Successful Therapy Research Articles

Significance of Bacillus Calmette-Guerin (BCG) vaccine intervention for patients with Type 1 Diabetes (T1D): A systematic review and meta-analysis

PurposeImmunotherapy is an emerging therapeutic modality for many autoimmune, oncology, and infectious diseases to cure or prevent the underlying causes. Several immunotherapeutic agents are investigated for their beneficial potential in patients with diabetes. However, none have culminated into a successful therapy. The present comprehensive meta-analysis and systematic review covers the last two decades of historical research evaluating the Bacillus Calmette-Guerin (BCG) vaccine as an immunotherapeutic agent in diabetes, along with updated information on similar recent publications. MethodA total of 278 articles were retrieved through literature databases, and after applying inclusion and exclusion criteria as per PRISMA guidelines, seven studies were selected for meta-analysis using Cochrane Q statistics. ResultsOur meta-analysis revealed marginal benefits, lowering glycosylated/glycated haemoglobin (HbA1C) levels and glutamic-acid-decarboxylase (GAD) autoantibodies in BCG treated people with Type 1 Diabetes (T1D) compared to the matched control individuals. The BCG intervention found to be ineffective in regulating C-peptide (connecting peptide) and clinical remission (CR) i.e. improved glycemic regulation, though beneficial tendency was observed. ConclusionOur systematic review and meta-analysis revealed benefits of BCG vaccine intervention in T1D patients, including improved HbA1C and GAD autoantibody levels. However, the study has several limitations stemming from BCG vaccine-related factors and patient characteristics. Therefore, a large clinical trial with an enhanced study design is needed to validate the immunity-related benefits of the BCG vaccine for glucose metabolism in patients with T1D.

Radiological and Hematological Parameters Predicting Success of Medical Expulsive Therapy in Patients With Ureteral Calculus.

Background Urolithiasis, characterized by the formation of stones in the urinary tract, is a common condition with significant morbidity. Medical expulsive therapy (MET) has emerged as a non-invasive treatment modality for facilitating the spontaneous passage of ureteral stones. However, MET success varies widely among individuals, and identifying predictive factors for treatment outcomes is crucial for optimizing patient care. Objective This study aimed to evaluate the predictive role of radiological and hematological parameters in the success of MET for ureteral stones. Methods A prospective observational cohort study was conducted at the Department of Urology, tertiary care center, Patna, involving consecutive patients who underwent MET for ureteral stones. Radiological parameters (stone size, location, and hydronephrosis) and hematological markers (C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR)) were assessed as predictors of treatment success. Univariate and multivariate logistic regression analyses were performed to identify significant predictors of MET success. Results Among the 156 patients included in the study (mean age: 42 years; range: 18-50 years), radiological parameters, such as smaller stone size (<10 mm) and absence of hydronephrosis, were significantly associated with higher rates of MET success (p<0.05). Lower CRP levels (p<0.001) and NLR (p<0.05) were also predictive of treatment success. Logistic regression analysis confirmed the independent predictive value of these parameters after adjusting for potential confounders. Conclusion Radiological and hematological parameters are valuable predictors of the success of MET for ureteral stones. Incorporating these predictive factors into clinical decision-making can optimize treatment outcomes and minimize unnecessary interventions in patients with a higher likelihood of spontaneous stone passage.

Graded Organ Response and Progression Criteria for Kidney Immunoglobulin Light Chain Amyloidosis

