentive for major pharmaceutical companies to develop one after another. The limitations of CAR-T cell therapy There are currently only six CAR-T cell preparations approved by the US Food and Drug Administration (FDA), all of which are used to treat blood and lymphoid cancers. Among them, CAR-T cells are most effective in the treatment of Acute B Lymphocytic Leukemia (ALL), with an effective rate of more than 90% for advanced patients. But CAR-T cell therapy is less effective for cancers with solid tumors, and there are three reasons. The first reason is the heterogeneity of solid tumors. From a microscopic perspective, each tumor is composed of many kinds of mutated cancer cells. That is to say, the location of the mutation in the cancer cells in the tumor is not the same. But CAR-T cell therapy is to find "commonly owned" antigens on the surface of cancer cells. So obviously, the heterogeneity of solid tumors has a great conflict with the fundamental principle of CAR-T cell therapy. If the mutations between cancer cells are different, the antigens presented on their surface will also be different. If CAR-T cells are administered, there will always be some cancer cells that are not killed, and these surviving cancer cells will multiply rapidly and occupy the position of the dead cancer cells. The second reason is that the blood vessels in the tumor cannot keep up with the proliferation of cancer cells, resulting in the tumor being always in a state of hypoxia. Even if the immune cells successfully enter the tumor, they will not be able to function due to hypoxia. Third, cancer cells secrete chemicals that suppress the activity of immune cells and also make immune cells unable to function. Of course, this is not completely insurmountable. Researchers are now trying to make more CAR on the surface of T cells, but the concept is still experimental. However, in addition to being unable to overcome solid cancers, CAR-T cell therapy has another dilemma waiting for a breakthrough. Since the current technology uses the patient's own T cells, this allows CAR-T cells to be reinfused into the patient without rejection. However, this production method also makes CAR-T cell therapy an extremely personalized therapy, which cannot be mass-produced, which makes the cost of treatment unaffordable. Therefore, the next step of CAR-T cell therapy is to find a way to find T cells that can be used by several people, so as to reduce the cost of the customization process, but so far, humans still cannot overcome the rejection of allogeneic transplantation. The side effects of CAR-T cell therapy Although CAR-T cell therapy drives the body's immune response to fight cancer cells, it also has a chance of causing side effects. Because a large number of T cells are injected into the human body in a short period of time, the immune system will still be disturbed to a certain extent. And when CAR-T cells attack cancer cells, a violent immune response will also occur. However, the length of time and symptoms of side effects are not the same for each person, and the side effects can be roughly divided into three categories. The first type is Inflammatory factors, leading to a series of symptoms such as fever, chills, rapid heartbeat, shortness of breath, dizziness, nausea, vomiting, diarrhea, and joint pain. In the most severe cases, coma may also occur. The second type is neurotoxic syndrome, a symptom which caused by immune cells "accidentally injuring" the central nervous system. When the nervous system carries the same type of antigen as the cancer cells, or the cancer cells are near the nervous system, the nervous system will be accidentally injured. The patient will develop headaches, tremors, muscle stiffness, convulsions, unresponsiveness, poor balance, or unconsciousness. The third type is side effects from other treatments, such as allergic reactions during infusions, or immune system reactions after treatment. weaken. All in all, CAR-T cell therapy has the risk of acute side effects, so it needs to be observed in the hospital for several days after treatment. The latest research direction of CAR-T cell therapy Since CAR-T cell therapy is a new technology developed in 2019, there are still many technical problems waiting to be overcome, which has attracted many scientists to invest in research. This article selects two recent breakthrough studies to share with you. Science Advances, April 8, 2022: CAR-T cells are encapsulated in a special hydrogel containing cell-stimulating factors that increase cell activity. Encapsulating CAR-T cells in hydrogel allows the body to maintain a certain concentration of cells and maintain cell activity. Science, December 16, 2022: Make CAR-T cells have their own stimulants, and add a gene to CAR-T cells so that they can secrete substances that stimulate their own excitement when they come into contact with cancer cells. TCR-T cell therapy The name of TCR-T cell therapy is similar to CAR-T cell therapy. TCR is the abbreviation of T cell receptor, which is a protein that can help T cells distinguish friend from enemy. By means of computer algorithms (guess how to modify the genes of T cells) and gene editing technology (Crispr-Cas9), humans can make T cells exhibit TCR. Even if