Personalized Therapy Research Articles

Circulating tumor cells: advancing personalized therapy in small cell lung cancer patients.

Small cell lung cancer (SCLC) is a highly aggressive cancer with a dismal 5-year survival of < 7%, despite the addition of immunotherapy to first-line chemotherapy. Specific tumor biomarkers, such as delta-like ligand 3 (DLL3) and schlafen11 (SLFN11), may enable the selection of more efficacious, novel immunomodulating targeted treatments like bispecific T-cell engaging monoclonal antibodies (tarlatamab) and chemotherapy with PARP inhibitors. However, obtaining a tissue biopsy sample can be challenging in SCLC. Circulating tumor cells (CTCs) have the potential to provide molecular insights into a patient's cancer through a "simple" blood test. CTCs have been studied for their prognostic ability in SCLC; however, their value in guiding treatment decisions is yet to be elucidated. This review explores novel and promising targeted therapies in SCLC, summarizes current knowledge of CTCs in SCLC, and discusses how CTCs can be utilized for precision medicine.

Molecular testing for personalized therapy is underutilized in patients with borderline resectable and locally advanced pancreatic cancer – real world data from the NORPACT-2 study

Background International guidelines currently recommend the use of molecular testing in patients with advanced pancreatic cancer. The rate of actionable molecular alterations is low. The utility of molecular testing in patients with borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer in real world clinical practice is unclear. Methods 188 consecutive patients included in a prospective, population-based study (NORPACT-2) in patients with BRPC and LAPC (2018–2020) were reviewed. Molecular testing was performed at the discretion of the treating oncologist and was not recommended as a routine investigation by the national guidelines. All patients were considered fit to undergo primary chemotherapy and potential surgical resection. The frequency and the results of molecular testing (microsatellite instability (MSI) and/or KRAS status) were assessed. Results Thirty patients (16%) underwent molecular testing. MSI tumour was detected in one (3.6%) of 28 tested patients. The patient received immunotherapy and subsequently underwent surgical resection. Histological assessment of the resected specimen revealed a complete response. KRAS wild type was detected in one (14.3%) of seven tested patient. Patients who initiated FOLFIRINOX as the primary chemotherapy regimen (p = 0.022), or were being treated at one of the eight hospital trusts (p = 0.001) were more likely to undergo molecular testing. Conclusions Molecular testing was rarely performed in patients with BRPC or LAPC. Routine molecular testing for all patients with BRPC and LAPC should be considered to increase identification of targetable mutations and improve outcomes.

Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions.

Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.

Comparing in Person to Telehealth Delivery of a Family Violence Intervention.

There is increasing evidence that therapy and intervention services delivered by telehealth are effective at reducing a variety of mental health symptoms. Limited studies have indicated online services can reduce intimate partner violence (IPV), but none have tested in-person compared to telehealth-delivered interventions for men who have used IPV. Clinical outcome data from 311 parents (192 fathers and 119 linked coparent mothers) engaged in the Fathers for Change (F4C) intervention following referral by child protective services for IPV were examined to determine if in-person delivery of the intervention differed in terms of client treatment engagement and retention or outcomes. Parents who enrolled during a 1-year period prior to the COVID pandemic received their F4C therapy in person, while those who enrolled during the pandemic received their intake and most of their sessions via telehealth delivery. Parents reported significantly greater symptoms of depression, anxiety, and stress prior to treatment if they enrolled prior to COVID than if they enrolled during the pandemic. There were few differences in completion rates or outcomes based on in-person compared to telehealth delivery. Fathers were slightly more likely to complete treatment and attended a significantly higher percentage of their sessions when it was delivered by telehealth during COVID. Fathers reported significantly lower stress scores posttreatment when they received COVID telehealth delivery compared to prior to COVID in-person delivery of F4C. These findings suggest that telehealth may be an appropriate and viable option for the delivery of IPV interventions for families.

Digital health delivery in respiratory medicine: adjunct, replacement or cause for division?