Kidney light chain (AL) amyloidosis is associated with a risk of progression to kidney replacement therapy (KRT) and death. Several studies have shown that a greater reduction in proteinuria following successful anticlonal therapy is associated with improved outcomes. To validate graded kidney response criteria and their association with kidney and overall survival (OS). This retrospective, multicenter cohort was conducted at 10 referral centers for amyloidosis from 2010 to 2015 and included patients with kidney AL amyloidosis that was evaluable for kidney response and who achieved at least hematologic partial response within 12 months of diagnosis. The median follow-up was 69 (54-88) months. Data analysis was conducted in 2023. Four kidney response categories based on the reduction in pretreatment 24-hour urine protein (24-hour UP) levels: complete response (kidCR, 24-hour UP ≤200 mg), very good partial response (kidVGPR, >60% reduction in 24-hour UP), partial response (kidPR, 31%-60% reduction), and no response (kidNR, ≤30% reduction). Kidney response was assessed at landmark points (6, 12, and 24 months) and best kidney response. Cumulative incidence of progression to KRT and OS. Seven-hundred and thirty-two patients (335 women [45.8%]) were included, with a median (IQR) age of 63 (55-69) years. The median (IQR) baseline 24-hour proteinuria and estimated glomerular filtration rate was 5.3 (2.8-8.5) g per 24 hours and 72 (48-92) mL/min/1.73m2, respectively. In a competing-risk analysis, the 5-year cumulative incidence rates of progression to KRT decreased with deeper kidney responses as early as 6 months from therapy initiation (11%, 12%, 2.1%, and 0% for kidNR, kidPR, kidVGPR, and kidCR, respectively; P = .002) and were maintained at 12 months and 24 months and best kidney response. Patients able to achieve kidCR/kidVGPR by 24 months and at best response had significantly better OS compared with kidPR/kidNR. Kidney progression, defined as a 25% or greater decrease in estimated glomerular filtration rate, was associated with cumulative incidence of progression to KRT and OS. The results of this cohort study suggest that graded kidney response criteria offers clinically and prognostically meaningful information for treating patients with kidney AL amyloidosis. The response criteria potentially inform kidney survival based on the depth of reduction in 24-hour proteinuria levels and demonstrate an OS advantage for those able to achieve kidCR/kidVGPR compared with kidPR/kidNR. Taken together, achievement of at least kidVGPR by 12 months is needed to ultimately improve kidney and patient survival.

Evaluating clinically translatable conditioning for platelet gene therapy in murine hemophilia A with inhibitors

BackgroundPlatelet gene therapy is effective in hemophilia A (HA) mice even with inhibitors. Fludarabine (Flu), along with busulfan (Bu) or melphalan (Mel), preconditioning has been shown to be highly effective for hematopoietic stem cell transplantation in the clinic. ObjectivesTo evaluate the efficacy of Bu–Flu and Mel–Flu preconditioning in platelet gene therapy of HA with inhibitors. MethodsBu–Flu and Mel–Flu were used to condition HA mice preimmunized with recombinant human factor (F)VIII. An optimal 660 centigray total body irradiation was used as a control regimen in parallel. Platelet–FVIII expression was introduced by transplantation of 2bF8 lentivirus (LV)-transduced hematopoietic stem cells. Animals were analyzed by fluorescence-activated cell sorting, quantitative polymerase chain reaction, FVIII assays, and tail bleeding tests. ResultsBu–Flu, but not Mel–Flu, enabled successful 2bF8 gene therapy. All recipients achieved >55% chimerism post hematopoietic stem cell transplantation in both Bu–Flu and 660 centigray groups, with comparable copy numbers of 2bF8 cassette and the platelet–FVIII levels. The bleeding phenotype was rescued in 2bF8LV-transduced recipients. FVIII inhibitor titers declined with time, with comparable disappearance time of inhibitors between the 2 groups. When animals were rechallenged with recombinant human FVIII after the titers dropped to undetectable levels, no inhibitors were detected in 2bF8LV-transduced recipients. In contrast, all untransduced transplanted control mice produced inhibitors. These data demonstrate that immune tolerance was established in 2bF8LV-transduced primed HA mice under Bu–Flu conditioning. ConclusionBu–Flu preconditioning allows for successfully introducing platelet–FVIII expression to restore hemostasis and induce immune tolerance in primed HA mice, suggesting that this approach is a promising clinically translatable strategy for gene therapy of HA with inhibitors.

Unraveling the Tapestry of Depression: A Cross-Sectional Study.

An often-occurring and severely disabling mental illness that mostly affects older people living in urban slums is depression. Developing successful therapies requires an understanding of the complex interactions between the different factors that contribute to depression in this susceptible population. This study aimed to find the prevalence of depression and identify the factors associated with depression in the geriatric population aged ≥60 years in the study area during the study period in Gujarat, India. This study was carried out among 450 participants aged ≥60 years. Face-to-face interviews and standardized assessment tools, including the Geriatric Depression Scale (GDS) for depression and the Mini-Cog test for cognitive impairment, were used to collect data on depression levels, sociodemographic characteristics, behavioral factors, medical conditions, life events, and psychiatric history. Statistical analyses, including chi-squared tests, were performed to assess the associations. Significant associations were found between various factors and depression levels, which were lower education (11.11% severe depression among non-literate vs. 2.11% among literate, p<0.001)and widowhood (11.56% severe depression among widowed vs. 4.53% among married, p<0.001), which were linked to higher depression severity. Behavioral risk factors like short sleep duration (<6 hours at night: 21.71% severe depression, p<0.001), tobacco snuffing (16.24% severe depression, p<0.001), and lack of physical activity (28.71% severe depression, p<0.001) were strongly associated with increased depression. Medical conditions such as hypertension (10.36% severe depression, p<0.001) and stressful life events like family conflicts (16.67% severe depression, p<0.001) exhibited strong associations. A personal history of depression (38.82% severe depression, p<0.001) was a potent predictor. The study highlights the multifaceted nature of depression in the geriatric population of the study area, underscoring the necessity of all-encompassing measures to tackle the recognized possible risk factors. The results provide valuable insights for developing targeted prevention strategies, healthcare policies, and support systems to enhance the mental well-being of this vulnerable population.

