Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Personalized medicine and opioid use disorder

Opioid use disorder(OUD)is a major public health problem affecting millions of people worldwide.Although OUD is a chronic and relapsing disorder,a variety of pharmacological and non-pharmacological interventions are available.Medication-assisted treatment of OUD generally relies on competition for opioid receptors against the addictive substance.The mechanisms of this competition are to block or inactivate the opioid receptor or activate the receptor with a substance that is intermittent or long acting.Methadone and buprenorphine are two United States Food and Drug Administration-approved medications that have long-term positive effects on the health of opioid-dependent individuals.Although clinical studies of drugs generally demonstrate efficacy in thousands of people and toxicity is excluded,it cannot be predicted whether the given drug will cause side effects in one of the patients at the treatment dose.Individual differences can be explained by many biological and environmental factors.Variations in genes encoding drug metabolism or cellular drug targets significantly explain the variability in drug response between individuals.Therefore,for the effects of candidate genes to be accepted and included in individual treatment protocols,it is important to repeat studies on individuals of different ethnic backgrounds and prove a similar effect.

Personalized medicine:Clinical oncology on molecular view of treatment

Cancer,the second leading global cause of death,impacts both physically and emotionally.Conventional treatments such as surgeries,chemotherapy,and radiotherapy have adverse effects,driving the need for more precise approaches.Precision medicine enables more targeted treatments.Genetic mapping,alongside other molecular biology approaches,identifies specific genes,contributing to accurate prognoses.The review addresses,in clinical use,a molecular perspective on treatment.Biomarkers like alpha-fetoprotein,beta-human chorionic gonadotropin,5-hydroxyindoleacetic acid,programmed death-1,and cytotoxic T lymphocyte-associated protein 4 are explored,providing valuable information.Bioinformatics,with an emphasis on artificial intelligence,revolutionizes the analysis of biological data,offering more accurate diagnoses.Techniques like liquid biopsy are emphasized for early detection.Precision medicine guides therapeutic strategies based on the molecular characteristics of the tumor,as evidenced in the molecular subtypes of breast cancer.Classifications allow personalized treatments,highlighting the role of trastuzumab and endocrine therapies.Despite the benefits,challenges persist,including high costs,tumor heterogeneity,and ethical issues.Overcoming obstacles requires collaboration,ensuring that advances in molecular biology translate into accessible benefits for all.

Banking of perinatal mesenchymal stem/stromal cells for stem cellbased personalized medicine over lifetime:Matters arising

Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefits for patients.MSCs derived from either human adult or perinatal tissues have their own unique advantages in their medical practices.Usually,clinical studies are conducted by using of cultured MSCs after thawing or short-term cryopreserved-then-thawed MSCs prior to administration for the treatment of a wide range of diseases and medical disorders.Currently,cryogenically banking perinatal MSCs for potential personalized medicine for later use in lifetime has raised growing interest in China as well as in many other countries.Meanwhile,this has led to questions regarding the availability,stability,consistency,multipotency,and therapeutic efficiency of the potential perinatal MSC-derived therapeutic products after longterm cryostorage.This opinion review does not minimize any therapeutic benefit of perinatal MSCs in many diseases after short-term cryopreservation.This article mainly describes what is known about banking perinatal MSCs in China and,importantly,it is to recognize the limitation and uncertainty of the perinatal MSCs stored in cryobanks for stem cell medical treatments in whole life.This article also provides several recommendations for banking of perinatal MSCs for potentially future personalized medicine,albeit it is impossible to anticipate whether the donor will benefit from banked MSCs during her/his lifetime.

Personalized medicine approach to osteoporosis management in women: integrating genetics, pharmacogenomics, and precision treatments

Osteoporosis has emerged as a significant health issue among postmenopausal women.Addressing this concern necessitates a multifaceted approach encompassing genetics,pharmacogenomics,bone turnover markers,lifestyle factors,concurrent medical conditions,biomarkers,and advanced imaging techniques.Nonetheless,challenges in terms of cost-effectiveness and ethical considerations do exist.Fortunately,the convergence of technological progress and research endeavors offers a promising trajectory.The integration of genetic testing and pharmacogenomics into clinical practice holds substantial potential.This integration empowers healthcare professionals to forecast treatment responses and pinpoint individuals with elevated susceptibility,thereby enabling the implementation of tailored and efficacious interventions that optimize outcomes–personalized medicine.Given the intricate nature of osteoporosis,personalized strategies stand to greatly benefit women grappling with this condition.Further research and collaborative efforts are imperative to propel advancements within this domain,paving the way for further breakthroughs.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

Nano-revolution in hepatocellular carcinoma:A multidisciplinary odyssey-Are we there yet?

