Frequent Relapses Research Articles

The successful use of rituximab in IgA nephropathy patients with podocytopathy: a case series.

Immunoglobulin A nephropathy (IgAN) with podocytopathy is a rare pathological type of glomerular disease. The use of rituximab (RTX) in the treatment of glomerular diseases has increased in recent decades, but the efficacy of RTX in the treatment of patients with IgAN and podocytopathy has rarely been reported. This was a single-centre retrospective study of IgAN patients with podocytopathy who were treated with RTX as second-line therapy was conducted at our centre from 2019 to 2022. The aim of this study was to investigate the efficacy and safety of RTX in IgAN patients with podocytopathy. Seven out of eight patients met the criteria for complete remission following RTX therapy. Only one patient experienced adverse events (infectious diarrhoea and pulmonary infection) and experienced relapse 6 months after RTX therapy. The maximum relapse-free time after RTX therapy was 20 months, while the maximum relapse-free time before RTX therapy was only 6 months. The number of relapses before RTX therapy (per year) was one to four; moreover, seven patients did not relapse and maintained remission at the last follow-up despite steroid withdrawal after RTX therapy. Overall, RTX effectively reduced proteinuria, increased the maximum relapse-free time, reduced the number of relapses per year and helped patients stop steroid use as soon as possible. RTX also helped most patients achieve clinical remission. RTX appears to be an effective and safe alternative for treating IgAN patients with podocytopathy with steroid dependence or frequent relapse.

The sensitivity of acute myeloid leukemia cells to cytarabine is increased by suppressing the expression of Heme oxygenase-1 and hypoxia-inducible factor 1-alpha

BackgroundAcute myeloid leukemia (AML), a malignancy Often resistant to common chemotherapy regimens (Cytarabine (Ara-c) + Daunorubicin (DNR)), is accompanied by frequent relapses. Many factors are involved in causing chemoresistance. Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1-alpha (HIF-1α) are two of the most well-known genes, reported to be overexpressed in AML and promote resistance against chemotherapy according to several studies. The main chemotherapy agent used for AML treatment is Ara-c. We hypothesized that simultaneous targeting of HO-1 and HIF-1α could sensitize AML cells to Ara-c.MethodIn this study, we used our recently developed, Trans-Activator of Transcription (TAT) - Chitosan-Carboxymethyl Dextran (CCMD) - Poly Ethylene Glycol (PEG) - Nanoparticles (NPs), to deliver Ara-c along with siRNA molecules against the HO-1 and HIF-1α genes to AML primary cells (ex vivo) and cell lines including THP-1, KG-1, and HL-60 (in vitro). Subsequently, the effect of the single or combinational treatment on the growth, proliferation, apoptosis, and Reactive Oxygen Species (ROS) formation was evaluated.ResultsThe designed NPs had a high potential in transfecting cells with siRNAs and drug. The results demonstrated that treatment of cells with Ara-c elevated the generation of ROS in the cells while decreasing the proliferation potential. Following the silencing of HO-1, the rate of apoptosis and ROS generation in response to Ara-c increased significantly. While proliferation and growth inhibition were considerably evident in HIF-1α-siRNA-transfected-AML cells compared to cells treated with free Ara-c. We found that the co-inhibition of genes could further sensitize AML cells to Ara-c treatment.ConclusionsAs far as we are aware, this study is the first to simultaneously inhibit the HO-1 and HIF-1α genes in AML using NPs. It can be concluded that HO-1 causes chemoresistance by protecting cells from ROS damage. Whereas, HIF-1α mostly exerts prolific and direct anti-apoptotic effects. These findings imply that simultaneous inhibition of HO-1 and HIF-1α can overcome Ara-c resistance and help improve the prognosis of AML patients.

Exploration of Nursing Care for Individuals With Bipolar Disorder in a Manic Episode: A Qualitative Study.