MHC-I is reduced, immune cells can Navigate proteins to find cancer cells. In addition to the similar naming methods, TCR-T cell therapy and CAR-T cell therapy also have the same side effects to be overcome. However, this new technology published in Nature in November 2022, is expected to treat cancers with solid tumors such as lung cancer, breast cancer, and colorectal cancer. Cancer vaccines Cancer vaccines are the direction that many biotechnology companies have invested in research in recent years, such as Moderna and BNT, the two biotechnology companies that have developed COVID-19 vaccines. The initial research directions of these two companies were both cancer vaccines. During the process, they just developed mRNA technology. As a result, they happened to meet the outbreak of COVID-19, so the two companies turned to research COVID-19 vaccines. The reason why the COVID-19 vaccine can be launched in just one year can be said to rely on previous research results in the field of cancer vaccines. It is not an exaggeration to say that the COVID-19 vaccine is an additional product of cancer vaccines. The cancer vaccines are different from vaccines that the general public is familiar with. Vaccination is not to "prevent" disease, but to prevent the "relapse" of disease. Take the hepatitis B vaccine as an example. Everyone is exposed to the same virus, so the ingredients of the vaccine are also the same. But in the case of cancer, the gene mutation of each cancer cell is different. It is tailor-made for each patient, so it is impossible to make a vaccine for the general public. However, cancer vaccines are not a research direction that has only emerged in the past few years. As early as 13 years ago, in 2010, the world's first cancer vaccine, Provenge vaccine, which also known as Sipuleucel-T vaccine was born. This vaccine is mainly used to treat prostate cancer. But it is a pity that the development of cancer vaccines hit the wall in the next ten years, no second vaccine has been on the market. Having said that, if broadly defined, there are two vaccines that are familiar to the public can also be positioned as cancer vaccines, namely the human papillomavirus (HPV) vaccine and the hepatitis B vaccine. HPV vaccine can effectively reduce the risk of cancer because it can prevent viral infection. The hepatitis B vaccine can prevent hepatitis and cirrhosis, and indirectly reduce the chance of liver cancer. All in all, because of the failure experience of more than ten years, many researchers or scientists still doubt the feasibility of cancer vaccines, but many people are optimistic. According to a review report in Lancent Onology in October 2022, there are many mRNA vaccines underway or about to undergo clinical trials, covering cancers such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, ovarian cancer, and head and neck cancer. At present, there are many data pointing out the brilliant performance of cancer vaccines. When cancer vaccines are combined with immunotherapy, the risk of recurrence or death of patients with advanced melanoma is reduced by 44%. On May 10, 2023, Nature  magazine published the results of a phase I human clinical trial of a pancreatic cancer vaccine, showed that some of the subjects produced cancer cells that could fight tumors. Pancreatic cancer is very difficult to treat, and it is also known as the "cancer king", so this result is very important and fell exhilarating. And in April 2023, Moderna told the British Guardian that they are confident that mRNA vaccines for cancer, cardiovascular disease and autoimmune diseases will be made before 2030. The chief of the medical officer even says the the cancer vaccines may be possible ready within five years. Bacterial therapy "Bacteria are not necessarily enemies, they may be allies" In 1891, American doctor William Coley injected Streptococcus pyogenes into the tumor for the first time, completely eliminating the cervical sarcoma cancer in the patient. In the following 30 years, Dr. Coley used bacterial therapy to save more than 1000 patients. However, at that time, Dr. Coley could not explain the principle of the therapy, and even the cause of the tumor could not be explained at that time, so he was opposed by the academic circles. In modern times, 100 years later, the academic community was finally able to explain the principles of bacterial therapy, and called Ke Lizun the father of immunotherapy. In the past 10 to 20 years, as the relationship between cancer and immunity has gradually become clear, bacterial cancer therapy has made a comeback, and scientists have used their favorite strains to conduct cancer treatment experiments. In this article, three kinds of bacteria that are more popular and have been clinically tested are selected to share with you. Listeria monocytogenes Listeria monocytogenes is an intracellular pathogen that can grow inside human cells. Phagocytes that invade the human body, grow and multiply inside the cell, and present specific antigens on the surface. Humans use gene transfer to make Listeria show specific antigens, such as mesothelin, which only appears in pancreatic cancer and ovarian cancer. Use the specific antigens displayed by bacteria to exercise the immune cells of the human