In this editorial we comment on the review by Zhou et al reviewing the landscape of nanomedicine in the treatment of hepatocellular carcinoma(HCC).We focus on the immense potential of nanotechnology,particularly ligand-receptor mediated nanotherapy,in revolutionizing the treatment landscape of HCC.Despite advan-cements in multidisciplinary treatment,HCC remains a significant global health challenge.Ligand-mediated nanotherapy offers the opportunity for precise drug delivery to tumor sites,targeting specific receptors overexpressed in HCC cells,thereby enhancing efficacy and minimizing side effects.Overcoming drug resistance and aggressive tumor biology is facilitated by nanomedicine,bypassing traditional hurdles encountered in chemotherapy.Examples include targeting glypican-3,asialoglycoprotein,transferrin receptor or folic acid receptors,capitalizing on their over-expression in tumor cells.The ability for multi-receptor targeting through dual-ligand nanoparticle modification holds the prospect of further enhancement in specificity and efficacy of directed therapy.However,challenges including immune responses,reproducibility in nanoparticle synthesis,and production scalability remain.Future directions involve refining targeting strategies,improving drug release mechanisms,and streamlining production processes to enable personalized and multifunctional nanotherapies.Overall,the integration of nanotherapy in HCC treatment holds immense promise,but continued partnership and effort are needed in offering hope for more effective,precise,and accessible clinical care in the management of HCC.

Frequency of and reasons behind non-listing in adult patients referred for liver transplantation: Results from a retrospective study

BACKGROUND Few studies have evaluated the frequency of and the reasons behind the refusal of listing liver transplantation candidates.AIM To assess the ineligibility rate for liver transplantation and its motivations.METHODS A single-center retrospective study was conducted on adult patients which entailed a formal multidisciplinary assessment for liver transplantation eligibility.The predictors for listing were evaluated using multivariable logistic regression.RESULTS In our center,314 patients underwent multidisciplinary work-up before liver transplantation enlisting over a three-year period.The most frequent reasons for transplant evaluation were decompensated cirrhosis(51.6%)and hepatocellular carcinoma(35.7%).The non-listing rate was 53.8%and the transplant rate was 34.4%for the whole cohort.Two hundred and five motivations for ineligibility were collected.The most common contraindications were psychological(9.3%),cardiovascular(6.8%),and surgical(5.9%).Inappropriate or premature referral accounted for 76(37.1%)cases.On multivariable analysis,a referral from another hospital(OR:2.113;95%CI:1.259–3.548)served as an independent predictor of non-listing.CONCLUSION A non-listing decision occurred in half of our cohort and was based on an inappropriate or premature referral in one case out of three.The referral from another hospital was taken as a strong predictor of non-listing.

Next Generation Sequencing in Oncological Diagnostics: Hype or Hope?

The understanding of how genetic and epigenetic factors influence tumorigenesis, progression and invasion, is vastly growing since new technologies allow the analysis of the functional genome namely the exome, the transcriptome and the epigenome, besides enabling genome-wide assessment of genetic variations. With the advent of new drugs that are indicated tissue agnostic, depending on certain mutations, there is a growing demand for fast and cost-effective genetic diagnosis. The method in focus that already became an indispensable tool in viral diagnosis is next-generation sequencing (NGS). This approach allows sequencing of literally every DNA molecule in the sample and can either be used to assess numerous genetic markers of one patient at a time, or to assess fewer markers of many patients in parallel, which reduces costs. We submitted 23 samples of different tumor entities to four diagnostic companies with different analysis profiles. The results as disclosed and discussed in this report indicate that so far, the main application of NGS is rather in cancer research than in diagnosis, as none of the reports had a real impact on the therapeutic scheme. We are perfectly aware that such a small cohort cannot be generalized, but considering the costs vs. benefits, NGS should be engaged upon a very stringent evaluation only. However, in cases where obtaining a tissue biopsy is impossible or unfavorable, analysis of liquid biopsy by NGS provides a vital alternative.

