Frequent Relapses Research Articles

Efficacy and safety of oral cyclophosphamide versus mycophenolate mofetil in childhood nephrotic syndrome: an open-label comparative study

IntroductionThere is a scarcity of research comparing the efficacy of cyclophosphamide and mycophenolate mofetil in childhood nephrotic syndrome. The aim was to evaluate the efficacy and safety of oral cyclophosphamide (CYC) and mycophenolate mofetil (MMF) in children with steroid-sensitive nephrotic syndrome in terms of the proportion of children who have been off steroids for at least 6 months without proteinuria (responders).MethodsThis open-label retrospective-prospective comparative study was conducted in a pediatric nephrology clinic of a referral center for children between 1 and 18 years of age with FR/SD nephrotic syndrome. Group A consisted of patients who received oral cyclophosphamide (100, 25% female) at a dose of 2–2.5 mg/kg once daily for a period of 8–12 weeks. Group B consisted of patients who received oral mycophenolate mofetil (n = 61, 18% female) (dose: 800–1200 mg/m2) for at least 12 months. Responders were defined as children who were off steroids for at least 6 months along with absence of proteinuria.ResultsIn the CYC group, 50% of the patients were responders, whereas 54% of the patients in the MMF group were responders (p = 0.614). The time to first relapse with CYC was 7 months (IQR 5.25–11) compared to 7 months (IQR 3.5–12) with MMF (p = 0.092). The relapse rate in the CYC group was 1.77 relapses per patient-year compared to 1.295 relapses per patient-year in the MMF group. The difference in relapse rate was significant (-0.474; 95% CI, 0.09 to 0.86 relapses/person-year) (p value = 0.009). Multivariate analysis revealed that an age of less than 5 years at the start of treatment was a significant factor for a better response to MMF (p value = 0.039, OR = 2.988, CI -1.055-8.468).ConclusionsThe efficacy of MMF was similar to that of CYC in terms of response (6 months without steroids) in children with FR/SD nephrotic syndrome. MMF showed a favorable response in terms of the frequency of relapse and treatment failure.Registration of the study with Clinical Trials Registry of India(http://ctri.nic.in;CTRI/2021/06/034421) (Dt: 28/06/2021).

Circumscribed Alopecia Areata Incognita and Response to Tofacitinib

<b><i>Introduction:</i></b> Alopecia areata incognita (AAI) remains a subject of ongoing debate in the literature, with some authors advocating its classification as a subtype of alopecia areata. A localized form of this condition, entitled circumscribed AAI, has been rarely reported in the literature. We report an unusual case of circumscribed AAI treated with oral tofacitinib. <b><i>Case Report:</i></b> A 21-year-old woman presented with a large patch of localized hair thinning on the parietal area. Trichoscopy revealed yellow dots and short thin hairs. A diagnosis of circumscribed AAI was established. Due to the frequent relapses to conventional treatment and associated weight gain secondary to oral dexamethasone, oral tofacitinib 5 mg twice daily was started with a sustained response. <b><i>Discussion:</i></b> AAI is a controversial condition, and its circumscribed variant is scarcely reported in the literature. We hypothesize that AAI clinical presentation may be secondary to cycle disturbance leading to rapid and incomplete hair follicle cycling. Most papers established that the best treatment for AAI is corticosteroids, either topical, intralesional or systemic. <b><i>Conclusion:</i></b> Oral tofacitinib represents a potential treatment for AAI cases that do not present a sustained response to corticosteroids.

Timing of relapse as a key indicator of steroid-sparing requirements in childhood idiopathic nephrotic syndrome.