Current status and perspectives of clinical trials for tumor-infiltrating lymphocyte therapy.

Immunotherapies, mainly immune checkpoint inhibitors (ICIs), have revolutionized cancer treatment strategies over the past decade, but their limitations have limited clinical applications. Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cell therapy (ACT), which collects infiltrating lymphocytes at the tumor site and expands them in vitro to obtain TIL final products cloned by various T-cell receptors, subsequently reinfused TIL into the patient, which is effective for the treatment of solid tumors. The approval of Lifileucel for commercialization marks the success of TIL therapy. This review summarizes the current status of clinical trials of TIL treatment. In addition, it is suggested that the current research trend of TIL should focus on improving the survival time of TIL in vivo, reducing drug toxicity, and searching for prognostic markers. Finally, it is expected that TIL therapy can be applied to a more wide range of clinical treatments.

Secretome from iPSC-derived MSCs exerts proangiogenic and immunosuppressive effects to alleviate radiation-induced vascular endothelial cell damage

BackgroundRadiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines.MethodsWe generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit.ResultsIncreasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment.ConclusionsThe iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

MRNA therapeutics in diseases: Light inspect into a new horizon

An in-depth analysis of messenger RNA (mRNA) therapeutics and their potential to treat a wide range of diseases is provided in this thorough review paper. mRNA therapy has a great deal of potential for treating various terminal illnesses. By introducing mRNA as a vaccine or therapeutic agent, recent developments in biotechnology and molecular medicine have made it possible to produce almost any functional protein or peptide in the human body. This offers a unique chance to prevent and treat various challenging illnesses, many of which have genetic roots. Moreover, the utilization of in vitro transcribed mRNA has brought about a revolution in the production process, rendering it more efficient, adaptable, customizable, and cost-effective when compared to traditional methods. For a long time, researchers have aspired to enhance various aspects of mRNA, including its stability, immunogenicity, translation efficiency, and delivery systems, with the aim of achieving an efficient and secure means of delivering mRNA. In this comprehensive review, we will delve into the essence of mRNA and mRNA-based therapies, encompassing their fundamental principles, methods of production, diverse applications, outcomes, and constraints. We will underscore the importance of optimizing mRNA and its delivery systems to ensure the success of mRNA therapy, all while addressing the pivotal challenges and prospects in the battle against cancer and COVID-19.

Exploring the Dark Matter of Human Proteome: The Emerging Role of Non-Canonical Open Reading Frame (ncORF) in Cancer Diagnosis, Biology, and Therapy.

Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatics and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the carcinogenic role of ncORFs such as pTINCR and HOXB-AS3 in regulating hallmarks of cancer, as well as the roles of ncORFs such as HOXB-AS3 and CIP2A-BP in cancer diagnosis and prognosis. We also discuss how ncORFs such as AKT-174aa and DDUP are involved in anti-cancer drug response and the underestimated potential of ncORFs as therapeutic targets.

Radiation therapy and IRreversible electroporation for intermediate risk prostate cancer (RTIRE)