Bipolar disorder is a mental illness that is chronic and has frequent relapses. The purpose of the research was to study the nursing care of patients with bipolar disorder in the mania phase. A qualitative study was employed in this study. The sample consisted of 10 nurses working in psychiatric clinics and data were collected through semi-structured interviews. Thematic analysis was applied for analysing the data. Of the10 participants, 70% were female and 30% were male. The mean age was 48.7 years. All participants were registered nurses and most of them held a Master of Science degree. Their work experience ranged from 10 to 30 years. Three main themes emerged when analysing the data obtained from the interviews with the nurses, those themes were a) Echoes of Vigilance: Navigating the journey, b) Amidst the Tempest: Attending to the Patients' Complex Needs, and c) Restoring Balance: The Nurturing Hands of Bipolar Nursing Care, each of which could be divided into several sub-themes. Nursing care plays an important role in symptom improvement and disease control by providing patient support, managing pharmacotherapy, preventing suicidality, and educating patients about the disease and self-management strategies.

Characteristics of Patients With Intractable Obsessive-Compulsive Disorder With High/Low Responsiveness to Gamma Knife Surgery.

Obsessive-compulsive disorder (OCD) is a psychiatric condition that causes significant distress and social costs and often follows a chronic course with frequent relapses. Approximately 20% of patients do not respond to medication or cognitive behavioral therapy; gamma knife surgery (GKS) has been proposed as a treatment option for these patients. However, research on GKS for OCD patients is rare. In this study, 10 patients with treatment-resistant OCD underwent GKS, and the treatment response and side effects were assessed. The improvement in patients' obsessive-compulsive symptoms was evaluated using the Yale-Brown Obsessive Compulsive Scale (YBOCS) scores following GKS. Additionally, the characteristics distinguishing the groups with favorable responses to GKS from those with less favorable responses were examined. GKS was well tolerated, and patients demonstrated a statistically significant reduction in YBOCS scores before and after GKS (p=0.016). Patients that responded to GKS exhibited distinct characteristics from those who did not respond. Patients who responded poorly tended to present an earlier age of onset, a longer duration of illness, more frequent hospitalizations, poorer social functioning, and a greater incidence of suicide attempts/thoughts. This study not only demonstrated that GKS is a safe and effective treatment method for intractable OCD but also revealed characteristics distinguishing patients who respond well to GKS from those who do not. These results may aid in the selection of patients for future application of GKS.

It is time for a unified definition of native vertebral osteomyelitis: a framework proposal.

In recent years, there has been a notable increase in research output on native vertebral osteomyelitis (NVO), coinciding with a rise in its incidence. However, clinical outcomes remain poor, due to frequent relapse and long-term sequelae. Additionally, the lack of a standardized definition and the use of various synonyms to describe this condition further complicate the clinical understanding and management of NVO. We propose a new framework to integrate the primary diagnostic tools at our disposal. These collectively fall into three main domains: clinical, radiological, and direct evidence. Moreover, they and can be divided into seven main categories: (a)clinical features, (b)inflammatory biomarkers, (c)imaging techniques, microbiologic evidence from (d)blood cultures and (e)invasive techniques, (f)histopathology, and (g)empirical evidence of improvement following the initiation of antimicrobial therapy. We provide a review on the evolution of these techniques, explaining why no single method is intrinsically sufficient to formulate an NVO diagnosis. Therefore, we argue for a consensus-driven, multi-domain approach to establish a comprehensive and universally accepted definition of NVO to enhance research comparability, reproducibility, and epidemiological tracking. Ongoing research effort is needed to refine these criteria further, emphasizing collaboration among experts through a Delphi method to achieve a standardized definition. This effort aims to streamline research, expedite accurate diagnoses, optimize diagnostic tools, and guide patient care effectively.