Managing children with frequent relapses or steroid-dependent nephrotic syndrome poses challenges due to recurrent relapses necessitating prolonged steroid exposure, thus increasing susceptibility to long-term complications. Identifying those at risk of poor response to steroid therapy may be helpful to guide timely intervention with steroid-sparing agents. This study aimed to identify factors associated with steroid-sparing agent needs in children with frequent relapses or steroid-dependent nephrotic syndrome. A retrospective multicenter cohort study was conducted by reviewing the medical records of children with idiopathic nephrotic syndrome treated between 2006 and 2023. Cox proportional regression analyzed prognostic factors for steroid-sparing agent requirements in children with frequent relapses or steroid-dependent nephrotic syndrome. The time-to-event analysis utilizing the Kaplan-Meier estimate examined the proportion of children needing steroid-sparing agents after diagnosis. Medical records of 121 children (85 males) diagnosed with idiopathic nephrotic syndrome at a median age of 4.5 years (range 1.3-12.8) were reviewed over a median follow-up of 3.7 years (range 1.0-15.0). Time to subsequent relapse post-frequent relapses or steroid-dependent nephrotic syndrome diagnosis (at 3-month threshold) emerged as the sole significant predictor of steroid-sparing agent requirement, adjustedhazard ratio (aHR) = 2.26, 95% confidence interval (CI) 1.26-4.05. Kaplan-Meier analysis indicated that an earlier first relapse (< 3 months) led to earlier steroid-sparing agent requirement (log-rank p = 0.005). Children who relapsed within 3 months post-frequent relapses or steroid-dependent nephrotic syndrome diagnosis exhibited a higher frequency of relapses, a greater incidence of steroid-related adverse events, and were more likely to develop steroid dependency. Early subsequent relapse following diagnosis of frequent relapses or steroid-dependent nephrotic syndrome was linked to earlier requirement of steroid-sparing agent therapy. Further prospective research is necessary to confirm this observation.

Bioinformatics analysis-based mining of potential markers for inflammatory bowel disease and their immune relevance.

The incidence of inflammatory bowel disease (IBD) is increasing every year and is characterized by a prolonged course, frequent relapses, difficulty in curing, and a lack of more efficacious therapeutic biomarkers. The aim of this study was to find key core genes as therapeutic biomarkers for IBD. GSE75214 in Gene Expression Omnibus (GEO) was used as the experimental set. The genes in the top 25% of standard deviation of all samples in the experimental set were subjected to systematic weighted gene co-expression network analysis (WGCNA) to find candidate genes. Then, least absolute shrinkage and selection operator (LASSO) logistic regression was used to further screen the central genes. Finally, the validity of hub genes was verified on GEO dataset GSE179285 using "BiocManager" R package. Twelve well-preserved modules were identified in the experimental set using the WGCNA method. Among them, five modules significantly associated with IBD were screened as clinically significant modules, and four candidate genes were screened from these five modules. Then TIMP1, GUCA2B, and HIF1A were screened as hub genes. These hub genes successfully distinguished tumor samples from healthy tissues by artificial neural network algorithm in an independent test set with an area under the working characteristic curve of 0.946 for the subjects. IBD differentially expressed gene (DEGs) are involved in immunoregulatory processes. TIMP1, GUCA2B, and HIF1A, as core genes of IBD, have the potential to be therapeutic targets for patients with IBD, and our findings may provide a new outlook on the future treatment of IBD.

Blood-tumor barrier in focus - investigation of glioblastoma-induced effects on the blood-brain barrier.

Glioblastoma (GBM) is the most prevalent, malignant, primary brain tumor in adults, characterized by limited treatment options, frequent relapse, and short survival after diagnosis. Until now, none of the existing therapy and treatment approaches have proven to be an effective cure. The availability of predictive human blood-tumor barrier (BTB) test systems that can mimic in-vivo pathophysiology of GBM would be of great interest in preclinical research. Here, we present the establishment of a new BTB in-vitro test system combining GBM spheroids and BBB models derived from human induced pluripotent stem cells (hiPSCs). We co-cultured hiPSC-derived brain capillary endothelial-like cells (iBCECs) with GBM spheroids derived from U87-MG and U373-MG cell lines in a cell culture insert-based format. Spheroids were monitored over 168hours (h) of culture, characterized for GBM-specific marker expression and treated with standard chemotherapeutics to distinguish inhibitory effects between 2D mono-culture and 3D spheroids. GBM-induced changes on iBCECs barrier integrity were verified via measurement of transendothelial electrical resistance (TEER), immunocytochemical staining of tight junction (TJ) proteins claudin-5 and occludin as well as the glucose transporter-1 (Glut-1). GBM-induced secretion of vascular endothelial growth factor (VEGF) was additionally quantified. Our hypothesis was validated by reduced expression of TJ proteins, occludin and claudin-5 together with significant barrier breakdown in iBCECs after only 24h of co-culture, demonstrated by reduction in TEER from 1313 ± 265 Ω*cm2 to 712 ± 299 Ω*cm2 (iBCECs + U87-MG) and 762 ± 316 Ω*cm2 (iBCECs + U373-MG). Furthermore, 3D spheroids show more resistance to standard GBM chemotherapeutics in-vitro compared to 2D cultures. We demonstrate the establishment of a simplified, robust in-vitro BTB test system, with potential application in preclinical therapeutic screening and in studying GBM-induced pathological changes at the BBB.