IntroductionRadiation Therapy and IRreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE) is a phase II clinical trial testing combination of radiation therapy and irreversible electroporation for intermediate risk prostate cancerBackgroundPCa is the most common non-cutaneous cancer in men and the second leading cause of cancer death in men. PCa treatment is associated with long term side effects including urinary, sexual, and bowel dysfunction. Management of PCa is based on risk stratification to prevent its overtreatment and associated treatment-related toxicity. There is increasing interest in novel treatment strategies, such as focal therapy, to minimize treatment associated morbidity. Focal therapy alone has yet to be included in mainstream guidelines, given ongoing concerns with potentially higher risk of recurrence. We hypothesize combining focal therapy with whole gland, reduced dose radiotherapy will provide acceptable oncologic efficacy with minimal treatment associated morbidity. RTIRE is a phase II single institution, investigator-initiated study combining a local ablative technique though local irreversible electroporation (IRE) with MR guided RT (MRgRT) to treat the entire prostate. The goal is to provide excellent oncologic outcomes and minimize treatment related side effects through leveraging benefits of locally ablative therapy with established radiation treatment techniques.MethodsA total of 42 men with intermediate risk PCa per NCCN guidelines and focal grade group (GG) 2 or 3, Gleason Score (GS) 3 + 4 or GS 4 + 3, cancer in an MRI target will be enrolled. Patients with MRI visible foci of GG2/GG3 will undergo focal therapy with IRE of this lesion. Following successful focal therapy, patients will then undergo a course of reduced dose, whole gland MRgRT with either 32.5 Gy in 5 Fractions or 22 Gy in 2 fractions. The primary objective of the study is to determine safety. Secondary outcomes include evaluation of oncologic efficacy (as measured by the proportion of patients free of clinically significant cancer as defined as > Grade Group 1 at 1-year follow-up biopsy), imaging characteristics of patients pre and post RTIRE, impact on quality of life (QoL), and PSA kinetics.DiscussionCombining IRE with a reduced dose radiotherapy may offer a new treatment paradigm for PCa by both reducing treatment effects of full dose radiotherapy and minimizing the risk of recurrence observed with focal therapy.Trial RegistrationClinicaltrials.gov identifier: NCT05345444. Date of registration: April 25, 2022. Protocol Version: 6.0, July 7, 2023.

Oral-hygiene-related self-efficacy in periodontal therapy: A 4-year longitudinal study.

Oral hygiene-related self-efficacy (OHSE) describes one's confidence to successfully execute oral hygiene behaviour. The aim of this study was to investigate the long-term course of OHSE in patients during initial periodontal therapy (IPT) and supportive periodontal therapy (SPT) and its association with clinical parameters. Patients diagnosed with periodontitis, undergoing either IPT or SPT, were evaluated at two timepoints. Clinical examination included pocket probing depths (PPDs), clinical attachment loss (CAL), bleeding on probing (BOP), plaque index (PI) and gingival index (GI). Patients' OHSE was assessed with a questionnaire. Statistical analyses included t-tests and linear regression models. Ninety-eight patients from an initial group of 201 patients were evaluated after 4 years. The overall OHSE score increased significantly in the IPT group (mean 11.65 ± 15.6, p = .001). The increase in the OHSE category 'interdental cleaning' was significantly correlated with a decrease in the number of pockets requiring treatment (Spearman correlation rs = -.2349, p = .022) and periodontal inflamed surface area (PISA) (rs = -.2099, p = .042). Patients under IPT showed a significant increase of OHSE compared to those under SPT. Improved OHSE, particularly in interdental cleaning, appears to be associated with sustained success of periodontal therapy.

A review of tissue engineering in regenerative endodontic treatment

Background: Regenerative endodontic treatments are classified based on approach in the procedures and principles. One is cell-free approach that involves a revitalization procedure to achieve continued root growth while the other is cell-based approach which involves pulp/dentin regeneration through isolation and ex vivo expansion of stem cells seeded in the scaffold and then transplanted into the canal space. Technically, the cell-free approach is simpler than cell-based approach because the former does not concern about external stem cell isolation and culture. Currently, the gold standard and the one that has been clinically performed is cell-free approach. Cell-based approach is still not a standard because currently the cell-based approach is still in the clinical trial stage. Purpose: to evaluate the biological basis and clinical protocols recently used in regenerative endodontic treatment and discuss potentially future treatment approaches. Review: The literature review was searched in PUBMED with the keywords: immature permanent teeth, pulp revascularization, stem cells and regenerative endodontics. The regenerative endodontic treatments with various procedures and techniques result in a significant increase in root length and dentinal wall thickness. Stimulation of stem cells in apical root canal system is required to induce tissue formation and continued root maturation. Conclusion: The success of regenerative endodontic therapy relies on the development of a technique that enables clinicians to create functional pulp tissue within cleaned and shaped root canal systems. It is hoped that further research studies are required to define advantages and limitations of cell-free and cell-based approach.

Exhausted Lag-3+ CD4+ T cells are increased in pediatric Inflammatory Bowel Disease.

