Personalized Drug Therapy: Innovative Concept Guided With Proteoformics.

Personalized medicine can reduce adverse effects, enhance drug efficacy, and optimize treatment outcomes, which represents the essence of personalized medicine in the pharmacy field. Protein drugs are crucial in the field of personalized drug therapy and are currently the mainstay, which possess higher target specificity and biological activity than small-molecule chemical drugs, making them efficient in regulating disease-related biological processes, and have significant potential in the development of personalized drugs. Currently, protein drugs are designed and developed for specific protein targets based on patient-specific protein data. However, due to the rapid development of two-dimensional gel electrophoresis and mass spectrometry, it is now widely recognized that a canonical protein actually includes multiple proteoforms, and the differences between these proteoforms will result in varying responses to drugs. The variation in the effects of different proteoforms can be significant and the impact can even alter the intended benefit of a drug, potentially making it harmful instead of lifesaving. As a result, we propose that protein drugs should shift from being targeted through the lens of protein (proteomics) to being targeted through the lens of proteoform (proteoformics). This will enable the development of personalized protein drugs that are better equipped to meet patients' specific needs and disease characteristics. With further development in the field of proteoformics, individualized drug therapy, especially personalized protein drugs aimed at proteoforms as a drug target, will improve the understanding of disease mechanisms, discovery of new drug targets and signaling pathways, provide a theoretical basis for the development of new drugs, aid doctors in conducting health risk assessments and making more cost-effective targeted prevention strategies conducted by artificial intelligence/machine learning, promote technological innovation, and provide more convenient treatment tailored to individualized patient profile, which will benefit the affected individuals and society at large.

Targeted community-based programmes for children's mental health: A systematic review and meta-analysis of the Australian literature.

OBJECTIVE: No synthesis of the Australian evidence regarding targeted prevention and early intervention for mental health concerns among young children exists. This review aimed to (1) describe the types of targeted community-based mental health programmes evaluated in Australia to support children aged 1-9 years exhibiting internalising and/or externalising symptoms and (2) examine their impact on children's internalising and externalising symptoms and disorder diagnosis. METHOD: A systematic review and meta-analysis was conducted (PROSPERO: CRD42021255257). Four databases (PsycINFO, PsycArticles, MEDLINE and CINAHL) were searched for Australian studies published in the past 10 years that quantitatively evaluated the impact of a targeted programme on children's mental health. The National Institute of Health Quality Assessment Tools were used to evaluate the study quality. RESULTS: Forty-two studies were included; the majority (67%) were medium quality. The mean sample size was 142 (SD = 170), children's average age was 5.78 years (SD = 2.44) and 58% were male. Aboriginal and Torres Strait Islander children were underrepresented. Studies evaluated 16 programmes that targeted (1) externalising symptoms (n = 20 studies, n = 6 programmes), (2) internalising symptoms (n = 14 studies, n = 7 programmes) or (3) both, termed transdiagnostic programmes (n = 8 studies, n = 3 programmes). Externalising programmes achieved a significant moderate mean reduction in externalising behaviours (standardised mean differences = -0.56), internalising programmes yielded a small mean improvement in anxiety symptoms (standardised mean differences = -0.25) and 57% reduced odds of anxiety disorder diagnosis. Evidence supporting transdiagnostic programmes was inconclusive. CONCLUSION: Parenting-focused programmes targeting young children's internalising or externalising behaviours have the largest local evidence base supporting their effectiveness. Limitations include a lack of engagement with fathers, triangulation of outcomes, homogeneity and implementation reporting. Greater implementation and evaluation of community-driven integrated and systemic approaches that identify, engage and support Australia's most disadvantaged cohorts of young children and their families are needed.

Targeted surgical prevention of epithelial ovarian cancer is cost effective and saves money in BRCA mutation carrying family members of women with epithelial ovarian cancer. A Canadian model.