Non-invasive neuromodulatory therapies applied in trigeminal neuralgia

Background: Estimates reveal that about 1 in 15,000 patients suffer from pain impulses from trigeminal neuralgia. Annually there are 5-6 new cases registered per 100,000 inhab-itants, with an increased frequency in women with a ratio of 3/2:W/M. It is revealed that the first manifestations appear at the ages between 40 and 60, but in recent decades cases have appeared at younger ages, starting even with 21. Given the high intensity of pain in the trigeminal pathology, significantly disabling pain for long periods of time, effective noninvasive approaches are required to reduce pain, reduce the frequency of exac-erbations and bring patients to a functioning state as close as possible to the physiological limit. Material and method: A low frequency pulsatile magnetic field is a non-pharmacological and non-invasive method which is widely used in a multitude of medi-cal conditions by medical and paramedical professionals for the management of chronic or acute pain. This original research aims to provide an insight view into the review of evi-dence available for the analgesic non-invasive therapy uses of the pulsed magnetic field. The before and after examinations the therapy have included a general assessment of the functional status, an assessment of pain severity. Result: With this study we hope to demonstrate the increased efficiency of the non-invasive rehabilitation methods with ap-plication in trigeminal neuralgia pathology that qualitatively affects the daily life of the pa-tients experiencing trigeminal neuralgia. Conclusion: Non-invasive rehabilitation in trigem-inal neuralgia registers remarkable results, similar to drug approaches, the major benefit being the absence of adverse effects both during treatment and late, in the long term. It in-creases the quality of life of patients, the frequency of relapses and the intensity of the pain-ful stimulus from the first treatment sessions.. Keywords: trigeminal, neuromodulation, pain, neuralgia, magnetotherapy, non-invasive

Titania-Graphene Oxide Nanocomposite-Based Philadelphia-Positive Leukemia Therapy.

Philadelphia-positive (Ph+) leukemia is a type of blood cancer also known as acute lymphoblastic leukemia (ALL), affecting 20-30% of adults diagnosed worldwide and having an engraved prognosis as compared to other types of leukemia. The current treatment regimens mainly rely on tyrosine kinase inhibitors (TKIs) and bone marrow transplants. To date, several generations of TKIs have been developed due to associated resistance and frequent relapse, with cardiovascular system anomalies being the most devastating complication. Nanotechnology has the potential to address these limitations by the targeted drug delivery and controlled release of TKIs. This study focused on the titanium dioxide (TiO2) and graphene oxide (GO) nanocomposite employment to load nilotinib and ponatinib TKIs for therapy of Ph+ leukemia cell line (K562) and Ba/F3 cells engineered to express BCR-ABL oncogene. Meanwhile, after treatment, the oncogene expressing fibroblast cells (Rat-1 P185) were evaluated for their colony formation ability under 3D conditions. To validate the nanocomposite formation, the TiO2-GO nanocomposites were characterized by scanning electron microscope, DLS, XRD, FTIR, zeta potential, EDX, and element mapping. The TKI-loaded TiO2-GO was not inferior to the free drugs after evaluating their effects by a cell viability assay (XTT), apoptosis induction, and colony formation inhibition. The cell signaling pathways of the mammalian target of rapamycin (mTOR), signal transducers and activators of transcription 5 (STAT5), and extracellular signal-regulated kinase (Erk1/2) were also investigated by Western blot. These signaling pathways were significantly downregulated in the TKI-loaded TiO2-GO-treated groups. Based on the findings above, we can conclude that TiO2-GO exhibited excellent drug delivery potential that can be used for Ph+ leukemia therapy in the future, subject to further investigations.

