Advancing personalized medicine in brain cancer: exploring the role of mRNA vaccines.

Advancing personalized medicine in brain cancer relies on innovative strategies, with mRNA vaccines emerging as a promising avenue. While the initial use of mRNA vaccines was in oncology, their stunning success in COVID-19 resulted in widespread attention, both positive and negative. Regardless of politically biased opinions, which relate more to the antigenic source than form of delivery, we feel it is important to objectively review this modality as relates to brain cancer. This class of vaccines trigger robust immune responses through MHC-I and MHC-II pathways, in both prophylactic and therapeutic settings. The mRNA platform offers advantages of rapid development, high potency, cost-effectiveness, and safety. This review provides an overview of mRNA vaccine delivery technologies, tumor antigen identification, combination therapies, and recent therapeutic outcomes, with a particular focus on brain cancer. Combinatorial approaches are vital to maximizing mRNA cancer vaccine efficacy, with ongoing clinical trials exploring combinations with adjuvants and checkpoint inhibitors and even adoptive cell therapy. Efficient delivery, neoantigen identification, preclinical studies, and clinical trial results are highlighted, underscoring mRNA vaccines' potential in advancing personalized medicine for brain cancer. Synergistic combinatorial therapies play a crucial role, emphasizing the need for continued research and collaboration in this area.

MicroRNA-21 Silencing in Diabetic Nephropathy: Insights on Therapeutic Strategies.

In diabetes, possibly the most significant site of microvascular damage is the kidney. Due to diabetes and/or other co-morbidities, such as hypertension and age-related nephron loss, a significant number of people with diabetes suffer from kidney diseases. Improved diabetic care can reduce the prevalence of diabetic nephropathy (DN); however, innovative treatment approaches are still required. MicroRNA-21 (miR-21) is one of the most studied multipotent microRNAs (miRNAs), and it has been linked to renal fibrosis and exhibits significantly altered expression in DN. Targeting miR-21 offers an advantage in DN. Currently, miR-21 is being pharmacologically silenced through various methods, all of which are in early development. In this review, we summarize the role of miR-21 in the molecular pathogenesis of DN and several therapeutic strategies to use miR-21 as a therapeutic target in DN. The existing experimental interventions offer a way to rectify the lower miRNA levels as well as to reduce the higher levels. Synthetic miRNAs also referred to as miR-mimics, can compensate for abnormally low miRNA levels. Furthermore, strategies like oligonucleotides can be used to alter the miRNA levels. It is reasonable to target miR-21 for improved results because it directly contributes to the pathological processes of kidney diseases, including DN.

Traumatic brain injury and immunological outcomes: the double-edged killer.

Traumatic brain injury (TBI) is a significant cause of mortality and morbidity worldwide resulting from falls, car accidents, sports, and blast injuries. TBI is characterized by severe, life-threatening consequences due to neuroinflammation in the brain. Contact and collision sports lead to higher disability and death rates among young adults. Unfortunately, no therapy or drug protocol currently addresses the complex pathophysiology of TBI, leading to the long-term chronic neuroinflammatory assaults. However, the immune response plays a crucial role in tissue-level injury repair. This review aims to provide a better understanding of TBI's immunobiology and management protocols from an immunopathological perspective. It further elaborates on the risk factors, disease outcomes, and preclinical studies to design precisely targeted interventions for enhancing TBI outcomes.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide due to falls, car accidents, sports and blast injuries. TBI causes severe, life-threatening consequences due to inflammation in the brain. Unfortunately, no current therapy or drug protocol can address the complexity of TBI, leading to long-term chronic inflammation. However, the immune response plays a crucial role in repairing injured brain tissue. This review aims to provide a better understanding of TBI's immunobiology and management protocols to design targeted interventions for better outcomes in TBI patients.

Exploring the role of cerebrospinal fluid as analyte in neurologic disorders.

The cerebrospinal fluid (CSF) is a clear ultrafiltrate of blood that envelopes and protects the central nervous system while regulating neuronal function through the maintenance of interstitial fluid homeostasis in the brain. Due to its anatomic location and physiological functions, the CSF can provide a reliable source of biomarkers for the diagnosis and treatment monitoring of different neurological diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and primary and secondary brain malignancies. The incorporation of CSF biomarkers into the drug discovery and development can improve the efficiency of drug development and increase the chances of success. This review aims to consolidate the current use of CSF biomarkers in clinical practice and explore future perspectives for the field.