OBJECTIVE: Survival but not cure rates have improved for epithelial ovarian cancer (EOC), demonstrating the need for effective prevention. Targeted prevention in BRCA carriers by risk reducing surgery (RRS) prevents 80% of cases but incurs additional up-front costs, compensated for by the potential for long term savings from treatment avoidance. Does prevention represent value for money? In the absence of long-term data from prospective trials, determining the cost effectiveness of a prevention strategy requires economic modelling. METHODS: A patient level simulation was developed comparing outcomes between two groups, using Canadian data. Group 1: no mutation testing with treatment if EOC developed. Group 2: cascade testing (index patient BRCA tested and the first and second-degree relatives tested if index patient or first-degree relative respectively were positive) with RRS in carriers. End points were Incremental Cost-Effectiveness Ratio (ICER) and budget impact. RESULTS: 2786 women with EOC (1 year incidence) had 766 first and 207 second-degree female relatives. BRCA mutations were present in 390 index cases, 366 first and 49 second-degree relatives. With 100% RRS uptake, 59 EOC were prevented and testing dominated no testing (more effective and less costly; ICER -$8919). The total cost saving over 50 years was $2,904,486 (cost saving of $9,660,381 in treatment costs versus increased cost from cascade testing/RRS of $6,755,895). At a threshold of $100,000 per QALY, prevention was cost effective in all modelled scenarios. CONCLUSIONS: Targeted prevention in BRCA mutation carriers not only prevents EOC but is cost-effective compared to treating EOC if it develops.

Disparities in hepatocellular carcinoma incidence by race/ethnicity and geographic area in California: Implications for prevention.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has been rising rapidly in the United States. California is an ethnically diverse state with the largest number of incident HCC cases in the country. Characterizing HCC disparities in California may inform priorities for HCC prevention. METHODS: By using data from the Surveillance, Epidemiology, and End Results 18-Registry Database and the California Cancer Registry, age-adjusted HCC incidence in California from 2009 through 2013 was calculated by race/ethnicity and neighborhood ethnic enclave status. A geographic analysis was conducted using Medical Service Study Areas (MSSAs) as the geographic unit, and race/ethnicity-specific standardized incidence ratios (SIRs) were calculated to identify MSSAs with higher-than-expected HCC incidence compared with the statewide average. RESULTS: During 2009 through 2013, the age-adjusted incidence of HCC in California was the highest in Asians/Pacific Islanders (APIs) and Hispanics (>100% higher than whites), especially those living in more ethnic neighborhoods (20%-30% higher than less ethnic neighborhoods). Of the 542 MSSAs statewide, 42 had elevated HCC incidence (SIR ≥ 1.5; lower bound of 95% confidence interval > 1) for whites, 14 for blacks, 24 for APIs, and 36 for Hispanics. These MSSAs have 24% to 52% higher proportions of individuals below the 100% federal poverty line than other MSSAs. CONCLUSIONS: APIs and Hispanics residing in more ethnic neighborhoods and individuals residing in lower income neighborhoods require more extensive preventive efforts tailored toward their unique risk factor profiles. The current race/ethnicity-specific geographic analysis can be extended to other states to inform priorities for HCC targeted prevention at the subcounty level, eventually reducing HCC burden in the country.

Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention.

Cancerous tissue transformation developing usually over years or even decades of life is a highly complex process involving strong stressors damaging DNA, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk within the neighboring tissues. Only the minor part of all cancer cases are caused by inborn predisposition; the absolute majority carry a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Amongst most promising candidates for dietary supplements are bioactive phytochemicals demonstrating strong anticancer effects. Abundant evidence has been collected for beneficial effects of flavonoids, carotenoids, phenolic acids, and organosulfur compounds affecting a number of cancer-related pathways. Phytochemicals may positively affect processes of cell signaling, cell cycle regulation, oxidative stress response, and inflammation. They can modulate non-coding RNAs, upregulate tumor suppressive miRNAs, and downregulate oncogenic miRNAs that synergically inhibits cancer cell growth and cancer stem cell self-renewal. Potential clinical utility of the phytochemicals is discussed providing examples for chemoprevention against and therapy for human breast cancer. Expert recommendations are provided in the context of preventive medicine.

Adolescent Alcohol Use: Protective and Predictive Parent, Peer, and Self-Related Factors.