Abstract PO-001: GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance

Abstract Chimeric antigen receptor (CAR)-T cell therapies can be curative for CD19+ hematological malignancies, though are limited by frequent patient relapse and response failures. Here, we identify GPR65 as a tumor-specific determinant of responsiveness to CAR-T cell therapy. In patients and an immune competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) response to CAR-T cell therapy, high GPR65 is associated with a complete tumor response. In mice, GPR65 knockout (GPR65 KO) tumors are resistant to CAR-T cell therapy in vivo, without antigen loss. Single-cell network analyses reveal that GPR65 deficiency remodels tumor interactions with host macrophages, partially through increasing tumor VEGFA. This leads to increased macrophage numbers and preferential M2 macrophage polarization. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restores responsiveness to CAR-T cell treatment. Anti-VEGFA therapy in combination with CAR-T cell administration also prolongs the survival of GPR65 KO tumor-bearing mice. Our results indicate that tumor GPR65 expression is important for B-ALL responses to CAR-T cell therapy through its impact on the tumor microenvironment and supports new approaches to identify and overcome CAR-T cell resistance. Citation Format: Jayadev Mavuluri. GPR65-low tumor clones reprogram macrophage via VEGF signaling and confer antigen-independent CAR-T resistance [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-001.

Abstract PO-002: Intrinsically disordered regions -induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers

Abstract Chimeric antigen receptor (CAR)-T cell-based therapies demonstrate remarkable efficacy for the treatment of otherwise intractable cancers, particularly B-cell malignancies. However, CAR-T cells respond to only a subset of cancers and are limited by low signaling efficiency: a few hundred or thousand antigen molecules are required to activate a CAR T cell whereas a single peptide-loaded MHC molecule is sufficient to trigger the activation of a normal T cell. This low antigen sensitivity not only limits the current CAR-T therapy to high antigen-expressing cancers, but also results in high frequencies of relapse, during which high antigen-expressing cancers downregulate their antigen levels to escape CAR-T’s attacking. To improve the antigen sensitivity of CAR-T cells, we engineered CARs targeting CD19 by including intrinsically disordered regions (IDRs) that promote signaling condensation. The “IDR CARs” triggered enhanced membrane-proximal signaling in the CAR-T synapse, which led to an increased release of cytotoxic factors, a higher killing activity towards low antigen-expressing cancer cells in vitro, and an improved anti-tumor efficacy in vivo. No elevated tonic signaling was observed in IDR CAR-Ts. Together, we demonstrated IDRs as a new tool set to enhance CAR-T cytotoxicity and to broaden CAR-T’s application to low antigen-expressing cancers. Citation Format: Xinyan Zhang, Qian Xiao, Longhui Zeng, Fawzaan Hashmi, Xiaolei Su. Intrinsically disordered regions -induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-002.

ETMR-06. PNOC031 - INTERNATIONAL TRIAL FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES

Abstract Embryonal tumors with multilayered rosettes (ETMR) are aggressive central nervous system neoplasms with unfavorable prognosis, exhibiting rapid disease progression and frequent post-therapeutic relapse. The rarity of ETMR necessitates global collaboration to advance therapies. Radiotherapy (RT) has been associated with improved survival outcomes in ETMR with case series revealing that nearly half of ETMR patients treated without RT relapse within six months of diagnosis. However, RT is often withheld due to young patient age and neurodevelopmental considerations. This high-rate of on-treatment relapse is unique to ETMR and suggests that radiation-sparing regimens may be suboptimal. PNOC031 is an international collaboration, establishing a global clinical trial to innovate and improve therapeutic interventions for children with ETMR. Eligible patients with newly-diagnosed ETMR are stratified into three cohorts: Cohort 1 - gross total resection/RT-eligible patients to receive early focal radiotherapy (RT); Cohort 2 – gross total resection/not RT-eligible to receive high-dose chemotherapy with autologous stem cell rescue; and Cohort 3 – less than gross total resection or with metastatic disease to receive RT or high-dose chemotherapy per RT eligibility, based on age and tumor location. Cohort 1 will test the hypothesis if early RT improves outcomes in a pilot cohort of 20 patients. Patients will receive six weeks of induction chemotherapy, followed by focal irradiation and an additional six weeks of chemotherapy. Six-month progression-free survival will be assessed to determine the impact of radiotherapy on the rate of early relapse. Cohorts 2 and 3 will allow collection of uniform prospective clinical data using a common treatment backbone, to inform future clinical trial design for ETMR. Incorporating a myriad of correlative studies, including next-generation sequencing, cerebrospinal fluid analyses, microbiome profiles, and evaluations of social determinants of health alongside cognitive outcomes, will enhance comprehensive understanding of clinical responses and advance therapeutic options for this high risk disease.