Role of molecular imaging in prognosis,diagnosis,and treatment of gastrointestinal cancers:An update on new therapeutic methods

One of the leading causes of cancer-related death is gastrointestinal cancer,which has a significant morbidity and mortality rate.Although preoperative risk assessment is essential for directing patient care,its biological behavior cannot be accurately predicted by conventional imaging investigations.Potential pathophysiological information in anatomical imaging that cannot be visually identified can now be converted into high-dimensional quantitative image features thanks to the developing discipline of molecular imaging.In order to enable molecular tissue profile in vivo,molecular imaging has most recently been utilized to phenotype the expression of single receptors and targets of biological therapy.It is expected that molecular imaging will become increasingly important in the near future,driven by the expanding range of biological therapies for cancer.With this live molecular fingerprinting,molecular imaging can be utilized to drive expression-tailored customized therapy.The technical aspects of molecular imaging are first briefly discussed in this review,followed by an examination of the most recent research on the diagnosis,prognosis,and potential future clinical methods of molecular imaging for GI tract malignancies.

Decoding the genetic landscape of autism:A comprehensive review

BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings.Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD,influencing both diagnosis and therapeutic strategies.AIM To explore the genetic architecture of ASD,elucidate mechanistic insights into genetic mutations,and examine gene-environment interactions.METHODS A comprehensive systematic review was conducted,integrating findings from studies on genetic variations,epigenetic mechanisms(such as DNA methylation and histone modifications),and emerging technologies[including Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)-Cas9 and single-cell RNA sequencing].Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar.RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD,yet many cases remain unexplained by known factors,suggesting undiscovered genetic components.Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving.Epigenetic modifications,particularly DNA methylation and non-coding RNAs,also play significant roles in ASD pathogenesis.Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data.CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments.Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice.Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies,ultimately enhancing outcomes for individuals affected by ASD.

Personalized immunotherapy in cancer precision medicine

With the significant advances in cancer genomics using next-generation sequencing technologies,genomic and molecular profilingbased precision medicine is used as a part of routine clinical test for guiding and selecting the most appropriate treatments for individual cancer patients.Although many molecular-targeted therapies for a number of actionable genomic alterations have been developed,the clinical application of such information is still limited to a small proportion of cancer patients.In this review,we summarize the current status of personalized drug selection based on genomic and molecular profiling and highlight the challenges how we can further utilize the individual genomic information.Cancer immunotherapies,including immune checkpoint inhibitors,would be one of the potential approaches to apply the results of genomic sequencing most effectively.Highly cancer-specific antigens derived from somatic mutations,the so-called neoantigens,occurring in individual cancers have been in focus recently.Cancer immunotherapies,which target neoantigens,could lead to a precise treatment for cancer patients,despite the challenge in accurately predicting neoantigens that can induce cytotoxic T cells in individual patients.Precise prediction of neoantigens should accelerate the development of personalized immunotherapy including cancer vaccines and T-cell receptor-engineered T-cell therapy for a broader range of cancer patients.

Tumor organoids for cancer research and personalized medicine

Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stimulation by signal factors and/or growth factors,organoids self-assemble to replicate the morphological and structural characteristics of the corresponding organs.They provide an extraordinary platform for investigating organ development and mimicking pathological processes.Organoid biobanks derived from a wide range of carcinomas have been established to represent different lesions or stages of clinical tumors.Importantly,genomic and transcriptomic analyses have confirmed maintenance of intra-and interpatient heterogeneities in organoids.Therefore,this technology has the potential to revolutionize drug screening and personalized medicine.In this review,we summarized the characteristics and applications of organoids in cancer research by the establishment of organoid biobanks directly from tumor organoids or from genetically modified non-cancerous organoids.We also analyzed the current state of organoid applications in drug screening and personalized medicine.