Digital medicine is already well established in respiratory medicine through remote monitoring digital devices which are used in the day-to-day care of patients with asthma, COPD and sleep disorders. Image recognition software, deployed in thoracic radiology for many applications including lung cancer screening, is another application of digital medicine. Used as clinical decision support, this software will soon become part of day-to-day practice once concerns regarding generalisability have been addressed. Embodied in the electronic health record, digital medicine also plays a substantial role in the day-to-day clinical practice of respiratory medicine. Given the considerable work the electronic health record demands from clinicians, the next tangible impact of digital medicine may be artificial intelligence that aids administration, makes record keeping easier and facilitates better digital communication with patients. Future promises of digital medicine are based on their potential to analyse and characterise the large amounts of digital clinical data that are collected in routine care. Offering the potential to predict outcomes and personalise therapy, there is much to be excited by in this new epoch of innovation. However, these digital tools are by no means a silver bullet. It remains uncertain whether, let alone when, the promises of better models of personalisation and prediction will translate into clinically meaningful and cost-effective products for clinicians.

Implementing pharmacogenetic testing to optimize proton-pump inhibitors use among Indian population based on CPIC-CYP2C19-PPI dosing guidelines: The need of the hour.

Proton-pump inhibitors (PPIs) are widely prescribed to decrease stomach acid and treat various acid-related Gastrointestinal tract (GIT) diseases. However, genetic variations, particularly in the CYP2C19 gene, affect PPIs metabolism and efficacy. Variants in CYP2C19 can result in different rates of PPI metabolism, influencing their effectiveness. Personalized medicine strategies, such as genotyping for CYP2C19, have the potential to enhance the effectiveness of PPI therapy and patient safety. This review aims to describe the relevance of CYP2C19 genetic profiling in the indian population, including normal function (e.g. CYP2C19*1, *11, *13, *15, *18, *28, and 38), decreased function (e.g., CYP2C19*9, *10, *16, *19, *25, and 26), loss of function (e.g., CYP2C19*2, *3, *4, *5, *6, *7, *8, *22, *24, *35, *36, and *37), and increased function (e.g., CYP2C19*17) variants. This review also examines the clinical pharmacogenomics implementation consortium (CPIC)-CYP2C19-PPI guidelines to highlight the importance of pharmacogenomics (PGx)-informed personalized PPI therapy for gastroesophageal reflux disease and peptic ulcer disease treatment. On average, each person in India possesses eight pharmacogenetic (PGx) variants that can be clinically significant, underscoring the need for preemptive testing. Implementing CYP2C19 genetic testing in India requires expanding laboratory capacity, increasing accessibility in primary care, increasing public awareness, collaboration between pharmacovigilance and PGx programs, investing in advanced sequencing technologies, data management systems, and integration with electronic health records and clinical decision support systems. Addressing challenges such as genetic diversity, socioeconomic factors, health-care access issues, and shortage of trained professionals is essential for implementation. Due to the lack of definitive country-specific policies and PGx guidelines from Indian drug regulatory agencies, guidelines from international consortia such as the Clinical Pharmacogenetics Implementation Consortium and drug labeling offer crucial foundational evidence. This evidence can be used to enhance patient outcomes and ensure the safe and effective use of PPIs in India.

Features of generation and differentiation of induced pluripotent stem cells into retinal cells for modeling human hereditary diseases

The utilization of technology for the generation of induced pluripotent stem cells (iPSCs) and their subsequent differentiation is a promising approach for the study of disease pathogenesis and development of methods for treating optical neuropathies and retinopathy, which are the most common types of visual pathologies, in which retinal ganglion cells degenerate (consequently, optic nerve atrophy) or pigment epithelial cells and photoreceptors are affected, respectively. The prospect of patient-specific iPSCs has become a powerful alternative tool for discovering novel disease-causing mutations, studying genotype–phenotype relationships, screening therapeutic toxicity, and developing personalized cell therapy for optical neuropathies and retinopathies. Numerous studies have demonstrated the possibility of creating different types of retinal cells from iPSCs, which provides a rapid development of the research area of human diseases for which no relevant animal models are available or access to primary human tissues and cells is limited. This review presents various protocols for generating iPSCs from somatic cells and their subsequent differentiation, with an emphasis on the observed biological effects of the resulting cell cultures, including organoids, and discusses the prospects of using such models. The article may be useful to researchers studying the pathogenesis of various hereditary forms of blindness and developers of approaches for the treatment of these diseases who need a relevant cellular model.

Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary

Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96), and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and FISH analysis identified FGFR2 gene amplification in both models, in the form of homogenously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ-398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.

Emotion recognition to support personalized therapy in the elderly: an exploratory study based on CNNs

Emotion recognition to support personalized therapy in the elderly: an exploratory study based on CNNs

DIAGNOSTIC AND PROGNOSTIC SIGNIFICANCE OF GINGIVAL FLUID CYTOKINES IN THE DEVELOPMENT OF INFLAMMATORY PERIODONTAL DISEASES

Inflammatory periodontal diseases are one of the most common dental diseases in the world, along with dental caries. In the modern concept of the development of inflammatory periodontal diseases, one of the important roles is assigned to the body's immune response to the action of periodontal pathogenic microorganisms. In modern scientific literature, the concept of cytokine development of inflammatory periodontal diseases has been formed and substantiated. Evaluation of the cytokine profile of oral and gingival fluids allows us to determine the activity and severity of the disease. Well-founded immunological and molecular genetic mechanisms for the development of inflammatory periodontal diseases, associated with the influence of cytokines, make it possible to adjust the complex treatment of inflammatory periodontal diseases, determine the direction of personalized therapy for patients, determine the effectiveness of the treatment and the prognosis of the disease.

The Progression and Prospects of the Gene Expression Profiling in Ovarian Epithelial Cancer.

Ovarian cancer is one of the most common cancers with a high mortality rate among females worldwide. The understanding of the pathogenesis of the disease is highly important to provide personalized therapy to the patients. Ovarian cancer is as heterogeneous as colon and breast cancer which makes it difficult to treat. The development of gene signature is the only hope in providing targeted therapy to improve the survival of ovarian cancer patients. Malignant epithelial carcinomas are the most common cancers of the ovary with different histological and molecular subtypes and clinical behavior. The development of precursor lesions of ovarian carcinoma in the tubes and endometrium has provided a new dimension to the origin of ovarian cancers. The clinical utility of various gene signatures may not be logical unless validated. Validated gene signatures can aid the clinician in deciding the appropriate line of treatment.

Preoperative prediction of microvascular invasion: new insights into personalized therapy for early-stage hepatocellular carcinoma.

Owing to advances in diagnosis and treatment methods over past decades, a growing number of early-stage hepatocellular carcinoma (HCC) diagnoses has enabled a greater of proportion of patients to receive curative treatment. However, a high risk of early recurrence and poor prognosis remain major challenges in HCC therapy. Microvascular invasion (MVI) has been demonstrated to be an essential independent predictor of early recurrence after curative therapy. Currently, biopsy is not generally recommended before treatment to evaluate MVI in HCC according clinical guidelines due to sampling error and the high risk of tumor cell seeding following biopsy. Therefore, the postoperative histopathological examination is recognized as the gold standard of MVI diagnosis, but this lagging indicator greatly impedes clinicians in selecting the optimal effective treatment for prognosis. As imaging can now noninvasively and completely assess the whole tumor and host situation, it is playing an increasingly important role in the preoperative assessment of MVI. Therefore, imaging criteria for MVI diagnosis would be highly desirable for optimizing individualized therapeutic decision-making and achieving a better prognosis. In this review, we summarize the emerging image characteristics of different imaging modalities for predicting MVI. We also discuss whether advances in imaging technique have generated evidence that could be practice-changing and whether advanced imaging techniques will revolutionize therapeutic decision-making of early-stage HCC.

Chronic Generalized Periodontitis in a Patient with Infiltrative Pulmonary Tuberculosis

Currently, the World Health Organization, in its annual Global Tuberculosis Report, notes an increase in the incidence of tuberculosis in the world associated with the failure of health systems. In 2022, 7.5 million people worldwide were diagnosed with tuberculosis, the highest rate since 1995. In the Russian Federation, the stabilization of reduced morbidity and mortality rates from tuberculosis infection is currently being determined. Patients with tuberculosis often have comorbid and concomitant diseases, which are one of the main causes that impressively affect the diagnosis and treatment of inflammatory periodontal diseases. There is a pathogenetic relationship and aggravation of the course of diseases. The aim of the study is to analyze the course of chronic generalized periodontitis in a patient with pulmonary tuberculosis and to select personalized therapy. A clinical case of combined pathology (dental and infectious diseases) is presented, which was observed on the basis of the pulmonary therapeutic department of the N.S. Pokhvisneva KUZ in the VOKPTD. The conducted studies allowed us to conclude about the positive effect of a personalized approach in treatment.