body, so that the immune cells can respond to the antigens carried by cancer. In 2015, researchers successfully used Listeria that had been weakened to express mesothelin to treat patients with end-stage pancreatic cancer. Clostridium butyricum Clostridium butyricum is a probiotic bacteria developed in Japan in 1933, also known as "butyric acid bacteria" or "CB bacteria". As a probiotic, Clostridium butyricum not only maintains gut health and relieves depression, but also significantly increases the response rate of immune checkpoint inhibitors (enhancing the effect of immune boosters). On February 28, 2022, a paper published in Nature pointed out that in patients with end-stage kidney cancer, if thalidomide butyrate is used together with immune checkpoint inhibitors, the patient's response rate can increase by 58%. Compared with the 20% response rate of immune checkpoint inhibitors alone, it is clear that the combination of the two is more effective. Mycobacterium tuberculosis Mycobacterium tuberculosis is an aerobic microorganism, which is the culprit that causes tuberculosis in humans. In 1882, German microbiologist Robert Koch was awarded the Nobel Prize in Physiology or Medicine in 1905 for his discovery of Mycobacterium tuberculosis as the causative agent of tuberculosis. In 1900, Albert Calmette and Camille Guérin began research on a tuberculosis vaccine. The research process can be said to be full of twists and turns, and the experiment process was interrupted many times due to the First World War. In the end, it took them nearly 20 years to develop a vaccine to overcome tuberculosis - Bacille Calmette-Guérin(BCG). The BCG vaccine is an active vaccine made from weakened tuberculosis bacteria, which can produce resistance to tuberculosis. In 1959, a Nature paper accidentally discovered that mice given BCG could greatly delay the growth of tumors. So on the basis of BCG, the researchers developed another drug, Onco-BCG. If Onco-BCG is injected into the bladder, it can treat early bladder cancer or prevent bladder cancer recurrence. After Onco-BCG is injected into the human body, it can call more white blood cells to the bladder and stimulate the activity of white blood cells to kill cancer cells. Onco-BCG itself also has the effect of directly inhibiting tumor growth. Conclusion After introducing so many kinds of immunotherapy, I believe everyone has realized the importance of immunotherapy for the treatment of cancer. Scientists are also optimistic that under the treatment of immunotherapy, cancer may have the opportunity to transform the deadly killer of human beings into a common chronic disease. However, no matter what kind of immunotherapy, there is still a long way to go, especially the high cost of treatment is also a difficulty waiting for researchers to overcome.

Author|Asteria Editor|Hecate Ye /Introduction/ Gene therapy is a field of medical research that aims to treat disorders through genetic modification. It involves transferring genetic materials into the cells of patients. In recent years, gene therapy has made significant progress and has been approved for clinical use to treat diseases such as cancer and neurodegenerative disorders. /Strategies/ DNA editing One way to manipulate gene therapy is through DNA editing. There are three main DNA-editing nucleases: zinc-finger nucleases(ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-associated nucleases. ZNFs have two domains: a DNA binding domain that recognizes the DNA in the host genome and a DNA-cleaving domain of Fok1, which is functional as a dimer and cleaves the DNA near the recognition sites. TALENs have Fok1 DNA-cleavage domains like ZNF and transcription activator-like effectors (TALEs)， which are proteins that bind to DNA and manipulate its expression. CRISPR systems use a guide RNA(gRNA) to target a Cas9 protein to target specific sites. gRNAs contain two parts: CRISPR RNA (crRNA) and transactivating CRISPR RNA (tracrRNA). crRNA contains sequences complementary to the DNA sequence that is to be modified and guides Cas9 to the desired location while tracrRNA provides stability. Cas9 modifies DNA by generating double-stranded breaks(DSBs), which are repaired by nonhomologous end-joining (NHEJ). NHEJ is an error-prone DNA repair mechanism that may result in sequence insertions and deletions (INDELs). INDELs typically cause premature termination codons (PTCs), meaning that the protein synthesis process stopped earlier than expected. PTCs would be degraded by nonsense-mediated decay (NMD), a mechanism that recognizes and eliminates mRNAs containing PTCs, thus knocking out the targeted gene. RNA editing RNA-based editing alters RNA, which is transient, resulting in less risk of permanent side effects. The downside of this strategy is that it needs to be injected repeatedly. Antisense oligonucleotides (ASOs), which are synthetic strands of nucleic acids that interfere with the maturation of pre-mRNA to RNA through Watson-Crick base pairing, are used. During maturation, splicing, which is the process in which introns are excluded and exons are joined together, occurs. The exonic enhancers promote exon inclusion and exonic silencers promote exon exclusion. ASOs interfere with this process by including exons