DERMOSCOPIC FEATURES OF BASAL CELL CARCINOMA: SYSTEMATIC REVIEW

Abstract Background: Basal cell carcinoma is one of the most common cancers worldwide, it is a locally destructive and slowly spreading tumor arising from the epidermis or hair follicles, in which the peripheral cells are similar to the cells of the basal layer of the epidermis and which rarely metastasize. Despite its slow growth and low potential for metastasis, basal cell carcinoma (BCC) is one of the most pressing problems in dermato-oncology due to its high incidence rates, variety of clinical forms and frequent relapses after any treatment methods. Currently, the most accessible non-invasive method for examining skin tumors is dermatoscopy. Aim: The purpose of this review is to highlight the dermoscopic features encountered in basal cell carcinoma and to outline the role of dermoscopy for diagnosis this cancer. Methodology: The systematic review included articles from Google Scholar, Medline, Scopus, Web Of Sciences, PubMed was conducted. For the search, the following keywords were included: dermoscopy of pigmented form of basal cell carcinoma; dermoscopy of nonpigmented form of basal cell carcinoma. Results: Conducted a preliminary search and reviewed 62 titles and abstracts in this review and 27 full-text articles were selected of high methodological quality. Dermoscopy is a non-invasive technique, which allows early diagnosis based on the presence of typical vascular structures, pigmented structures, and ulceration and the absence of specific melanocytic structures. However, the use of dermoscopic technique is limited by the lack of prognostically significant dermatoscopic criteria confirming the different morphological nature of tumor growth. Conclusion: The current systematic review demonstrated, based on the observed features, this method allows for differential diagnosis of malignant and benign, as well as melanocytic and non-melanocytic skin neoplasms, as well as diagnosis of tumors at the earliest stage of their development.

IVAC-XS15-CLL01: personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients undergoing BTK-inhibitor-based regimens.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton's tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured "peptide warehouse" based on the patient's individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

Rituximab in secondary progressive multiple sclerosis: a meta-analysis.

To evaluate the efficacy of rituximab (RTX) in stabilizing disability progression in secondary progressive multiple sclerosis (SPMS). A systematic review was conducted, encompassing studies from inception to April 2023, utilizing the MEDLINE and EMBASE databases. Inclusion criteria comprised studies with a minimum of 3 SPMS patients receiving intravenous RTX in at least one infusion, with a follow-up duration of at least 6 months. Primary outcome measures included changes in Expanded Disability Status Scale (EDSS) scores. Mean differences in pre- and post-RTX EDSS scores were analyzed using a random-effects model. Meta-regression examined age at RTX initiation, pre-RTX EDSS scores, disease duration, and outcome reported time as variables. Secondary outcomes assessed changes in the annualized relapse rate (ARR). Thirteen studies, involving 604 SPMS patients, met the inclusion criteria. Following a mean follow-up of 2 years, the mean difference in EDSS scores (ΔEDSS = EDSSpre-RTX - EDSSpost-RTX) was -0.21 (95% CI -0.51 to 0.08, p = 0.16), indicating no significant variation. Multivariable meta-regression identified significant associations between EDSS score mean difference and pre-RTX EDSS scores, disease duration at RTX initiation, and outcome reported time. However, age at RTX initiation showed no significant association. Pre- and post-RTX ARR data were available for 245 out of 604 SPMS patients across seven studies, revealing a mean difference in ARR (ΔARR = ARRpre-RTX - ARRpost-RTX) of 0.74 (95% CI 0.19-1.29, p = 0.008). RTX demonstrates efficacy in reducing relapse frequency and exhibits potential in stabilizing disability progression over a 2-year follow-up, particularly among individuals with shorter disease duration.

Bupropion in Comorbid Post-Traumatic Stress Disorder and Methamphetamine Use Disorder.