Applications of artificial intelligence in, early detection of cancer, clinical diagnosis and personalized medicine

Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often using deep learning and computer-guided programs that analyze and process raw data into clinical decision making for effective treatment.New techniques for predicting cancer at an early stage are needed as conventional methods have poor accuracy and are not applicable to personalized medicine.AI has the potential to use smart,intelligent computer systems for image interpretation and early diagnosis of cancer.AI has been changing almost all the areas of the medical field by integrating with new emerging technologies.AI has revolutionized the entire health care system through innovative digital diagnostics with greater precision and accuracy.AI is capable of detecting cancer at an early stage with accurate diagnosis and improved survival outcomes.AI is an innovative technology of the future that can be used for early prediction,diagnosis and treatment of cancer.

Translational genomics in cancer research: converting profiles into personalized cancer medicine

Cancer genomics is a rapidly growing discipline in which the genetic molecular basis of malignancy is studied at the scale of whole genomes.While the discipline has been successful with respect to identifying specific oncogenes and tumor suppressors involved in oncogenesis,it is also challenging our approach to managing patients suffering from this deadly disease.Specifically cancer genomics is driving clinical oncology to take a more molecular approach to diagnosis,prognostication,and treatment selection.We review here recent work undertaken in cancer genomics with an emphasis on translation of genomic findings.Finally,we discuss scientific challenges and research opportunities emerging from findings derived through analysis of tumors with high-depth sequencing.

Patient-derived organoids for therapy personalization in inflammatory bowel diseases

Inflammatory bowel diseases(IBDs)are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries.Knowledge of IBD pathogenesis is still incomplete,and the most widely-accepted interpretation considers genetic factors,environmental stimuli,uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD,leading to dysfunction of the intestinal epithelial functions.In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture.An important innovation is represented by organoids,3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures.Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile.These models are powerful pharmacological tools to better understand IBD pathogenesis,to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD,and to evaluate novel target-directed molecules which could improve therapeutic strategies.The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.

Use of zebrafish embryos as avatar of patients with pancreatic cancer:A new xenotransplantation model towards personalized medicine

BACKGROUND The response to chemotherapy treatment of patients with pancreatic ductal adenocarcinoma(PDAC)is difficult to predict and the identification of patients who most likely will benefit from aggressive chemotherapy approaches is crucial.The concept of personalized medicine has emerged in the last years with the objective to tailor the medical treatment to the individual characteristics of each patient,and particularly to the tumor biology of each patient.The need for invivo xenotransplantation models for cancer patients has increased exponentially,and for this reason zebrafish avatars have gained popularity.Preliminary studies were conducted also with PDAC tissue.AIM To develop a simple,not expensive,diffusible zebrafish embryo model as avatar for patients affected by PDAC.METHODS Tumor tissue was taken from the surgical specimen by the histopathologist.After its fragmentation into small pieces,they are stained with CM-Dil.Small pieces of stained tissue were transplanted into the yolk of wt AB zebrafish embryos with a glass capillary needle.Embryos were incubated at 35°C in E3 medium supplemented with 1%Pen/Strep in the presence or absence of drugs for the following days in respect of the treatment plan(Gemcitabine;Gemcitabine and Oxaliplatin;Gemcitabine and nab-Paclitaxel;5-Fluorouracil and Folinic acid and Oxaliplatin and Irinotecan).The response of zebrafish xenografts to the chemotherapy options has been analyzed by monitoring the fluorescent stained area at 2 h post injection(hpi),1 d and 2 d post injection(dpi).In each time point,the mean size of the stained area was measured by ImageJ and it was normalized with respect to the 1 dpi time point mean relative tumor area(RTA).We evaluated the effect of the chemotherapy exposition comparing the mean RTA of each treated subgroup and the control group and evaluating the percentage reduction of the mean RTA by comparing each treated subgroup with the control group.RESULTS Between July 2018 and October 2019,a total of 15 patients with pancreatic cancer were prospectively enrolled.In all cases,it was possible to take a fragment of the tumor from the surgical specimen for the xenotransplantation in the zebrafish embryos.The histological examination confirmed the presence of a PDAC in all cases.In absence of chemotherapy(control group),over time the Dil-stained area showed a statistically significant increase in all cases.A statistically significant reduction of the mean RTA in the treated subgroups for at least one chemotherapy scheme was reported in 6/15(40%)cases.The analysis of the percentage reduction of the RTA in treated subgroups in comparison to the control group revealed the presence of a linear relationship in each subgroup between the percentage reduction of the RTA and the number of cases reporting each percentage threshold considered for the analysis.CONCLUSION Our model seems to be effective for the xenotransplantation of PDAC tissue and evaluation of the effect of each chemotherapy scheme on the xenotransplanted tumor tissue.