Cerebrospinal fluid (CSF) is a clear fluid that protects our brain and spinal cord, and can help diagnose and monitor neurological diseases like Alzheimer's and Parkinson's. Biomarkers in CSF are like clues that help doctors and researchers better understand these diseases. By using CSF biomarkers, doctors can diagnose and monitor patients more accurately, while researchers can develop more effective treatments. This review looks at how we use CSF biomarkers in medicine and how they might help us in the future. Better understanding of CSF biomarkers can improve the lives of people living with neurological diseases.

Designing neoantigen cancer vaccines, trials, and outcomes.

Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells. Improvements in sequencing technology and computational tools have resulted in several clinical trials of neoantigen vaccines on cancer patients. In this review, we have looked into the design of the vaccines which are undergoing several clinical trials. We have discussed the criteria, processes, and challenges associated with the design of neoantigens. We searched different databases to track the ongoing clinical trials and their reported outcomes. We observed, in several trials, the vaccines boost the immune system to combat the cancer cells while maintaining a reasonable margin of safety. Detection of neoantigens has led to the development of several databases. Adjuvants also play a catalytic role in improving the efficacy of the vaccine. Through this review, we can conclude that the efficacy of vaccines can make it a potential treatment across different types of cancers.

Binned Data Provide Better Imputation of Missing Time Series Data from Wearables.

The presence of missing values in a time-series dataset is a very common and well-known problem. Various statistical and machine learning methods have been developed to overcome this problem, with the aim of filling in the missing values in the data. However, the performances of these methods vary widely, showing a high dependence on the type of data and correlations within the data. In our study, we performed some of the well-known imputation methods, such as expectation maximization, k-nearest neighbor, iterative imputer, random forest, and simple imputer, to impute missing data obtained from smart, wearable health trackers. In this manuscript, we proposed the use of data binning for imputation. We showed that the use of data binned around the missing time interval provides a better imputation than the use of a whole dataset. Imputation was performed for 15 min and 1 h of continuous missing data. We used a dataset with different bin sizes, such as 15 min, 30 min, 45 min, and 1 h, and we carried out evaluations using root mean square error (RMSE) values. We observed that the expectation maximization algorithm worked best for the use of binned data. This was followed by the simple imputer, iterative imputer, and k-nearest neighbor, whereas the random forest method had no effect on data binning during imputation. Moreover, the smallest bin sizes of 15 min and 1 h were observed to provide the lowest RMSE values for the majority of the time frames during the imputation of 15 min and 1 h of missing data, respectively. Although applicable to digital health data, we think that this method will also find applicability in other domains.

MTAP loss: a possible therapeutic approach for glioblastoma.

Glioblastoma is the most lethal form of brain tumor with a recurrence rate of almost 90% and a survival time of only 15 months post-diagnosis. It is a highly heterogeneous, aggressive, and extensively studied tumor. Multiple studies have proposed therapeutic approaches to mitigate or improve the survival for patients with glioblastoma. In this article, we review the loss of the 5'-methylthioadenosine phosphorylase (MTAP) gene as a potential therapeutic approach for treating glioblastoma. MTAP encodes a metabolic enzyme required for the metabolism of polyamines and purines leading to DNA synthesis. Multiple studies have explored the loss of this gene and have shown its relevance as a therapeutic approach to glioblastoma tumor mitigation; however, other studies show that the loss of MTAP does not have a major impact on the course of the disease. This article reviews the contrasting findings of MTAP loss with regard to mitigating the effects of glioblastoma, and also focuses on multiple aspects of MTAP loss in glioblastoma by providing insights into the known findings and some of the unexplored areas of this field where new approaches can be imagined for novel glioblastoma therapeutics.

Smart Consumer Wearables as Digital Diagnostic Tools: A Review.