Adolescent alcohol use has been linked with a multitude of problems and a trajectory predictive of problematic use in adulthood. Thus, targeting factors that enhance early prevention efforts is vital. The current study highlights variables that mitigate or predict alcohol use and heavy episodic drinking. Using Monitoring the Future (MTF) data, multiple path analytic models revealed links between parental involvement and alcohol abstinence and initiation. Parental involvement predicted enhanced self-esteem and less self-derogation and was negatively associated with peer alcohol norms for each MTF grade sampled, with stronger associations for 8th and 10th graders than 12th graders. For younger groups, self-esteem predicted increased perceptions of alcohol risk and reduced drinking. Self-derogation was associated with peers' pro-alcohol norms, which was linked to lower risk perceptions, lower personal disapproval of use, and increased drinking. Peer influence had a stronger association with consumption for 8th and 10th graders, whereas 12th graders' drinking was related to personal factors of alcohol risk perception and disapproval. In all grades, general alcohol use had a strong connection to heavy episodic drinking within the past 2 weeks. Across-grade variations in association of parent, peer, and personal factors suggest the desirability of tailored interventions focused on specific factors for each grade level, with the overall goal of attenuating adolescent alcohol use.

Targeting HIV Prevention Based on Molecular Epidemiology Among Deeply Sampled Subnetworks of Men Who Have Sex With Men.

BACKGROUND: Molecular epidemiology can be useful in identifying clusters of human immunodeficiency virus (HIV) transmission that can be targeted for prevention. METHODS: Regular screening of 2000 men who have sex with men (MSM) in Beijing, China, for HIV infection every 2 months identified 179 primary infections (2007-2010). HIV-1 pol sequences were obtained and used to infer the transmission network and identify transmitted drug resistance (TDR) among these individuals. We evaluated the use of clinical and network information to target prevention efforts. Prevention efficiency was calculated as the number of infections saved per number of interventions. RESULTS: This cohort was infected with HIV-1 subtype B (28%), circulating recombinant form (CRF)_01 AE (53%), and CRF_07 BC (16%). The overall rate of TDR was low (5%), but the rate of clustering was high (64%), suggesting deep sampling of the subnetwork. Provision of a theoretically high-efficacy intervention like antiretroviral therapy to all participants had a prevention efficiency of 23%. The efficiency of targeting prevention based on lower CD4 counts (<200 cells/mL, <350 cells/mL, or <500 cells/mL) and higher viral loads (>100 000 copies/mL and >50 000 copies/mL) was between 10% and 18%. The efficiency of targeting prevention based on number of network connections was much higher (30%-42%). For example, treating the 33 participants with ≥5 connections in 2009 would have theoretically prevented 14 infections in 2010 (42% prevention efficiency). CONCLUSIONS: Regular HIV testing of MSM in Beijing can deeply sample the local transmission subnetwork, and targeting prevention efforts based on network connectivity may be an efficient way to deliver prevention interventions.

CADASIL: A NOTCH3-associated cerebral small vessel disease.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic and non-amyloid diffuse angiopathy primarily involving small to medium-sized penetrating arteries and leptomeningeal arteries. In 1996, mutation in the notch receptor 3 gene (NOTCH3) was identified as the cause of CADASIL. However, since that time other genetic CSVDs have been described, including the HtrA serine peptidase 1 gene-associated CSVD and the cathepsin A gene-associated CSVD, that clinically mimic the original phenotype. Though NOTCH3-associated CSVD is now a well-recognized hereditary disorder and the number of studies investigating this disease is increasing, the role of NOTCH3 in the pathogenesis of CADASIL remains elusive. AIM OF REVIEW: This review aims to provide insights into the pathogenesis and the diagnosis of hereditary CSVDs, as well as personalized therapy, predictive approach, and targeted prevention. In this review, we summarize the current progress in CADASIL, including the clinical, neuroimaging, pathological, genetic, diagnostic, and therapeutic aspects, as well as differential diagnosis, in which the role of NOTCH3 mutations is highlighted. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, CADASIL is revisited as a NOTCH3-associated CSVD along with other hereditary CSVDs.

N6-methyldeoxyadenosine modification difference contributes to homocysteine-induced mitochondrial perturbation in rat hippocampal primary neurons and PC12 cells.