DosePatch: physics-inspired cropping layout for patch-based Monte Carlo simulations to provide fast and accurate internal dosimetry

BackgroundDosimetry-based personalized therapy was shown to have clinical benefits e.g. in liver selective internal radiation therapy (SIRT). Yet, there is no consensus about its introduction into clinical practice, mainly as Monte Carlo simulations (gold standard for dosimetry) involve massive computation time. We addressed the problem of computation time and tested a patch-based approach for Monte Carlo simulations for internal dosimetry to improve parallelization. We introduce a physics-inspired cropping layout for patch-based MC dosimetry, and compare it to cropping layouts of the literature as well as dosimetry using organ-S-values, and dose kernels, taking whole-body Monte Carlo simulations as ground truth. This was evaluated in five patients receiving Yttrium-90 liver SIRT.ResultsThe patch-based Monte Carlo approach yielded the closest results to the ground truth, making it a valid alternative to the conventional approach. Our physics-inspired cropping layout and mosaicking scheme yielded a voxel-wise error of < 2% compared to whole-body Monte Carlo in soft tissue, while requiring only ≈\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\approx$$\\end{document} 10% of the time.ConclusionsThis work demonstrates the feasibility and accuracy of physics-inspired cropping layouts for patch-based Monte Carlo simulations.

Integrating metabolic profiling of pancreatic juice with transcriptomic analysis of pancreatic cancer tissue identifies distinct clinical subgroups.

Metabolic reprogramming is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC). A pancreatic juice (PJ) metabolic signature has been reported to be prognostic of oncological outcome for PDAC. Integration of PJ profiling with transcriptomic and spatial characterization of the tumor microenvironment would help in identifying PDACs with peculiar vulnerabilities. We performed a transcriptomic analysis of 26 PDAC samples grouped into 3 metabolic clusters (M_CL) according to their PJ metabolic profile. We analyzed molecular subtypes and transcriptional differences. Validation was performed by multidimensional imaging on tumor slides. Pancreatic juice metabolic profiling was associated with PDAC transcriptomic molecular subtypes (p=0.004). Tumors identified as M_CL1 exhibited a non-squamous molecular phenotype and demonstrated longer survival. Enrichment analysis revealed the upregulation of immune genes and pathways in M_CL1 samples compared to M_CL2, the group with worse prognosis, a difference confirmed by immunofluorescence on tissue slides. Enrichment analysis of 39 immune signatures by xCell confirmed decreased immune signatures in M_CL2 compared to M_CL1 and allowed a stratification of patients associated with longer survival. PJ metabolic fingerprints reflect PDAC molecular subtypes and the immune microenvironment, confirming PJ as a promising source of biomarkers for personalized therapy.

Artificial Intelligence application for the analysis of personality traits and disorders in social media: A Survey

Personality analysis has a positive influence on humanity as it aids in identifying personality traits and disorders. In addition, it facilitates the monitoring of cases and enriches doctors’ knowledge bases, particularly in decision-making processes. This study includes a comprehensive literature review on personality analysis approaches from social media, aiming to gain a thorough understanding of the current studies on personality therapy. Moreover, the objective of this study is to identify various limitations present in these studies and explore potential avenues for enhancement. More specifically, this research begins with an introduction that discusses the main concepts of traits and personality disorders, as well as the importance of psychological analysis. Following that, four cluster studies related to personality analysis on social media are presented: personality traits, personality disorders, detection of links between diseases, and monitoring patient status. Then, the majority of the currently available works for each cluster are exposed. Afterward, a comparative study of the different presented works is proposed. Finally, an outline of plans for further research in this area is provided, detailing potential paths for exploration.

Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma

The CUSP9 protocol is a polypharmaceutical strategy aiming at addressing the complexity of glioblastoma by targeting multiple pathways. Although the rationale for this 9-drug cocktail is well-supported by theoretical and in vitro data, its effectiveness compared to its 511 possible subsets has not been comprehensively evaluated. Such an analysis could reveal if fewer drugs could achieve similar or better outcomes.We conducted an exhaustive in vitro evaluation of the CUSP9 protocol using COMBImageDL, our specialized framework for testing higher-order drug combinations. This study assessed all 511 subsets of the CUSP9v3 protocol, in combination with temozolomide, on two clonal cultures of glioma-initiating cells derived from patient samples. The drugs were used at fixed, clinically relevant concentrations, and the experiment was performed in quadruplicate with endpoint cell viability and live-cell imaging readouts. Our results showed that several lower-order drug combinations produced effects equivalent to the full CUSP9 cocktail, indicating potential for simplified regimens in personalized therapy. Further validation through in vivo and precision medicine testing is required.Notably, a subset of four drugs (auranofin, disulfiram, itraconazole, sertraline) was particularly effective, reducing cell growth, altering cell morphology, increasing apoptotic-like cells within 4–28 h, and significantly decreasing cell viability after 68 h compared to untreated cells.This study underscores the importance and feasibility of comprehensive in vitro evaluations of complex drug combinations on patient-derived tumor cells, serving as a critical step toward (pre-)clinical development.

Minimally-invasive implantable device enhances brain cancer suppression

Current brain tumor treatments are limited by the skull and BBB, leading to poor prognosis and short survival for glioma patients. We introduce a novel minimally-invasive brain tumor suppression (MIBTS) device combining personalized intracranial electric field therapy with in-situ chemotherapeutic coating. The core of our MIBTS technique is a wireless-ultrasound-powered, chip-sized, lightweight device with all functional circuits encapsulated in a small but efficient “Swiss-roll” structure, guaranteeing enhanced energy conversion while requiring tiny implantation windows ( ~ 3 × 5 mm), which favors broad consumers acceptance and easy-to-use of the device. Compared with existing technologies, competitive advantages in terms of tumor suppressive efficacy and therapeutic resolution were noticed, with maximum ~80% higher suppression effect than first-line chemotherapy and 50–70% higher than the most advanced tumor treating field technology. In addition, patient-personalized therapy strategies could be tuned from the MIBTS without increasing size or adding circuits on the integrated chip, ensuring the optimal therapeutic effect and avoid tumor resistance. These groundbreaking achievements of MIBTS offer new hope for controlling tumor recurrence and extending patient survival.

Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn's Disease.

The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn's disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation.

Specific microbiome patterns and their association with breast cancer: the intestinal microbiota as a potential biomarker and therapeutic strategy.

Breast cancer (BC) is one of the most diagnosed cancers in women. Based on histological characteristics, they are classified as non-invasive, or in situ (tumors located within the milk ducts or milk lobules) and invasive. BC may develop from in situ carcinomas over time. Determining prognosis and predicting response to treatment are essential tools to manage this disease and reduce its incidence and mortality, as well as to promote personalized therapy for patients. However, over half of the cases are not associated with known risk factors. In addition, some patients develop resistance to treatment and relapse. Therefore, it is necessary to identify new biomarkers and treatment strategies that improve existing therapies. In this regard, the role of the microbiome is being researched as it could play a role in carcinogenesis and the efficacy of BC therapies. This review aims to describe specific microbiome patterns associated with BC. For this, a literature search was carried out in PubMed database using the MeSH terms "Breast Neoplasms" and "Gastrointestinal Microbiome", including 29 publications. Most of the studies have focused on characterizing the gut or breast tissue microbiome of the patients. Likewise, studies in animal models and in vitro that investigated the impact of gut microbiota (GM) on BC treatments and the effects of the microbiome on tumor cells were included. Based on the results of the included articles, BC could be associated with an imbalance in the GM. This imbalance varied depending on molecular type, stage and grade of cancer, menopause, menarche, body mass index, and physical activity. However, a specific microbial profile could not be identified as a biomarker. On the other hand, some studies suggest that the GM may influence the efficacy of BC therapies. In addition, some microorganisms and bacterial metabolites could improve the effects of therapies or influence tumor development.