MDB-26. GENE REGULATORY NETWORK LANDSCAPE OF GROUP 3/4 MEDULLOBLASTOMA

Abstract Intra-tumor heterogeneity in brain cancers contributes to therapy resistance and relapse through positive selection of resistant tumor cell populations. Resolving the molecular mechanisms driving intra-tumor heterogeneity will uncover tumor-specific vulnerabilities and advance effective treatment strategies. Group 3/4 medulloblastomas, the most common embryonal cerebellar tumor subgroup, are highly heterogeneous tumors with high frequency of relapse which are almost certainly fatal. Here, we generated and analyzed a comprehensive single-cell multi-omic Group 3/4 medulloblastoma atlas, comprising 355,295 cells from 38 tumor patients representing eight Group 3/4 molecular subtypes. We identified transcription factor gene regulatory networks driving intra- and inter-tumor heterogeneity in Group 3/4 medulloblastoma, and determined the common regulatory framework that drives this heterogeneity. We show that Group 3/4 tumor diversity stems from differential enrichment of cell-states along four molecular identity axes: photoreceptor, MYC, precursor, and unipolar brush cell-like. Further, we show that intermediate subtype I/VII tumors exhibit a unique biology where a tumor exhibits dual Group 3 and Group 4-like tumor cell-states in a single tumor, and for a subset of these tumors, we identified a potential role of PAX6 in driving the observed dual trajectory. Altogether, our study demonstrates how oncogenic events together with key lineage determinants hijack normal developmental programs and drive Group 3/4 tumor identity away from the normal cerebellar unipolar brush cell-lineage.

EPEN-01. DISTINCT RELAPSE PATTERN ACROSS MOLECULAR EPENDYMOMA TYPES

Abstract BACKGROUND Ependymoma (EPN) is not a uniform disease but represents different tumor types with biological and clinical heterogeneity. Some types have an excellent prognosis; others display frequent relapse. However, the pattern of when and where different types of EPN relapse is largely unknown. METHODS We assembled 552 intracranial EPN from pediatric (n=445) and adult (n=107) patients from European and Northern American cohorts and correlated DNA methylation patterns and copy-number alterations with clinical information. Median age at diagnosis was 13.4±18.8 (0.1 – 80) years. RESULTS In 271/552 (49.1%) of included EPN relapse occurred. First relapses occurred in the initial tumor bed in 70.9%, 22.4% were metastatic only, and 6.7% were combined local and metastatic. First relapses of PF-EPN-B (PF: posterior-fossa) and PF-EPN-SE (SE: subependymoma) occurred later than of PF-EPN-A, ST-EPN-YAP (ST: supratentorial), or ST-EPN-ZFTA (median time to relapse: 4.3 and 6.0 years vs. 1.9/1.0/2.5 years; p<0.01). Metastatic or combined recurrences in PF-EPN-B and -A occurred more often in the spinal cord than in ST-EPN-ZFTA (75.0% and 40.0% vs. 12.5%; p<0.01). In the latter, relapse occurred more frequently when harboring an alternative fusion or CDNK2A loss (p<0.01, respectively). No distant relapses were observed in ST-EPN-YAP (n=9) or PF-EPN-SE (n=60). Post-relapse survival (PRS) was poor for PF-EPN-A and ST-EPN-ZFTA (5-year PRS: 44.5±4.4/ 47.8±9.1%), whereas PF-EPN-B and PF-EPN-SE displayed a 5-year PRS of 89.5±7.1/ 90.0±9.5% (p=0.03). However, 10-year PRS for PF-EPN-B dropped to 45.8±17.3%. CONCLUSIONS Relapse patterns of specific EPN types are different. Duration of surveillance and diagnostics should be planned incorporating entity-specific relapse information. Follow-up should be performed longer than 5 years after diagnosis. Spinal MRI should be considered as standard procedure during surveillance, particularly for PF-EPN-A, PF-EPN-B and ST-EPN-ZFTA.