Elevated homocysteine (Hcy) levels are detrimental to neuronal cells and contribute to cognitive dysfunction in rats. Mitochondria plays a crucial role in cellular energy metabolism. Interestingly, the damaging effects of Hcy in vivo and in vitro conditions exhibit distinct results. Herein, we aimed to investigate the effects of Hcy on mitochondrial function in primary neurons and PC12 cells and explore the underlying mechanisms involved. The metabolic intermediates of Hcy act as methyl donors and play important epigenetic regulatory roles. N6-methyldeoxyadenosine (6 mA) modification, which is enriched in mitochondrial DNA (mtDNA), can be mediated by methylase METTL4. Our study suggested that mitochondrial perturbation caused by Hcy in primary neurons and PC12 cells may be attributable to mtDNA 6 mA modification difference. Hcy could activate the expression of METTL4 within mitochondria to facilitate mtDNA 6 mA status, and repress mtDNA transcription, then result in mitochondrial dysfunction.

Clinically relevant stratification of lung squamous carcinoma patients based on ubiquitinated proteasome genes for 3P medical approach.

Relevance: The proteasome is a crucial mechanism that regulates protein fate and eliminates misfolded proteins, playing a significant role in cellular processes. In the context of lung cancer, the proteasome's regulatory function is closely associated with the disease's pathophysiology, revealing multiple connections within the cell. Therefore, studying proteasome inhibitors as a means to identify potential pathways in carcinogenesis and metastatic progression is crucial in in-depth insight into its molecular mechanism and discovery of new therapeutic target to improve its therapy, and establishing effective biomarkers for patient stratification, predictive diagnosis, prognostic assessment, and personalized treatment for lung squamous carcinoma in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Methods: This study identified differentially expressed proteasome genes (DEPGs) in lung squamous carcinoma (LUSC) and developed a gene signature validated through Kaplan-Meier analysis and ROC curves. The study used WGCNA analysis to identify proteasome co-expression gene modules and their interactions with the immune system. NMF analysis delineated distinct LUSC subtypes based on proteasome gene expression patterns, while ssGSEA analysis quantified immune gene-set abundance and classified immune subtypes within LUSC samples. Furthermore, the study examined correlations between clinicopathological attributes, immune checkpoints, immune scores, immune cell composition, and mutation status across different risk score groups, NMF clusters, and immunity clusters. Results: This study utilized DEPGs to develop an eleven-proteasome gene-signature prognostic model for LUSC, which divided samples into high-risk and low-risk groups with significant overall survival differences. NMF analysis identified six distinct LUSC clusters associated with overall survival. Additionally, ssGSEA analysis classified LUSC samples into four immune subtypes based on the abundance of immune cell infiltration with clinical relevance. A total of 145 DEGs were identified between high-risk and low-risk score groups, which had significant biological effects. Moreover, PSMD11 was found to promote LUSC progression by depending on the ubiquitin-proteasome system for degradation. Conclusions: Ubiquitinated proteasome genes were effective in developing a prognostic model for LUSC patients. The study emphasized the critical role of proteasomes in LUSC processes, such as drug sensitivity, immune microenvironment, and mutation status. These data will contribute to the clinically relevant stratification of LUSC patients for personalized 3P medical approach. Further, we also recommend the application of the ubiquitinated proteasome system in multi-level diagnostics including multi-omics, liquid biopsy, prediction and targeted prevention of chronic inflammation and metastatic disease, and mitochondrial health-related biomarkers, for LUSC 3PM practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00352-w.

[Skin aging exposome]. / Hautalterungsexposom.

The skin is a barrier organ and thus exposed to environmental factors from birth, which essentially determine skin aging. In order to describe and understand this complex process exactly, we applied the concept of the "exposome" to the environmentally induced skin aging process. In this review, we summarize current knowledge on the skin aging exposome. In this context, we characterize the most important exposomal factors, address their relative importance for skin aging and also the relevance of their mutual interactions. Finally, we discuss the clinical consequences resulting from this concept for an effective prevention of skin aging.

Global burden of cancers attributable to tobacco smoking, 1990-2019: an ecological study.