Background: Post-traumatic stress disorder (PTSD) and substance use disorder (SUD) frequently occur together. Serotonergic agents are preferred medications to treat PTSD, while bupropion is reserved due to limited evidence. Ongoing studies suggest bupropion may be effective for treating methamphetamine use disorder (MUD). Investigators aimed to evaluate if bupropion would confer benefit to patients with Diagnostic and Statistical Manual of Mental Disorders, Fifth edition diagnoses for PTSD and MUD compared to traditional pharmacotherapy. Methods: This report describes four patients with comorbid PTSD and MUD who had a positive response to medication regimens containing bupropion compared to non-bupropion regimens for their trauma symptoms. Investigators were able to compare this to a control group of 41 patients receiving serotonergic agents alone. Case Report: PTSD checklist-civilian scores at time of medication initiation, site discharge, and post-discharge in the bupropion and non-bupropion group were 77, 35, and 29, compared to 51 ± 15, 52 ± 20 and 53 ± 10, respectively. Rates of relapse, average time to relapse, and hospital utilization in the bupropion vs non-bupropion group were 25.0% vs 48.8%, 107 days vs 210 ± 191 days, and 0% vs 29.3%, respectively. Discussion: Use of bupropion showed a greater reduction in PTSD symptom severity and a lower frequency of methamphetamine relapse and hospital utilization. Though missing data limited inclusion of patients in all outcomes, quantitative data suggests benefit with bupropion in comorbid PTSD and MUD. Conclusion: This case series suggests the potential for earlier initiation of bupropion treatment in those with PTSD who have comorbid MUD.

Corticosteroid therapy for nephrotic syndrome in children.

In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. However about 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. The aim of this review was to determine the benefits and harms of different corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). We searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2002), Cochrane Renal Group Specialised Register (July 2002), MEDLINE (1966 - July 2002) and EMBASE (1980 - July 2002) without language restriction, reference lists of articles, abstracts from conference proceedings and contact with known investigators in the area. Randomised controlled trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SSNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk (RR), risk difference (RD)) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. Nineteen trials have been included in this review. A meta-analysis of six trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (RR 0.70; 95% CI 0.58 to 0.84) without an increase in adverse events. There was an inverse linear relationship between the duration of treatment and risk of relapse (RR = 1.26 - 0.112 duration; r(2) = 0.56; p = 0.03). The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25 to 0.78). Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. In children who relapse frequently, deflazacort deserves further study.

Impact of Rituximab on Remission Rates in Granulomatosis With Polyangiitis: A Systematic Review.

This systematic review evaluates the efficacy of rituximab in inducing and maintaining remission in patients with granulomatosis with polyangiitis (GPA). We conducted a comprehensive search across multiple databases, identifying 81 studies, of which 11 met our inclusion criteria after rigorous screening and assessment for relevance and quality. Our analysis shows that rituximab, compared to traditional treatments such as cyclophosphamide and azathioprine, significantly improves remission rates and reduces relapse frequency in GPA patients. Notably, rituximab's benefits extend across various patient demographics, including pediatric groups, and are evident in different dosing regimens, highlighting its versatility and potential as a first-line therapy. The review also underscores the importance of personalized medicine approaches in managing GPA, as rituximab's effectiveness was particularly pronounced in patients with relapsing disease forms. Future research should focus on long-term outcomes, optimal dosing strategies, and the economic implications of widespread rituximab use in clinical practice. Our findings advocate for the integration of rituximab into standard treatment protocols for GPA, offering new hope for patients afflicted with this challenging autoimmune disorder.

Distinct pulmonary patterns in ANCA-associated vasculitides: insights from a retrospective single center cohort study.