MDB-41. TARGETING PBK IN GROUP 3 MEDULLOBLASTOMA

Abstract BACKGROUND Group 3 medulloblastoma (MB) remains a challenging diagnosis especially due to a tendency for higher prevalence in infants and to develop frequent relapse. Targeted therapy remains elusive for these patients due to a lack of targetable alterations as well as poor understanding of driver mutations. PBK/TOPK has previously been identified as a hub gene in medulloblastoma and we have recently demonstrated that the LIN28B-PBK axis may be playing a crucial role in Group 3 MB development. METHODS Here we utilize transcriptomic profiling to identify pathways regulated by PBK in Group 3 MB to help identify potential vulnerabilities, immunofluorescence and cell viability analysis to calculate drug synergy. RESULTS Our analysis demonstrates that PBK knockdown leads to significant down regulation of cell cycle pathway genes. We also demonstrate that combining PBK inhibitor HI-TOPK-032 with the CDK 4/6 inhibitor palbociclib is synergistic in Group 3 MB cells. CONCLUSION Our investigations suggest PBK inhibition alone or in combination with other targeted agents may be a useful addition to existing therapy for these hard to treat cancers.

MDB-46. ARE RAB40 SMALL GTPASES DRIVERS OF MEDULLOBLASTOMA PATHOGENESIS?

Abstract BACKGROUND Medulloblastoma is the most common solid paediatric neoplasm and is among the leading causes of cancer-related deaths in children. Patients associated with high-risk molecular subgroups convey poor outcomes due to frequent relapse and metastasis, with two thirds of survivors experiencing life-changing developmental deficits. Poor patient outcomes and significant co-morbidities highlight an urgent need for specific, molecularly targeted therapies. The RAB40 subfamily of atypical small GTPases regulate cytoskeletal structure and cell adhesion via their ubiquitin ligase activity. Although previous studies have linked the RAB40 subfamily with cell invasiveness, their role in paediatric brain cancer remains undefined. METHODS Patient methylation and survival data from Cavalli et. al (2017) was analysed via the R2 Genomics Analysis and Visualisation Platform. RAB40 gene and protein expression were determined in eight in vitro models of medulloblastoma via qRT-PCR and western blotting. Cells were transfected with EGFP-Cas9 mRNA and RAB40-targeted CRISPR sgRNA and seeded singly using fluorescence-activated cell sorting. RAB40 knockout clones were identified via western blot and Sanger sequencing. RESULTS Patient data demonstrated that higher RAB40 gene expression correlates with worse outcomes in group 3 and 4 medulloblastoma. RAB40 genes were also significantly more highly expressed in high-risk groups 3 and 4 compared to low-risk WNT group medulloblastoma. RAB40 mRNA was enriched in cell lines derived from high-risk group 3 and 4 medulloblastoma relative to SHH controls. RAB40 knockout models were subsequently generated in HD-MB03, an in vitro model of metastatic Group 3 medulloblastoma using CRISPR/Cas9. CONCLUSIONS Our data supports the hypothesis that RAB40 small GTPases are enriched in high-risk medulloblastoma subgroups, and that their expression correlates with worse patient outcomes. We have generated knockout models which will be used to characterise the impact of RAB40 GTPases on cell growth, adhesion, invasiveness, and chemotherapeutic tolerance.

Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

Assessing biomarkers of remission in female patients with anorexia nervosa (REMANO): a protocol for a prospective cohort study with a nested case–control study using clinical, neurocognitive, biological, genetic, epigenetic and neuroimaging markers in a French specialised inpatient unit

BackgroundAnorexia nervosa (AN) is a severe psychiatric disorder associated with frequent relapses and variability in treatment responses. Previous literature suggested that such variability is influenced by premorbid vulnerabilities such as...