Aim and background: Identifying risk factors for cancer initiation and progression is the cornerstone of the preventive approach to cancer management and control (EPMA J. 4(1):6, 2013). Tobacco smoking is a well-recognized risk factor for initiation and spread of several cancers. The predictive, preventive, and personalized medicine (PPPM) approach to cancer management and control focuses on smoking cessation as an essential cancer prevention strategy. Towards this end, this study examines the temporal patterns of cancer burden due to tobacco smoking in the last three decades at global, regional, and national levels. Data and methods: The data pertaining to the burden of 16 cancers attributable to tobacco smoking at global, regional, and national levels were procured from the Global Burden of Disease 2019 Study. Two main indicators, deaths and disability-adjusted life years (DALYs), were used to describe the burden of cancers attributable to tobacco smoking. The socio-economic development of countries was measured using the socio-demographic index (SDI). Results: Globally, deaths due to neoplasms caused by tobacco smoking increased from 1.5 million in 1990 to 2.5 million in 2019, whereas the age-standardized mortality rate (ASMR) decreased from 39.8/100,000 to 30.6/100,000 and the age-standardized DALY rate (ASDALR) decreased from 948.9/100,000 to 677.3/100,000 between 1990 and 2019. Males accounted for approximately 80% of global deaths and DALYs in 2019. Populous regions of Asia and a few regions of Europe account for the largest absolute burden, whereas countries in Europe and America have the highest age-standardized rates of cancers due to tobacco smoking. In 8 out of 21 regions, there were more than 100,000 deaths due to cancers attributable to tobacco smoking led by East Asia, followed by Western Europe in 2019. The regions of Sub-Saharan Africa (except southern region) had one of the lowest absolute counts of deaths, DALYs, and age-standardized rates. In 2019, tracheal, bronchus, and lung (TBL), esophageal, stomach, colorectal, and pancreatic cancer were the top 5 neoplasms attributable to tobacco smoking, with different burdens in regions as per their development status. The ASMR and ASDALR of neoplasms due to tobacco smoking were positively correlated with SDI, with pairwise correlation coefficient of 0.55 and 0.52, respectively. Conclusion: As a preventive tool, tobacco smoking cessation has the biggest potential among all risk factors for preventing millions of cancer deaths every year. Cancer burden due to tobacco smoking is found to be higher in males and is positively associated with socio-economic development of countries. As tobacco smoking begins mostly at younger ages and the epidemic is unfolding in several parts of the world, more accelerated efforts are required towards tobacco cessation and preventing youth from entering this addiction. The PPPM approach to medicine suggests that not only personalized and precision medicine must be provided to cancer patients afflicted by tobacco smoking but personalized and targeted preventive solutions must be provided to prevent initiation and progression of smoking. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00308-y.

Multi-Omic Candidate Screening for Markers of Severe Clinical Courses of COVID-19.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) disease courses are characterized by immuno-inflammatory, thrombotic, and parenchymal alterations. Prediction of individual COVID-19 disease courses to guide targeted prevention remains challenging. We hypothesized that a distinct serologic signature precedes surges of IL-6/D-dimers in severely affected COVID-19 patients. METHODS: We performed longitudinal plasma profiling, including proteome, metabolome, and routine biochemistry, on seven seropositive, well-phenotyped patients with severe COVID-19 referred to the Intensive Care Unit at the German Heart Center. Patient characteristics were: 65 ± 8 years, 29% female, median CRP 285 ± 127 mg/dL, IL-6 367 ± 231 ng/L, D-dimers 7 ± 10 mg/L, and NT-proBNP 2616 ± 3465 ng/L. RESULTS: Based on time-series analyses of patient sera, a prediction model employing feature selection and dimensionality reduction through least absolute shrinkage and selection operator (LASSO) revealed a number of candidate proteins preceding hyperinflammatory immune response (denoted ΔIL-6) and COVID-19 coagulopathy (denoted ΔD-dimers) by 24-48 h. These candidates are involved in biological pathways such as oxidative stress/inflammation (e.g., IL-1alpha, IL-13, MMP9, C-C motif chemokine 23), coagulation/thrombosis/immunoadhesion (e.g., P- and E-selectin), tissue repair (e.g., hepatocyte growth factor), and growth factor response/regulatory pathways (e.g., tyrosine-protein kinase receptor UFO and low-density lipoprotein receptor (LDLR)). The latter are host- or co-receptors that promote SARS-CoV-2 entry into cells in the absence of ACE2. CONCLUSIONS: Our novel prediction model identified biological and regulatory candidate networks preceding hyperinflammation and coagulopathy, with the most promising group being the proteins that explain changes in D-dimers. These biomarkers need validation. If causal, our work may help predict disease courses and guide personalized treatment for COVID-19.

Vascular dysregulation in glaucoma: retinal vasoconstriction and normal neurovascular coupling in altitudinal visual field defects.