T cells are one of the main drivers of inflammatory bowel diseases (IBD). Infliximab (IFX) is used in the treatment of IBD as an anti-inflammatory drug to induce remission by neutralizing TNFα. We determined the individual chemokine/homing receptor and cytokine profile in pediatric IBD patients before and during IFX therapy to identify predictive biomarkers for therapy success. Peripheral blood CD4+ cells from pediatric patients with IBD were immunomagnetically isolated and either directly analyzed by FACS for cell distribution and chemokine/homing receptor expression or evaluated for cytokine production after in-vitro-stimulation. 21 responders (RS) and 21 non-responders (NRS) were recruited. Before IFX therapy, flow cytometry revealed decreased percentages of naïve conventional T cells in pediatric IBD patients. The proportions of CD62-L+ T cells were decreased in both CD and UC therapy responders. The cytokine profile of T cells was highly altered in IBD patients compared to healthy controls (HC). During IFX therapy, the frequencies of conventional memory and regulatory memory T cells expanded in both cohorts. IFX response was marked by a decrease of α4β7+ and IFNγ+ memory T cells in both CD and UC. In contrast, frequencies of Lag-3+ T cells proved to be significantly increased in NRS. These observations were irrespective of the underlying disease. T cells of pediatric IBD patients display an activated and rather Th1/Th17 shifted phenotype The increased expression of the checkpoint molecule Lag-3 on T cells of NRS resembles a more exhausted phenotype than in RS and HC which appeared to be a relevant predictive marker for therapy failure.

Approach to the Patient: New Era Emerges for Craniopharyngioma Management.

Papillary craniopharyngioma (PCP) and adamantinomatous craniopharyngioma (ACP) are distinct, slow-growing tumors of the suprasellar region. Their location, composition, and biology have historically evaded successful surgical radiation and medical therapy. Meanwhile compromise of critical structures either by tumor or treatments increase morbidity, impacting patient and carer quality of life. There has been a paradigm shift in the management of PCP, stemming from the discovery of BRAFV600E mutation in its tumorigenesis. Such a treatment breakthrough may soon be the case for ACP, changing the landscape of craniopharyngioma management. We use a case of ACP partially responding to ERK inhibitor therapy to demonstrate chronicity of disease progression and discuss modern management strategies highlighting the importance of access to tumor agnostic clinical trials, and future directions.

Transforming the Dark into Light: A Siglec-9 Switch.

Tumor-associated immune repression dampens the success of T-cell therapy for cancer by a plethora of inhibitory mechanisms including aberrant glycosylation. In this issue, Eisenberg and colleagues show that IFNγ induces hyper-sialylation of cancer cells and that this acts as the "checkpoint" through binding to the inhibitory molecule Siglec-9 on immune cells. A chimeric Siglec-9 "switch" receptor converts the suppressive signal into a stimulatory signal, thereby restoring T-cell responses in the tumor tissue, which has multiple implications for the use of adoptive cell therapy in cancer. See related article by Eisenberg et al., p. 1380 (3).

The genetic evolution of acral melanoma

Acral melanoma is an aggressive type of melanoma with unknown origins. It is the most common type of melanoma in individuals with dark skin and is notoriously challenging to treat. We examine exome sequencing data of 139 tissue samples, spanning different progression stages, from 37 patients. We find that 78.4% of the melanomas display clustered copy number transitions with focal amplifications, recurring predominantly on chromosomes 5, 11, 12, and 22. These complex genomic aberrations are typically shared across all progression stages of individual patients. TERT activating alterations also arise early, whereas MAP-kinase pathway mutations appear later, an inverted order compared to the canonical evolution. The punctuated formation of complex aberrations and early TERT activation suggest a unique mutational mechanism that initiates acral melanoma. The marked intratumoral heterogeneity, especially concerning MAP-kinase pathway mutations, may partly explain the limited success of therapies for this melanoma subtype.