ANCA-associated vasculitides (AAV) comprise granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis. All forms may involve different organ systems, yet kidney and lung involvement are common and fatal in many cases. Here, we aimed to determine the predictive value of pulmonary disease manifestation and individual CT findings in AAV patients. Available CT scans and clinical information on mortality, renal outcomes, occurrence of relapses and damage scores were analysed retrospectively from a tertiary rheumatology center in Germany. We included a total of 94 AAV patients (49 with GPA, 41 with MPA). Forty-four patients had lung involvement with available CT scans, 70.5% of which with GPA and 72.7% with renal involvement. Nodule formation and cavities were more frequent among GPA patients, whereas ground-glass opacities (GGO), ILD and pleural effusion were observed predominantly in MPA patients. Over a median follow-up of 37months, GPA patients had a slightly higher overall mortality, whereas end-stage kidney failure rates were significantly increased in MPA patients. Relapse frequencies were comparable between both entities. The presence of GGO and pleural effusion were associated with higher relapse rates, whereas nodules were negatively correlated with relapses. Notably, RTX-treated patients had less infections as compared to individuals under different therapies. Our data demonstrate the outstanding importance of characteristic CT patterns in AAV diagnosis assessment. Especially certain CTpatterns including GGO and pleura effusion may help to identify patients who are at higher risk for relapsing disease.

The role of the tonsils in the genesis of PFAPA syndrome: a modern view and description of two clinical cases

In ENT clinical practice, there are cases of a disease similar to those ones of chronic adenotonsillitis, but insensitive to the designated conservative therapy. This disease was first described in 1987 and is called PFAPA syndrome. Its symptoms periodicity and its regression when corticosteroids are prescribed were established. Adenotomy/adenotonsillectomy can eliminate the symptoms of the disease or significantly reduce the frequency of relapses. The histological features of the structure of the palatine and pharyngeal tonsils, as well as the characteristics of the PFAPA-syndrome, were revealed. Clinical Case Description: patient K., 3 years old, repeated cases of fever were recorded in the child from the age of 1 year 3 months. They were initially regarded as manifestations of acute respiratory viral infections, complicated by adenoiditis, pharyngitis, aphthous stomatitis and cervical lymphadenitis, with a frequency of 1.5–2 months, 6–7 episodes per year. The antiviral therapy was prescribed without any effect. A prednisolone test (1.5 mg/kg) was positive; it led to a rapid normalization of body temperature and condition improvement. The adenotonsillectomy was done. Surgical intervention and the postoperative period were uneventful. The follow-up period was without any recurrence of the disease for more than 1 year. Patient F., 6 years old, had, the recurrent (each 1.5–2 months), acute respiratory viral infections, adenotonsillitis, accompanied by lymphadenitis and febrile fever. A prednisolone test was positive. The patient was diagnosed with PFAPA syndrome by the age of 6. The adenotonsillectomy was done. No disease relapses were noted in the follow-up.

Integrative Analysis of Multi-Omics Data to Identify Deregulated Molecular Pathways and Druggable Targets in Chronic Lymphocytic Leukemia.

Chronic Lymphocytic Leukemia (CLL) is the most common B-cell malignancy in the Western world, characterized by frequent relapses despite temporary remissions. Our study integrated publicly available proteomic, transcriptomic, and patient survival datasets to identify key differences between healthy and CLL samples. We exposed approximately 1000 proteins that differentiate healthy from cancerous cells, with 608 upregulated and 415 downregulated in CLL cases. Notable upregulated proteins include YEATS2 (an epigenetic regulator), PIGR (Polymeric immunoglobulin receptor), and SNRPA (a splicing factor), which may serve as prognostic biomarkers for this disease. Key pathways implicated in CLL progression involve RNA processing, stress resistance, and immune response deficits. Furthermore, we identified three existing drugs-Bosutinib, Vorinostat, and Panobinostat-for potential further investigation in drug repurposing in CLL. We also found limited correlation between transcriptomic and proteomic data, emphasizing the importance of proteomics in understanding gene expression regulation mechanisms. This generally known disparity highlights once again that mRNA levels do not accurately predict protein abundance due to many regulatory factors, such as protein degradation, post-transcriptional modifications, and differing rates of translation. These results demonstrate the value of integrating omics data to uncover deregulated proteins and pathways in cancer and suggest new therapeutic avenues for CLL.

Discovery of NFκB2-Coordinated Dual Regulation of Mitochondrial and Nuclear Genomes Leads to an Effective Therapy for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial-nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific "TTGGGGGGTG" region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2's novel function of regulating mitochondrial-nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.

NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLL-r B-ALL by regulating NR3C1 expression

AbstractB-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ∼85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival, relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL, and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here, we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)–mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1–mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.