Purpose: Vision loss in glaucoma is not only associated with elevated intraocular pressure and neurodegeneration, but vascular dysregulation (VD) is a major factor. To optimize therapy, an improved understanding of concepts of predictive, preventive, and personalized medicine (3PM) is needed which is based on a more detailed understanding of VD pathology. Specifically, to learn if the root cause of glaucomatous vision loss is of neuronal (degeneration) or vascular origin, we now studied neurovascular coupling (NVC) and vessel morphology and their relationship to vision loss in glaucoma. Methods: In patients with primary open angle glaucoma (POAG) (n = 30) and healthy controls (n = 22), NVC was studied using dynamic vessel analyzer to quantify retinal vessel diameter before, during, and after flicker light stimulation to evaluate the dilation response following neuronal activation. Vessel features and dilation were then related to branch level and visual field impairment. Results: Retinal arterial and venous vessels had significantly smaller diameters in patients with POAG in comparison to controls. However, both arterial and venous dilation reached normal values during neuronal activation despite their smaller diameters. This was largely independent of visual field depth and varied among patients. Conclusions: Because dilation/constriction is normal, VD in POAG can be explained by chronic vasoconstriction which limits energy supply to retinal (and brain) neurons with subsequent hypo-metabolism ("silent" neurons) or neuronal cell death. We propose that the root cause of POAG is primarily of vascular and not neuronal origin. This understanding can help to better personalize POAG therapy of not only targeting eye pressure but also vasoconstriction to prevent low vision, slowing its progression and supporting recovery and restoration. Trial registration: ClinicalTrials.gov, # NCT04037384 on July 3, 2019.

Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes.

Protein tyrosine nitration is a selectively and reversible important post-translational modification, which is closely related to oxidative stress. Astrocytoma is the most common neuroepithelial tumor with heterogeneity and complexity. In the past, the diagnosis of astrocytoma was based on the histological and clinical features, and the treatment methods were nothing more than surgery-assisted radiotherapy and chemotherapy. Obviously, traditional methods short falls an effective treatment for astrocytoma. In late 2021, the World Health Organization (WHO) adopted molecular biomarkers in the comprehensive diagnosis of astrocytoma, such as IDH-mutant and DNA methylation, which enabled the risk stratification, classification, and clinical prognosis prediction of astrocytoma to be more correct. Protein tyrosine nitration is closely related to the pathogenesis of astrocytoma. We hypothesize that nitroproteome is significantly different in astrocytoma relative to controls, which leads to establishment of nitroprotein biomarkers for patient stratification, diagnostics, and prediction of disease stages and severity grade, targeted prevention in secondary care, treatment algorithms tailored to individualized patient profile in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Nitroproteomics based on gel electrophoresis and tandem mass spectrometry is an effective tool to identify the nitroproteins and effective biomarkers in human astrocytomas, clarifying the biological roles of oxidative/nitrative stress in the pathophysiology of astrocytomas, functional characteristics of nitroproteins in astrocytomas, nitration-mediated signal pathway network, and early diagnosis and treatment of astrocytomas. The results finds that these nitroproteins are enriched in mitotic cell components, which are related to transcription regulation, signal transduction, controlling subcellular organelle events, cell perception, maintaining cell homeostasis, and immune activity. Eleven statistically significant signal pathways are identified in astrocytoma, including remodeling of epithelial adherens junctions, germ cell-sertoli cell junction signaling, 14-3-3-mediated signaling, phagosome maturation, gap junction signaling, axonal guidance signaling, assembly of RNA polymerase III complex, and TREM1 signaling. Furthermore, protein tyrosine nitration is closely associated with the therapeutic effects of protein drugs, and molecular mechanism and drug targets of cancer. It provides valuable data for studying the protein nitration biomarkers, molecular mechanisms, and therapeutic targets of astrocytoma towards PPPM (3P medicine) practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00348-y.

Evidence-based capacity of natural cytochrome enzyme inhibitors to increase the effectivity of antineoplastic drugs.

