BACKGROUND: Personalized disease models are crucial for evaluating how diseased cells respond to treatments, especially in case of innovative biological therapeutics. Extracellular vesicles (EVs), nanosized vesicles released by cells for intercellular communication, have gained therapeutic interest due to their ability to reprogram target cells. We here utilized urinary podocytes obtained from children affected by steroid-resistant nephrotic syndrome with characterized genetic mutations as a model to test the therapeutic potential of EVs derived from kidney progenitor cells (nKPCs).
METHODS: EVs were isolated from nKPCs derived from the urine of a preterm neonate. Three lines of urinary podocytes obtained from nephrotic patients\' urine and a line of Alport syndrome patient podocytes were characterized and used to assess albumin permeability in response to nKPC-EVs or various drugs. RNA sequencing was conducted to identify commonly modulated pathways after nKPC-EV treatment. siRNA transfection was used to demonstrate the involvement of SUMO1 and SENP2 in the modulation of permeability.
RESULTS: Treatment with the nKPC-EVs significantly reduced permeability across all the steroid-resistant patients-derived and Alport syndrome-derived podocytes. At variance, podocytes appeared unresponsive to standard pharmacological treatments, with the exception of one line, in alignment with the patient\'s clinical response at 48 months. By RNA sequencing, only two genes were commonly upregulated in nKPC-EV-treated genetically altered podocytes: small ubiquitin-related modifier 1 (SUMO1) and Sentrin-specific protease 2 (SENP2). SUMO1 and SENP2 downregulation increased podocyte permeability confirming the role of the SUMOylation pathway.
CONCLUSIONS: nKPCs emerge as a promising non-invasive source of EVs with potential therapeutic effects on podocytes with genetic dysfunction, through modulation of SUMOylation, an important pathway for the stability of podocyte slit diaphragm proteins. Our findings also suggest the feasibility of developing a non-invasive in vitro model for screening regenerative compounds on patient-derived podocytes.

UNASSIGNED: The plasma concentration of 5-Fluorouracil (5-FU) is affected by numerous factors, thereby limiting its efficacy. The current therapeutic regimen\'s doses based on body surface area (BSA) are linked to increased toxicity and sometimes inadequate drug exposure.
UNASSIGNED: The study aims to develop an in-vitro assay to monitor 5-Fluorouracil\'s therapeutic efficacy in cancer patients\' blood samples, focusing on pharmacokinetics to improve therapy precision.
UNASSIGNED: Drug levels were determined from standards, quality controls, and experimental samples using protein precipitation, liquid-liquid extraction, and separation using a C18 analytical column with an isocratic program.
UNASSIGNED: In EXP-1A, the mean concentration of 5-Fluorouracil was 1.15 μg/ml; in EXP-1B, it was 1.16 μg/ml, while in EXP-1C, the mean concentration was 0.9 μg/ml. The percentage difference in mean 5-Fluorouracil concentration between the experiment sample containing a DPD inactivator and EXP-1C (without a DPD inactivator) was 21.5 % higher for EXP-1A and 0.68 % higher for EXP-1B. In the second phase of the experiment, the overall stability of 5-Fluorouracil in samples containing a DPD inactivator was 24.5 % superior compared to samples without a DPD inactivator.
UNASSIGNED: A modified extraction technique has been developed to accurately measure 5-Flourouracil concentration in blood, preserving its stability and concentration by adding a DPD inactivator.

In 2021, the Clinical Pharmacology Department of Hospital Universitario de La Princesa launched the PriME-PGx initiative (Multidisciplinary Initiative of the Hospital Universitario de La Princesa for the Implementation of Pharmacogenetics) to promote the expansion of pharmacogenetics in hospitalized patients. We establish seven pharmacogenetic profiles based on the specific needs of seven departments: Oncology, Pain Unit, Neuropsychiatry, Internal or Infectious Medicine, Cardiology, Gastroenterology and Immunosuppressants. The experience of the last 3 years reflects a total of 1421 reports (37.4% being oncology profiles), with a gradual increase in the number of requests each year. With this project, we aim to expand the availability and utility of pharmacogenetic biomarkers to achieve personalised therapy that avoids adverse drug reactions and therapeutic failure.
[Box: see text].