Healthcare practice strategies for integrating personalized medicine:Management of COVID-19

Personalized medicine is the tailor-made clinical treatment to the individual characteristics of each patient.It may be considered an extension of traditional approaches to knowing and treating diseases.Personalized medicine has the potential to change the way of identification and management of health problems.Coronavirus disease 2019(COVID-19)is an infectious disease that primarily affects the patients’lungs.The first case of pneumonia of unknown cause was reported in Wuhan,China on December 31,2019.As thus,we are quickly approaching the era of personalized medicine.This review discusses the practices currently used in the management of COVID-19 and how they relate to person-alized medicine.

Harnessing pharmacological knowledge for personalized medicine and pharmacotyping: Challenges and lessons learned

The contribution of the genetic make-up to an individual’s capacity has long been recognized in modern pharmacology as a crucial factor leading to therapy ineffciency and toxicity, negatively impacting the economic burden of healthcare and restricting the monitoring of diseases. In practical terms, and in order for drug prescription to be improved toward meeting the personalized medicine concept in drug delivery, the maximum clinical outcome for most, if not all, patients must be achieved, i.e. , pharmacotyping. Such a direction although promising and of high expectation from the society, it is however hardly to be afforded for healthcare worldwide. To overcome any existed hurdles, this means that practical clinical utility of personalized medicine decisions have to be documented and validated in the clinical setting. The latter implies for drug delivery the effcient implementation of previously gained in vivo pharmacology experience with pharmacogenomics knowledge. As an approach to work faster and in a more productive way, the elaboration of advanced physiologically based phar-macokinetics models is discussed. And in better clarifying this topic, the example of tamoxifen is thoroughly presented. Overall, pharmacotyping represents a major challenge in modern therapeutics for which pharmacologists need to work in successfully fulflling this task.

Translation in Data Mining to Advance Personalized Medicine for Health Equity

Personalized medicine is the development of “tailored” therapies that reflect traditional medical approaches with the incorporation of the patient’s unique genetic profile and the environmental basis of the disease. These individualized strategies encompass disease prevention and diagnosis, as well as treatment strategies. Today’s healthcare workforce is faced with the availability of massive amounts of patient- and disease-related data. When mined effectively, these data will help produce more efficient and effective diagnoses and treatment, leading to better prognoses for patients at both the individual and population level. Designing preventive and therapeutic interventions for those patients who will benefit most while minimizing side effects and controlling healthcare costs requires bringing diverse data sources together in an analytic paradigm. A resource to clinicians in the development and application of personalized medicine is largely facilitated, perhaps even driven, by the analysis of “big data”. For example, the availability of clinical data warehouses is a significant resource for clinicians in practicing personalized medicine. These “big data” repositories can be queried by clinicians, using specific questions, with data used to gain an understanding of challenges in patient care and treatment. Health informaticians are critical partners to data analytics including the use of technological infrastructures and predictive data mining strategies to access data from multiple sources, assisting clinicians’ interpretation of data and development of personalized, targeted therapy recommendations. In this paper, we look at the concept of personalized medicine, offering perspectives in four important, influencing topics: 1) the availability of “big data” and the role of biomedical informatics in personalized medicine, 2) the need for interdisciplinary teams in the development and evaluation of personalized therapeutic approaches, and 3) the impact of electronic medical record systems and clinical data warehouses on the field of personalized medicine. In closing, we present our fourth perspective, an overview to some of the ethical concerns related to personalized medicine and health equity.