Cytochrome (CYP) enzymes catalyze the metabolism of numerous exogenous and endogenous substrates in cancer therapy leading to significant drug interactions due to their metabolizing effect. CYP enzymes play an important role in the metabolism of essential anticancer medications. They are shown to be overexpressed in tumor cells at numerous locations in the body. This overexpression could be a result of lifestyle factors, presence of hereditary variants of CYP (Bio individuality) and multi-drug resistance. This finding has sparked an interest in using CYP inhibitors to lower their metabolizing activity as a result facilitating anti-cancer medications to have a therapeutic impact. As a result of the cytotoxic nature of synthetic enzyme inhibitors and the increased prevalence of herbal medication, natural CYP inhibitors have been identified as an excellent way to inhibit overexpression sighting their tendency to show less cytotoxicity, lesser adverse drug reactions and enhanced bioavailability. Nonetheless, their effect of lowering the hindrance caused in chemotherapy due to CYP enzymes remains unexploited to its fullest. It has been observed that there is a substantial decrease in first pass metabolism and increase in intestinal absorption of chemotherapeutic drugs like paclitaxel when administered along with flavonoids which help suppress certain specific cytochrome enzymes which play a role in paclitaxel metabolism. This review elaborates on the role and scope of phytochemicals in primary, secondary and tertiary care and how targeted prevention of cancer could be a breakthrough in the field of chemotherapy and oncology. This opens up a whole new area of research for delivery of these natural inhibitors along with anticancer drugs with the help of liposomes, micelles, nanoparticles, the usage of liquid biopsy analysis, artificial intelligence in medicine, risk assessment tools, multi-omics and multi-parametric analysis. Further, the site of action, mechanisms, metabolites involved, experimental models, doses and observations of two natural compounds, quercetin & thymoquinone, and two plant extracts, liquorice & garlic on CYP enzymes have been summarized.

Homocysteine as a marker for predicting disease severity in patients with COVID-19.

Aim: Our study was designed on the hypothesis that homocysteine levels are a prognostic parameter that can predict the severity of COVID-19 disease. Materials & methods: 117 COVID-19 patients and 34 non COVID-19 individuals were included in the study. Receiver operating characteristic (ROC) analysis was performed for homocysteine, D-dimer and monocyte/lymphocyte ratio (MLR) levels. Results: According to the ROC analysis, in COVID-19 patients group, Area under curve (AUC) values were 0.835 for homocysteine, 0.859 for D-dimer and 0.882 for MLR. According to the ROC analysis, in which homocysteine, MLR and D-dimer parameters were evaluated together, AUC values were 0.951 in the mild disease group, 1000 in severe disease group and 0.967 in COVID-19 patients group. Conclusion: It was concluded that homocysteine level is an important parameter in the follow-up of COVID-19 disease.

Predictive factors, preventive implications, and personalized surgical strategies for bone metastasis from lung cancer: population-based approach with a comprehensive cancer center-based study.

Background: Bone metastasis (BM) and skeletal-related events (SREs) happen to advanced lung cancer (LC) patients without warning. LC-BM patients are often passive to BM diagnosis and surgical treatment. It is necessary to guide the diagnosis and treatment paradigm for LC-BM patients from reactive medicine toward predictive, preventive, and personalized medicine (PPPM) step by step. Methods: Two independent study cohorts including LC-BM patients were analyzed, including the Surveillance, Epidemiology, and End Results (SEER) cohort (n = 203942) and the prospective Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 59). The epidemiological trends of BM in LC patients were depicted. Risk factors for BM were identified using a multivariable logistic regression model. An individualized nomogram was developed for BM risk stratification. Personalized surgical strategies and perioperative care were described for FUSCC cohort. Results: The BM incidence rate in LC patients grew (from 17.53% in 2010 to 19.05% in 2016). Liver metastasis was a significant risk factor for BM (OR = 4.53, 95% CI = 4.38-4.69) and poor prognosis (HR = 1.29, 95% CI = 1.25-1.32). The individualized nomogram exhibited good predictive performance for BM risk stratification (AUC = 0.784, 95%CI = 0.781-0.786). Younger patients, males, patients with high invasive LC, and patients with other distant site metastases should be prioritized for BM prevention. Spine is the most common site of BM, causing back pain (91.5%), pathological vertebral fracture (27.1%), and difficult walking (25.4%). Spinal surgery with personalized spinal reconstruction significantly relieved pain and improved daily activities. Perioperative inflammation, immune, and nutrition abnormities warrant personalized managements. Radiotherapy needs to be recommended for specific postoperative individuals. Conclusions: The presence of liver metastasis is a strong predictor of LC-BM. It is recommended to take proactive measures to prevent BM and its SREs, particularly in young patients, males, high invasive LC, and LC with liver metastasis. BM surgery and perioperative management are personalized and required. In addition, adjuvant radiation following separation surgery must also be included in PPPM-guided management. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00270-9.

miR-623 Targets Metalloproteinase-1 and Attenuates Extravasation of Brain Metastatic Triple-Negative Breast Cancer Cells.