that are not usually translated, known as splice inclusion, or the opposite, known as splice exclusion or exon skipping. Cas13d is another tool for RNA editing. It can be packed into a single adeno-associated virus (AAV) for delivery. AAVs are the main non-integrating vectors for in vivo gene therapy, meaning that they deliver the gene into the host cell directly without integrating the DNA into the cell. Cas13 has spacer sequences that are complementary to RNA, and it binds to target RNA, breaking it into small parts and resulting in gene knockdown. /Application/ Alzheimer’s Disease（AD） Alzheimer’s disease is a neurodegenerative disorder characterized by memory loss, difficulties in communication, and impairment of daily functioning. Three genes are targeted for gene-based therapies of AD: APP and microtubule-associated protein tau (MAPT). MAPT encodes tau proteins, which form neurofibrillary tangles in brains, causing symptoms of AD. ASOs decrease MAPT expression and thus prevent tau phosphorylation, thus lowering the levels of tau proteins in cells. APPs are glycoproteins that are cleaved by β-secretases and γ-secretases, proteolytic enzymes in brains, to produce Aβ peptides. One hallmark of AD is the accumulation of plaques, which are primarily made of amyloid β（Aβ）peptides, in brains. Parkinson’s Disease（PD） PD is a neurodegenerative disorder that affects movement control. It has the symptoms of rigidity, tremor, and hypokinesia, which is a decrease in physical activities. One cause of PD is the loss of dopaminergic neurons, neurons that produce and release the neurotransmitter dopamine. Gene therapies have been employed to upregulate dopaminergic signaling in PD. The dopamine synthesis pathway is regulated by three rate-limiting enzymes—GTP cyclohydrolase 1 (GCH1), tyrosine hydroxylase (TH), and aromatic amino acid DOPA decarboxylase (AADC). Gene transfer of GCH1, TH, and AADC into cells enables a high level of conversion of Levodopa precursor of dopamine and medication used in the treatment of PD, into dopamine This therapy is AAV-based and has achieved a modest relief in the symptoms. Disease genes can also serve as gene targets. SMCA, a gene encoding α‐synuclein, acts as a gene target, as mutations in SNCA result in increased levels of α‐synuclein. In rodent models of PD, the knockdown of α‐synuclein through ASO prevents neurodegeneration, and CRISPR-mediated downregulation of α-synuclein has also shown a positive effect. LRRK2 is another disease gene. Variants in LRRK2 increase the risk of developing neurodegenerative disorders, so inhibition of LLRK2 is a viable approach for therapy. However, LLRK2 is also expressed in the lungs, kidneys, and spleen, so global inhibition of LRRK2 is risky. Gene therapy is useful as it specifically inhibits LRRK2 in brains. Intracerebral injection of LRRK2 ASOs is effective in decreasing LRRK2 mRNA levels without obvious side effects. Chimeric antigen receptor (CAR)-T cell therapy CAR-T therapy is a type of immune therapy that uses the power of the patient’s immune system against cancer cells. This therapy involves genetically modifying T cells to express CARs, which are synthetic receptors that are added to T cells to enhance their ability to recognize and attack cancer cells. The first step of CAR-T therapy is to collect the T cells from the patient through blood, then genetically modify the cells to express CAR, forming CAR-T cells. These cells are then cultured and expand in numbers before they are infused into the patient’s body, where they travel and seek out cancer cells. When CARs on the surface of CAR-T cells recognize the antigen in the cancer cells, they attack and destroy the cancer cells. CARs consist of four main domains. The first domain, the extracellular target antigen-binding domain, binds to a particular antigen on the target cell. It consists of variable heavy (VH) and light (VL) chains, linked together by a linker to form a single-chain variable fragment (scFv). The second domain, the hinge region, is a flexible linker that provides stability and allows the scFv domain to bind to the targeted antigen. The length and composition of the hinge region have an impact on CAR functionality. The third domain, the transmembrane domain, anchors CAR to the T cell membrane, and it’s often derived from CD28 or CD8, which are glycoproteins found on the surface of cytotoxic T cells. It ensures that CAR inserts into T cells properly, allowing the extracellular domain to face outward and interact with the target antigen. The fourth domain is the intracellular signaling domain, which is responsible for transmitting signals and activating immune responses when the target antigen is recognized. Most intracellular signaling domain contains proteins called CD3ζ. CD3ζ contains three immunoreceptor tyrosine-based activation motifs (ITAMs), which release signals when it is phosphorylated, activating T cells. /Conclusion/ Though gene therapies are still in the early stages and face several challenges, they provide great hope for countless patients demonstrate huge potential, and hold immense promise for the future of medicine. We hope that more research can be done so that the therapies can be used effectively and can be used to treat more patients.