Clinical course of respiratory tuberculosis relapses in the Kazakh population depending on HLA-DRB1 gene alleles.

The study aimed to ascertain the prevalence and frequency of relapses of respiratory tuberculosis (TB) and examine the characteristics of its clinical progression in members of the Kazakh population based on the alleles of the HLA-DRB1 gene. Methods of clinical and genetic research, statistical processing and analysis of the obtained data were used to achieve this goal. The research led to an analysis of the statistical processing of clinical and genetic investigations that found out how often TB in the respiratory tract is found and how different HLA-DRB1 gene alleles affect the disease's progression. To find out how exposure to certain HLA-DRB1 gene alleles affects the chance of relapse, the number of times they were found was compared between people who had relapsed and people who had just been diagnosed with TB. The impact of these alleles on the progression of the disease was assessed based on their frequency of detection of different clinical forms of TB (infiltrative, fibro-cavernous, generalised, disseminated), unilateral and bilateral lung damage, lung tissue deterioration, and the presence of bacterial secretions. The highest detection rate for all comparisons had gene alleles HLA-DRB1*01 (9.5%), *08 (4.2%), *15 (3.9%), *09 (1.6%), *12 (1.3%), *13 (0.9%), *11 (0.2%). The study found that Kazakhs with the HLA-DRB1*01, *08, and 15 gene alleles are more likely to develop recurrent respiratory TB. The study's practical value lies in its potential to utilise its findings for the prompt identification and eradication of genetic variables contributing to the recurrence of TB.

Effect of a novel anti-PD-1-proIL-2 bifunctional fusion protein on potent anti-tumor activity via PD-1 checkpoint inhibition and conditional IL-2R agonism.

e14697 Background: HD IL-2 was approved by FDA for metastatic melanoma (mM) and renal cell carcinoma (mRCC) but the treatment is associated with severe toxicities. PD-1 blockade has improved the overall survival, but only in 20-30% of cancer patients and many of them experience frequent relapses. Interestingly, HD IL-2 therapy displayed durable anti-tumor activity in mM and mRCC patients who progressed on anti-PD-1. Furthermore, combination therapy of IL-2 and pembrolizumab in mRCC has shown durable 70% response rate, while the ORR of monotherapy is 20% and 33% for IL-2 and pembrolizumab, respectively. Thus, combining IL-2 receptor activation and PD-1 blockade may represent a promising strategy in the post PD-1 era to overcome the resistance and improve the clinical efficacy. PTX-912 is a novel bifunctional PD-1-proIL-2v fusion protein designed to simultaneously harness PD-1 blockade and PD-1-cis directed IL-2R agonism conditionally in TME without the peripheral toxicities associated with IL-2. Methods: The biological functions were demonstrated in human PBMC assays. Anti-tumor efficacy and biomarker studies were evaluated in mouse / human PBMC xenograft models. Tox studies were performed in NHP. Results: PTX-912 shows dose-dependent inhibition of PD-1 pathway measured by GM-CSF and IFNgamma production in an MLR assay. Protease activated PTX-912, but not the intact drug, stimulates the phosphorylation of STAT5 of NK and T cells, the proliferation of CD8 T cells as well as the cytokine production in human whole blood. The potency of pSTAT5 by protease activated product is enhanced by > 10 folds on PD-1+ T cells than T cells without PD-1. When tested in mouse tumor models resistant to PD-1 blockade, PTX-912 demonstrated high potency of tumor inhibition at as low as 0.1 mg/kg dose. In contrast, non-targeted proIL-2v at molar equivalent or higher dose showed minimal antitumor effect in either monotherapy or combination with anti-PD-1. Analysis of PTX-912 treated mice showed increased tumor infiltrating CD4+ and CD8+ T cells, including PD-1+Tcf-1+ and PD-1+ IL-18Ra+TIM3- CD8+ T cells, referred to “stem-like” progenitor effector cells and “better” effector cells, respectively. Activation of the IL-2v in PTX-912 was observed in mouse tumor tissues but not in the plasma. In monkey GLP-compliant 4-week repeat-dose toxicity study, PTX-912 demonstrated excellent safety profiles without overt irAEs that are characteristic of IL-2. Conclusions: Our preclinical data demonstrated that PTX-912 effectively stimulated the expansion and reinvigoration of antigen specific T cells in the tumor tissue resulting in strong anti-tumor efficacy while it did not cause significant peripheral toxicity. Phase 1 clinical trial of PD-1-proIL-2v is planned to start in early 2024 to evaluate the safety, pharmacokinetics and anti-tumor activity in patients with advanced solid tumors.