Background: Most breast cancer-related deaths result from metastasis. Understanding the molecular basis of metastasis is needed for the development of effective targeted and preventive strategies. Matrix metalloproteinase-1 (MMP1) plays an important role in brain metastasis (BM) of triple-negative breast cancer (TNBC) by promoting extravasation of cancer cells across the brain endothelium (BE). MMP1 expression is controlled by endogenous microRNAs. Preliminary bioinformatics analysis has revealed that miR-623, known to target the 3'UTR of MMP1, is significantly downregulated in brain metastatic tumors compared to primary BC tumors. However, the involvement of miR-623 in MMP1 upregulation in breast cancer brain metastatic cells (BCBMC) remains unexplored. Here, we investigated the role of miR-623 in MMP1 regulation and its impact on the extravasation of TNBC cells through the BE in vitro. Materials and Methods: A loss-and-gain of function method was employed to address the effect of miR-623 modulation on MMP1 expression. MMP1 regulation by miR-623 was investigated by real-time PCR, western blot, luciferase and transwell migration assays using an in vitro human BE model. Results: Our results confirmed that brain metastatic TNBC cells express lower levels of miR-623 compared with cells having low propensity to spread toward the brain. miR-623 binds to the 3'-untranslated region of MMP1 transcript and downregulates its expression. Restoring miR-623 expression significantly decreased MMP1 expression, preserved the endothelial barrier integrity, and attenuated transmigration of BCBMC through the BE. Conclusion: Our study elucidates, for the first time, the crucial role of miR-623 as MMP1 direct regulator in BCBMC and sheds light on miR-623 as a novel therapeutic target that can be exploited to predict and prevent brain metastasis in TNBC. Importantly, the presents study helps in unraveling a brain metastasis-specific microRNA signature in TNBC that can be used as a guide to personalized metastasis prediction and preventive approach with better therapeutic outcome.

Rapid triage for ischemic stroke: a machine learning-driven approach in the context of predictive, preventive and personalised medicine.

Background: Recognising the early signs of ischemic stroke (IS) in emergency settings has been challenging. Machine learning (ML), a robust tool for predictive, preventive and personalised medicine (PPPM/3PM), presents a possible solution for this issue and produces accurate predictions for real-time data processing. Methods: This investigation evaluated 4999 IS patients among a total of 10,476 adults included in the initial dataset, and 1076 IS subjects among 3935 participants in the external validation dataset. Six ML-based models for the prediction of IS were trained on the initial dataset of 10,476 participants (split participants into a training set [80%] and an internal validation set [20%]). Selected clinical laboratory features routinely assessed at admission were used to inform the models. Model performance was mainly evaluated by the area under the receiver operating characteristic (AUC) curve. Additional techniques-permutation feature importance (PFI), local interpretable model-agnostic explanations (LIME), and SHapley Additive exPlanations (SHAP)-were applied for explaining the black-box ML models. Results: Fifteen routine haematological and biochemical features were selected to establish ML-based models for the prediction of IS. The XGBoost-based model achieved the highest predictive performance, reaching AUCs of 0.91 (0.90-0.92) and 0.92 (0.91-0.93) in the internal and external datasets respectively. PFI globally revealed that demographic feature age, routine haematological parameters, haemoglobin and neutrophil count, and biochemical analytes total protein and high-density lipoprotein cholesterol were more influential on the model's prediction. LIME and SHAP showed similar local feature attribution explanations. Conclusion: In the context of PPPM/3PM, we used the selected predictors obtained from the results of common blood tests to develop and validate ML-based models for the diagnosis of IS. The XGBoost-based model offers the most accurate prediction. By incorporating the individualised patient profile, this prediction tool is simple and quick to administer. This is promising to support subjective decision making in resource-limited settings or primary care, thereby shortening the time window for the treatment, and improving outcomes after IS. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00283-4.