Precision medicine in breast cancer: Targeting molecular subtypes with gold nanoparticle-loaded liposomes

PurposeBreast cancer is a complex disease with several molecular subtypes that respond differently to therapy. This paper describes liposomes loaded with gold nanoparticles as a targeted drug delivery method in the rapidly developing precision breast cancer treatment area. The aim was to investigate the cytotoxicity level and cellular uptake using several breast cancer cell lines and a normal breast cell line. Materials and methodsWe synthesized gold nanoparticles incorporated in liposomes. Nanostructures were incubated with breast cancer cell lines of different subtypes. The analysis included MTT assay, flow cytometry and immunofluorescence. ResultsCell viability varied among different cancer cells. Moreover, the time- and concentration-dependent manner of viability change was observed. The internalization of liposomes with gold nanoparticles and nanoparticles alone determined different results depending on molecular breast cancer subtypes. The luminal B and triple-negative breast cancer cells demonstrated the highest resistance and sensitivity, respectively. The intensity of cells’ interaction with the proposed nanostructures was observed in both cell lines. In this study, we compare the molecular subtypes of breast cancer and discuss how this novel method might improve the therapy success. ConclusionsOur research sheds light on the possibility of new individualized treatments for breast cancer patients, opening the path for better results and a more detailed cancer therapy strategy.

Successful Steroid Therapy in a Child with Suspected Autoimmune Hepatitis

Introduction: Autoimmune Hepatitis (AIH) is an unexplained cause of chronic and progressive liver inflammation. The incidence of AIH is about 4.82/per 100,000 people in Korea, but based on global research the incidence is increasing and it should be taken more seriously. Laboratory and imaging tests were performed which led to the diagnosis of AIH but to diagnose AIH is difficult. Steroid therapy is an option for this patient by considering the side effects that are well-monitored. A favourable outcome was shown and this report is expected to highlight the importance of early diagnosis and treatment in AIH cases. Case presentation: A 6-year-old, 5-month-old girl presented to Dr. Soetomo General Academic Hospital, Surabaya with jaundice for 2 weeks. She had been unable to walk for the past 1 month due to pain in both legs, nausea and vomiting, anorexia, right-sided abdominal pain, and an enlarged abdomen. She has had a history of fever for the past 1 month. Laboratory parameters showed cholestasis, abnormal liver function test (aspartate aminotransferase (AST) 1406 U/L, alanine aminotransferase (ALT) 1392 U/L, and prolonged coagulation factor), and positive antinuclear antibody (ANA) test (79.10 AU/mL). Hepatitis markers were negative. Liver biopsy and autoantibodies examination (LKM and SMA) was not done due to limited facilities. Hepatitis, cholecystitis, and ascites were noted on abdominal ultrasonography. Ascites and cholecystitis were seen on an abdominal CT scan. Steroid therapy was administered and there was improvement in clinical condition and laboratory results following two weeks duration of treatment. Conclusion: This case report illustrates that steroid treatment for a child with AIH results in a good improvement and provides achievement of treatment goals following existing guidelines. The use of steroid therapy in suspected cases of AIH, without further diagnostic modalities, may be of value in the prevention of further liver damage, especially in healthcare settings with limited resources.

Maintaining Hygiene in Orthodontic Miniscrews: Patient Management and Protocols-A Literature Review.

Oral hygiene is crucial for the success of orthodontic therapy involving temporary anchoring devices like miniscrews. Plaque buildup, exacerbated by orthodontic appliances, causes inflammation that can undermine treatment outcomes. Individualized prevention plans based on patient risk factors are essential. This review emphasizes the importance of oral hygiene in orthodontic therapy with miniscrews, identifies optimal devices for ensuring long-term stability, and explores protocols for high-risk patients. A comprehensive search was conducted on two primary databases, PubMed and Google Scholar, for relevant articles on oral hygiene and inflammation. Fourteen articles meeting the inclusion criteria were selected, covering topics such as "orthodontic miniscrew", "miniscrew and laser", "miniscrew and mouthwash", "electric toothbrush", and "GBT". Inflammation can compromise miniscrew stability by damaging surrounding bone. Miniscrews of 10 mm length have lower failure rates due to better bone contact and stability. Chlorhexidine reduces inflammation risk and inhibits epithelialization around the implant head. Laser therapy enhances miniscrew stability and reduces inflammation. Chitosan effectively suppresses inflammatory mediators and prevents microorganism adhesion. Both sonic and roto-oscillating electric toothbrushes remove plaque effectively, with roto-oscillating brushes showing superior results. The Guided Biofilm Therapy (GBT) protocol offers professional hygiene benefits similar to traditional methods, with improved patient engagement and motivation. Home oral hygiene maintenance is paramount for preventing inflammatory complications. Professional interventions such as diode laser usage, particularly in adult patients with a history of periodontitis or underlying systemic conditions, can mitigate orthodontic therapy failure risks. The GBT protocol fosters a more comfortable and participatory professional hygiene experience for patients, promoting better oral health awareness and compliance.