Advancements in the CRISPR technology, a game-changer in experimental research, have revolutionized various fields of life sciences and more profoundly, cancer research. Cell death pathways are among the most deregulated in cancer cells and are considered as critical aspects in cancer development. Through decades, our knowledge of the mechanisms orchestrating programmed cellular death has increased substantially, attributed to the revolution of cutting-edge technologies. The heroic appearance of CRISPR systems have expanded the available screening platform and genome engineering toolbox to detect mutations and create precise genome edits. In that context, the precise ability of this system for identification and targeting of mutations in cell death signaling pathways that result in cancer development and therapy resistance is an auspicious choice to transform and accelerate the individualized cancer therapy. The concept of personalized cancer therapy stands on the identification of molecular characterization of the individual tumor and its microenvironment in order to provide a precise treatment with the highest possible outcome and minimum toxicity. This study explored the potential of CRISPR technology in precision cancer treatment by identifying and targeting specific cell death pathways. It showed the promise of CRISPR in finding key components and mutations involved in programmed cell death, making it a potential tool for targeted cancer therapy. However, this study also highlighted the challenges and limitations that need to be addressed in future research to fully realize the potential of CRISPR in cancer treatment.

Objective Non-Hodgkin lymphoma (NHL) arising as a secondary malignancy in patients treated for classical Hodgkin lymphoma (cHL) is an infrequent and challenging clinical scenario. NHL can be presented synchronously with cHL or may develop later, sequentially, up to years after treatment for cHL. The relationship between the two lymphomas is unclear, and there are no clear guidelines for the management of these patients. We would like to find a better clinical understanding of this issue so this study investigates the occurrence and clinical characteristics of secondary NHL. Materials and methods In this retrospective cohort examination, we collected cHL cases when NHL occurred during or after the course of treating cHL. We performed the histopathologic revisions of the samples, and in every case where the quality of the sample was lower, we performed molecular examinations to find the association between cHL and NHL. We performed next-generation genome sequencing (NGS) and immunoglobulin heavy-chain variable region gene (IgHV) clonality testing. Results In a cohort of 164 cHL patients diagnosed between 2011 and 2020, six patients were identified with NHL during rebiopsy prompted by lymphoma relapse or progression. Among these, five patients were diagnosed with post-germinal center-originated diffuse large B-cell lymphoma (post-GC DLBCL), and one patient presented high-grade B-cell lymphoma (HG-BCL). The NHL manifestation differed in its timing: three cases emerged after successful cHL treatment, with at least 18 months of complete remission, while the other three patients faced primary refractory cHL. Notably, the primary refractory cases did not exhibit a confirmed clonal relationship between cHL and NHL, but NGS data raised the possibility of synchronous NHL in one case. In contrast, among the patients with sequentially occurring NHL, polymerase chain reaction (PCR) testing of the IgHV gene affirmed a clonal connection between cHL and secondary DLBCL in one case, while the high morphological similarity suggested a potential clonality between the two lymphomas in another case. Conclusion This study reveals that secondary NHL may manifest both synchronously and sequentially following cHL. Our results suggest that synchronous NHL has a worse prognosis compared to sequential cases when the different lymphomas are not recognized at the time of diagnosis. As our data showed, in some cases, mutations that accompany the tumor cells throughout their clonal evolution can be identified, with additional mutations later on. In the future, next-generation sequencing (NGS)-based processing of liquid biopsy samples can overcome the limitations resulting from the spatial heterogeneity of lymphoid malignancies. Over the long term, this identification could lead to early patient selection and alternative treatment strategies, ultimately leading to improved prospects for cure.

UNASSIGNED: Postoperative delirium (POD) is a serious complication following deep brain stimulation (DBS) but only received little attention. Its main risk factors are higher age and preoperative cognitive deficits. These are also main risk factors for long-term cognitive decline after DBS in Parkinson\'s disease (PD).
UNASSIGNED: To identify risk factors for POD severity after DBS surgery in PD.
UNASSIGNED: 57 patients underwent DBS (21 female; age 60.2±8.2; disease duration 10.5±5.9 years). Preoperatively, general, PD- and surgery-specific predictors were recorded. Montreal Cognitive Assessment and the neuropsychological test battery CANTAB ConnectTM were used to test domain-specific cognition. Volumes of the cholinergic basal forebrain were calculated with voxel-based morphometry. POD severity was recorded with the delirium scales Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Nursing Delirium Scale (NU-DESC). Spearman correlations were calculated for univariate analysis of predictors and POD severity and linear regression with elastic net regularization and leave-one-out cross-validation was performed to fit a multivariable model.
UNASSIGNED: 21 patients (36.8%) showed mainly mild courses of POD following DBS. Correlation between predicted and true POD severity was significant (spearman rho = 0.365, p = 0.001). Influential predictors were age (p < 0.001), deficits in attention and motor speed (p = 0.002), visual learning (p = 0.036) as well as working memory (p < 0.001), Nucleus basalis of Meynert volumes (p = 0.003) and burst suppression (p = 0.005).
UNASSIGNED: General but also PD- and surgery-specific factors were predictive of POD severity. These findings underline the multifaceted etiology of POD after DBS in PD. Valid predictive models must therefore consider general, PD- and surgery-specific factors.