Clinical and statistical characteristics of patients with infertility on the background of chronic pelvic inflammatory diseases of the genital organs

Reproductive health and the formation of an adequate attitude to motherhood depend significantly on the social status of a woman. An increased number of people of fertile age with burdened somatic and obstetric and gynecological pathologies, a long-term stress load caused by the social and economic crisis and military actions in the country, a high specific weight of obstetric and perinatal complications - all these factors lead to a rapid decrease in the birth rate.Pathological changes in the hormonal status of female patients, sexual health disorders, and the progressive spread of inflammatory diseases of the reproductive system lead to an increased frequency of infertility. The etiological factor is most often a microbial association, which can be represented by both absolute pathogens with a predominantly sexual transmission route, and endogenous anaerobes and aerobes.Microbial associations contribute to better adaptation of the causative agent and its parasitism, increase the pathogenicity of each causative agent, their resistance to the antibiotics, which complicates the treatment of the disease as a whole. The prevalence of papillomavirus, herpes, cytomegalovirus infection in the structure of sexually transmitted inflammatory diseases negatively affects reproductive function.The objective: to analyze the risk factors for infertility in patients with inflammatory diseases of the genital organs which are determined by urogenital mixed infection.Materials and methods. A comprehensive clinical and laboratory examination of 154 married couples with infertility was carried out. The main group included 92 women who were examined for infertility and had chronic pelvic inflammatory disease (PID) caused by urogenital mixed infection.Depending on the detected pathogens, the women of the main group were divided into groups. During the In Pouch™ test in 30 (32.6%) patients who were included in the I observation group, Trichomonas vaginalis was found in biomaterial from the vagina in association with other conditionally pathogenic factors.Chlamydia trachomatis was diagnosed in polycomponent associations with other opportunistic flora in 34 (37.0%) women using polymerase chain reaction (PCR) in scrapings from the cervical canal - the II observation group.In 28 (30.4%) examined women, the human papillomavirus (HPV) was identified in the biological material from the cervix by PCR in Real time. Women with papillomavirus infection associated with opportunistic flora were included in the III observation group.To evaluate the results of the cytological examination, the Papanicolaou classification (CIN classification) and the Bethesda terminological system (The Bethesda system, TBS, 2014) were used.Results. As a result of a complex clinical and laboratory examination of women of reproductive age from 154 married couples who were observed for infertility, 60% (92 cases) of patients were diagnosed with PID due to urogenital mixed infection.Among the specific etiological factors, Trichomonas vaginalis was found in 32.6% (30 cases), Chlamydia trachomatis in 37.0% (34 cases), and HPV in 30.4% (28 cases) in multicomponent associations with representatives of opportunistic flora. It was established that, in addition to pathogenic agents of sexually transmitted infections, representatives of opportunistic flora negatively affect the reproductive function of women, among which the leading positions are occupied by mollicutes (Mycoplasma hominis, Ureaplasma urealyticum) - 67.4%; Enterococcus faecalis – 44.6%; Esherichia coli – 38.0%; Gardnerella vaginalis – 26.0%, with a maximum decrease in the vaginal content of the number or even absence of Lactobacillus spp.In the majority of women - 78.0% (64 cases), the inflammatory process had no pronounced clinical signs, in 22.0% it was almost asymptomatic, but was accompanied by frequent (up to 3-6 per year) relapses. Among the examined women of the III group, an association of two highly oncogenic HPV genotypes was found - 11 (39.5%) cases, three or more - 7 (25.0%) cases.A tendency to an earlier onset of sexual life was determined in women with sexually transmitted diseases, especially in the group with papillomavirus infection. Risk factors for infertility include the pathological course of childbirth and the postpartum period, surgical interventions, and infectious diseases. Among the diseases of the hepatic and biliary system, chronic cholecystitis prevailed.Conclusions. On the basis of the anamnestic assessment of reproductive health in the examined women with infertility on the background of chronic PID, it is possible to single out the most important factors that negatively affect the realization of the reproductive function: the age of a woman is less than 20 and more than 30 years, social maladaptation, working conditions and harmful habits, in particular smoking, as one of the cofactors of HPV-associated diseases of the cervix, as well as early sexual debut (up to 16 years), promiscuity, ignoring barrier contraception.In the genesis of pathological changes occurring in the urogenital tract, there are mixed infections, which potentially complicates diagnosis and negatively affects the results of treatment of associated forms of diseases.