The increasing usage of smart wearable devices has made an impact not only on the lifestyle of the users, but also on biological research and personalized healthcare services. These devices, which carry different types of sensors, have emerged as personalized digital diagnostic tools. Data from such devices have enabled the prediction and detection of various physiological as well as psychological conditions and diseases. In this review, we have focused on the diagnostic applications of wrist-worn wearables to detect multiple diseases such as cardiovascular diseases, neurological disorders, fatty liver diseases, and metabolic disorders, including diabetes, sleep quality, and psychological illnesses. The fruitful usage of wearables requires fast and insightful data analysis, which is feasible through machine learning. In this review, we have also discussed various machine-learning applications and outcomes for wearable data analyses. Finally, we have discussed the current challenges with wearable usage and data, and the future perspectives of wearable devices as diagnostic tools for research and personalized healthcare domains.

Anomaly Detection Framework for Wearables Data: A Perspective Review on Data Concepts, Data Analysis Algorithms and Prospects.

Wearable devices use sensors to evaluate physiological parameters, such as the heart rate, pulse rate, number of steps taken, body fat and diet. The continuous monitoring of physiological parameters offers a potential solution to assess personal healthcare. Identifying outliers or anomalies in heart rates and other features can help identify patterns that can play a significant role in understanding the underlying cause of disease states. Since anomalies are present within the vast amount of data generated by wearable device sensors, identifying anomalies requires accurate automated techniques. Given the clinical significance of anomalies and their impact on diagnosis and treatment, a wide range of detection methods have been proposed to detect anomalies. Much of what is reported herein is based on previously published literature. Clinical studies employing wearable devices are also increasing. In this article, we review the nature of the wearables-associated data and the downstream processing methods for detecting anomalies. In addition, we also review supervised and un-supervised techniques as well as semi-supervised methods that overcome the challenges of missing and un-annotated healthcare data.

Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome.

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a "cytokine storm", as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells (MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing anti-inflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a "living anti-inflammatory", which can "rebalance" the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.

Metabolic Differences in Glutamine Utilization Lead to Metabolic Vulnerabilities in Prostate Cancer.

The new oncologic paradigm of precision medicine is focused on identifying metabolic, proteomic, transcriptomic and genomic variabilities in tumors that can be exploited to tailor treatments and improve patient outcomes. Metabolic changes are a hallmark of cancer, and inhibition of metabolic pathways is now a major strategy in medicinal chemistry for targeting cancers. However, non-invasive biomarkers to categorize metabolic subtypes are in short supply. The purpose of this study was to characterize the intracellular and extracellular metabolic profiles of four prostate cancer cell lines with varying degrees of aggressiveness. We observed metabolic differences between the aggressive prostate cancer cell line PC3 and the even more aggressive, metastatic subline PC3M assessed by hyperpolarized in vivo pyruvate studies, nuclear magnetic resonance spectroscopy, and carbon-13 feeding studies. On further examination of the differences between these two cell lines, we found increased glutamine utilization in the metastatic PC3M subline that led directly to sensitivity to glutaminase inhibitor CB-839. Our study supports the theory that metastatic progression increases glutamine utilization and the inhibition of glutaminolysis could have clinical implications.

Extreme event medicine: considerations for the organisation of out-of-hospital care during obstacle, adventure and endurance competitions.

Obstacle, adventure and endurance competitions in challenging or remote settings are increasing in popularity. A literature search indicates a dearth of evidence-based research on the organisation of medical care for wilderness competitions. The organisation of medical care for each event is best tailored to specific race components, participant characteristics, geography, risk assessments, legal requirements, and the availability of both local and outside resources. Considering the health risks and logistical complexities inherent in these events, there is a compelling need for guiding principles that bridge the fields of wilderness medicine and sports medicine in providing a framework for the organisation of medical care delivery during wilderness and remote obstacle, adventure and endurance competitions. This narrative review, authored by experts in wilderness and operational medicine, provides such a framework. The primary goal is to assist organisers and medical providers in planning for sporting events in which participants are in situations or locations that exceed the capacity of local emergency medical services resources.

Solar Photovoltaic and Wind Energy Providing Water.

Renewable energy technologies can make a major contribution to universal access to both energy and water in a sustainable way. In many regions of the world with energy poverty there are abundant renewable energy sources. In this review it is described how solar photovoltaic (PV) and wind energy have a huge potential to supply clean water, in particular in areas with no grid connection. Off-grid technologies can form a significant part of the solution, all the way from household level to village or community level. Small scale off-grid systems can provide not only lighting but also energy for pumping to gain access to water and to purify and re-use water. In rapidly growing peri-urban areas electric power grids may be available but need to be complemented with decentralized energy sources. Solar and wind can be part of a new kind of hybrid energy supplies. It is noted that there is a confluence of factors, such as greater urbanization, population increase, economic development that will determine the energy mix. The United Nations Sustainable Development Goals of clean water and energy for all are strongly related and will depend to a large extent on solar PV and wind.