The 21st Association for Cancer Immunotherapy (CIMT) Annual Meeting took place from May 15th to May 17th in Mainz, Germany, and was attended by a total of 855 academic and clinical professionals hailing from 33 different countries. The conference served as a platform for these experts to convene and discuss the latest breakthroughs in cancer immunology and immunotherapy research. Dedicated sessions covering advancements in artificial intelligence tools for cancer immunotherapy research, as well as the landscape of cancer care and cancer immunotherapy trials on the African continent, prompted lively and informative discussions among the attendees. This report aims to provide an overview of the most noteworthy highlights and key takeaways from CIMT2024.

OBJECTIVE: Fibromyalgia Syndrome (FMS) is a complex chronic pain condition characterized by widespread musculoskeletal pain and numerous other debilitating symptoms. The purpose of this review is to provide a comprehensive overview, based on everyday clinical practice, of the drugs presently employed in the treatment of FMS.
RESULTS: The treatment of FMS is based on a multimodal approach, with pharmacologic treatment being an essential pillar. The drugs used include tricyclic antidepressants, serotonin and noradrenaline reuptake inhibitors, other antidepressants, anticonvulsants, myorelaxants, and analgesics. The effectiveness of these medications varies, and the choice of drug often depends on the specific symptoms presented by the patient. Many drugs tend to either address only some domains of the complex FMS symptomatology or have a limited effect on pain. Each treatment option comes with potential side effects and risks that necessitate careful consideration. It may be beneficial to divide patients into clinical subpopulations, such as FMS with comorbid depression, for more effective treatment. Despite the complexities and challenges, the pharmacological treatment remains a crucial part for the management of FMS. This review aims to guide clinicians in prescribing pharmacological treatment to individuals with FMS.

UNASSIGNED: Hip replacement surgeries are increasing in demand, requiring rigorous improvements to a mature surgical protocol. Postoperative patient dissatisfaction mainly stems from postoperative complications resulting from the inappropriate selection of prostheses to meet the needs of each patient. This results in prosthesis loosening, hospital-related fractures, and postoperative complex pain, which can all be attributed to inappropriate sizing. In this study, we aimed to further explore the intraoperative and postoperative benefits of incorporating computer-aided design (CAD) in preoperative planning for total hip arthroplasty (THA).
UNASSIGNED: A total of 62 patients requiring total hip replacement surgery from January 2021 to December 2021 were collected and randomly divided into a preoperative computer-aided simulated group and a conventional x-ray interpretation group. The accuracy of implant size selection (femoral and acetabular implant) between the preoperative planning and surgical procedure of the two groups was compared. Patient parameters, perioperative Harris hip scores, operative time (skin-to-skin time), surgical blood loss, and postoperative hospital stay were recorded, and the differences between the two groups were statistically compared using a single sample t-test.
UNASSIGNED: All patients in the study were successfully operated on and achieved good postoperative functional recovery. With CAD, the selection of the most suitable-sized prosthesis was significantly more accurate compared to the control group (accuracy of the acetabular component between the CAD/control: 80.6%/61.3%, and accuracy of the femoral component: 83.9%/67.7%). Intraoperative blood loss (177.4/231.0 ml, P = 0.002), operation time (84.2 ± 19.8 min/100.3 ± 25.9 min, P = 0.008), duration of hospital stay (6.5 ± 3/9.1 ± 3.9 days, P = 0.003), and postoperative Harris hip score (81.9 ± 6.5/74.7 ± 11.1, P = 0.003) were compared to the control group and showed statistical significance.
UNASSIGNED: Incorporating CAD into the preoperative planning of total hip arthroplasty can effectively guide the selection of the most suitable-sized prosthesis, reduce intraoperative blood loss, and promote short-term functional recovery after THA.

Digital therapeutics (DTx) is a recently conceived idea in health care that aims to cure ailments and modify patient behavior by employing a range of digital technologies. Notably, when traditional medication is not entirely efficacious, DTx offers an innovative avenue for treatments linked to dysfunctional behaviors and lifestyle management. DTx involves extremely adaptable therapeutic devices that empower greater patient engagement in treating illness, using algorithms to collect, transfer and analyze the patient\'s data. Efficient clinical monitoring and supervision at the individual level by remote access and algorithms for a range of diseases is made possible by integrating machine learning and artificial intelligence with DTx. There is a potentially large worldwide market for DTx owing to its convenient, personalized therapies.