Enhancing Multiple Myeloma Treatment Outcomes with Ixazomib: Insights and Perspectives

Introduction: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells in the bone marrow, resulting in diverse clinical manifestations. Despite treatment advancements, MM remains incurable, with frequent relapses and therapy resistance. Proteasome inhibitors have revolutionized MM treatment, with ixazomib emerging as a promising oral option. Ixazomib selectively inhibits the 20S proteasome, disrupting the ubiquitin-proteasome pathway crucial for malignant plasma cell survival. Clinical trials demonstrate ixazomib's efficacy and safety, alone or combined with lenalidomide and dexamethasone. Notably, the TOURMALINE-MM1 trial showed improved progression-free survival with ixazomib, establishing its significance in MM therapy. This article comprehensively reviews ixazomib's pharmacological properties, clinical efficacy, safety, and future perspectives in MM management, aiming to enhance therapeutic outcomes in this challenging malignancy. Material and methods. This retrospective study at Fundeni Clinical Institute included 35 multiple myeloma patients treated with Ixazomib over a period of 5 years.Treatment included ixazomib, lenalidomide, and dexamethasone (IRd) for 34 patients.Data analysis assessed treatment response, progression-free survival (PFS), overall survival (OS), and adverse events. This evaluation aims to provide insight into ixazomib-based therapy's efficacy and safety in a predominantly frail patient population. Results. The study included 35 multiple myeloma patients aged 48 to 89, with 33 considered frail. The IRd group achieved an 80% overall response rate, with a median progression-free survival (PFS) of 18 months. Adverse events were common, with gastrointestinal disturbances, fatigue, and peripheral neuropathy being notable. Grade 3/4 adverse events occurred in 57% of patients, leading to dose reductions in 60% of cases. Frail patients showed a 78% response rate and a 1-year overall survival rate of 82%. Overall, ixazomib-based therapy demonstrated efficacy but was associated with manageable adverse events. Conclusion. In summary, our study confirms ixazomib's effectiveness and safety in treating multiple myeloma, especially in elderly and frail patients. With its high response rates and tolerable side effects, ixazomib proves to be a good treatment option for relapse refractory multiple myeloma patients.

Sustained release of stem cell secretome from nano-villi chitosan microspheres for effective treatment of atopic dermatitis

Canine atopic dermatitis (AD) arises from hypersensitive immune reactions. AD symptoms entail severe pruritus and skin inflammation, with frequent relapses. Consequently, AD patients require continuous management, imposing financial burdens and mental fatigue on pet owners. In this study, we aimed to investigate the therapeutic relevance of secretome from canine adipose tissue-derived mesenchymal stem cells (MSCs), especially after encapsulation in nano-villi chitosan microspheres (CS-MS) to expect improved efficacy. Conditioned media (CM) from MSCs significantly inhibited the proliferation of splenocytes, induced the generation of regulatory T cells, and decreased mast cell degranulation. We found that beneficial soluble factors known to reduce AD symptoms, including transforming growth factor-beta 1, were detectable after sequential concentration and lyophilization of CM. The CS-MS, developed by a phase inversion regeneration method, showed high loading and sustained release of the secretome. Local injection of secretome-loaded CS-MS (ST/SC-MS) effectively reduced clinical severity compared to groups treated with secretome. Histological analysis revealed that ST/SC-MS potently suppressed epidermal hyperplasia, immunocyte infiltration and mast cell activation in the lesion. Taken together, this study presents a novel therapeutic approach exhibiting more potent and prolonged immunoregulatory efficacy of MSC secretome for canine AD treatment.

Diabetic macular edema: Upcoming therapies.

Diabetic macular edema (DME) is a serious vision-threatening complication that can arise at any stage of diabetic retinopathy. Primary treatment involves anti-vascular endothelial growth factor (VEGF) agents, which are highly effective but associated with challenges, such as the need for frequent injections, relapses, and resistance to therapy. Therefore, there has been a growing interest in developing new treatments that offer similar or superior outcomes in DME. This review article explores emerging treatments, including WNT agonists, gene therapy, protein inhibitors, and, most importantly, the first-ever non-invasive and oral drugs. The evolving therapies in diabetic retinopathy offer hope for continued improvement in vision loss associated with one of the most common chronic conditions worldwide.