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells.

Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

SRC family kinase FYN promotes the neuroendocrine phenotype and visceral metastasis in advanced prostate cancer.

FYN is a SRC family kinase (SFK) that has been shown to be up-regulated in human prostate cancer (PCa) tissues and cell lines. In this study, we observed that FYN is strongly up-regulated in human neuroendocrine PCa (NEPC) tissues and xenografts, as well as cells derived from a NEPC transgenic mouse model. In silico analysis of FYN expression in prostate cancer cell line databases revealed an association with the expression of neuroendocrine (NE) markers such as CHGA, CD44, CD56, and SYP. The loss of FYN abrogated the invasion of PC3 and ARCaPM cells in response to MET receptor ligand HGF. FYN also contributed to the metastatic potential of NEPC cells in two mouse models of visceral metastasis with two different cell lines (PC3 and TRAMPC2-RANKL). The activation of MET appeared to regulate neuroendocrine (NE) features as evidenced by increased expression of NE markers in PC3 cells with HGF. Importantly, the overexpression of FYN protein in DU145 cells was directly correlated with the increase of CHGA. Thus, our data demonstrated that the neuroendocrine differentiation that occurs in PCa cells is, at least in part, regulated by FYN kinase. Understanding the role of FYN in the regulation of NE markers will provide further support for ongoing clinical trials of SFK and MET inhibitors in castration-resistant PCa patients.

Metastasis initiating cells in primary prostate cancer tissues from transurethral resection of the prostate (TURP) predicts castration-resistant progression and survival of prostate cancer patients.

BACKGROUND: We previously reported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS: We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS: PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS: The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naïve patients can predict the progression to castration resistance and the overall survival of PC patients.

Proton exchange reactions in isotope chemistry (II) synthesis of stable isotope-labeled LCQ908.

The proton exchange reaction was applied to the preparation of stable isotope-labeled LCQ908. For this synthesis, a suitable intermediate with protons alpha to a carbonyl group was first subjected to the H-D exchange reaction; subsequent coupling of a carbonyl group with [(13)C2 ]triethyl phosphonoacetate, followed by hydrogenation and hydrolysis, led to the stable labeled compound. Incorporation of two carbon-13 atoms in the molecule eliminated the presence of undesired M+0.

The baby, the bathwater and the bath itself: a response to Tyrer et al.'s review of the successes and failures of dangerous and severe personality disorder.

A recent paper by Tyrer et al. in this journal has reviewed the dangerous and severe personality disorder (DSPD) initiative in the assessment and management of severe personality disorder associated with high risk. This previous paper summarized the authors' perceptions of the successes and failures of the DSPD pilot. In the present paper we identify some inaccuracies in the previous review and provide a critique of the conclusions reached.

Are those who use specific complementary and alternative medicine therapies less likely to be immunized?

OBJECTIVE: Some authorities are concerned that the use of complementary and alternative medications (CAM) may replace recommended preventive health practices. This study was done to determine if users of individual types of CAM were less likely to receive recommended immunizations. METHODS: We used data from the 2007 National Health Interview Survey of over 23,000 adult, non-institutionalized U.S. citizens using bivariate and multivariate analysis to determine if users of individual types of CAM were less likely to receive influenza and/or pneumococcal vaccinations. RESULTS: Using a weighted logistic regression analysis, we found that respondents who used chiropractic care were less likely to receive flu shots (OR=0.68, CI=0.55,0.83, p<0.001). There was a mildly positive trend toward receiving the pneumococcal vaccine in users of deep breathing exercises and toward not receiving both in followers of qi gong. Prayer use was prevalent and had a positive impact on receiving immunizations, especially in Blacks and those in poor health. Regular exercise, having a primary care provider and more frequent office visits were also positively associated with receiving immunizations. CONCLUSION: Chiropractic users are less likely to get flu shots, perhaps reflecting their national body's attitude, which could affect morbidity and mortality. Providers should be aware of their patients' CAM use and encourage accepted primary care practices.