Alemtuzumab, Cladribine, Fingolimod, Natalizumab, and Rituximab as First-Line Treatments in Adults With Highly Active Relapsing-Remitting Multiple Sclerosis

What Is the Problem? Relapsing-remitting multiple sclerosis (RRMS), the most common disease course of multiple sclerosis (MS), is a chronic immune-mediated disease with clearly defined episodes of new or increasing neurologic symptoms followed by periods of relative stability. In contrast, the highly active, aggressive disease course leads to rapid disability, and these patients face an unmet need. The principal goal of MS treatment is to delay and prevent the accumulation of disability by reducing the frequency of relapses. Currently reimbursed first-line drugs fail to prevent the consequences of irreversible damage to the nervous system. There has been a paradigm shift in clinical practice toward the use of a high-efficacy treatment strategy as early as possible during the inflammatory process to provide optimal clinical benefits in preserving neurologic function in patients with highly active RRMS. What Did We Do? A systematic review of the clinical effectiveness and safety of alemtuzumab, natalizumab, cladribine, fingolimod, and rituximab relative to current first-line drugs in adults with highly active RRMS was conducted; it identified post hoc subgroup analyses from 5 randomized controlled trials (RCTs) and 1 prospective comparative cohort study. What Did We Find? Evidence was uncertain and conclusions were limited by risk of bias and small sample sizes; conclusions for some outcome comparisons were also limited by imprecision and incomplete reporting. Compared to placebo, cladribine and natalizumab may result in a clinically important reduction in relapses, disability, and key MRI lesions. Alemtuzumab may result in a clinically important reduction in relapses compared to interferon, while fingolimod may result in a clinically important reduction in relapses compared to placebo. The clinical evidence was insufficient to determine the effect of fingolimod on relapses when compared with interferon. Harms outcomes, when reported, appeared consistent with the known harms profile of the drugs. Assessment of the effectiveness and safety of rituximab could not be performed due to the lack of evidence. Evidence was also lacking for many important outcomes such as health-related quality of life (HRQoL), instrumental activities of daily living, symptoms, and cognitive outcomes. No evidence could be identified to inform on treatment sequencing. Two pragmatic RCTs (the TREAT-MS and DELIVER-MS trials) are currently ongoing, aiming to compare an early, high-efficacy treatment strategy versus a traditional escalation treatment strategy, which may inform treatment sequencing. Further research is needed to compensate for clinical data gaps to inform an appropriate and relevant economic evaluation. What Does This Mean? Jurisdictions may reconsider the current reimbursement criteria for drugs used in the first-line setting specifically for adults demonstrating highly active RRMS; however, caution should be taken given the gaps and uncertainty in evidence. Upon request from public drug plans, this review may inform a future implementation advice panel or expert committee recommendation.

Identifying Giant Cell Arteritis patients with higher risk of relapse and vascular events: a cluster analysis.

Giant cell arteritis (GCA) is one of the most common large vessel (LVV) vasculitis and is associated with a high risk of relapse and cardiovascular complications. Improving risk stratification remains a significant issue in this patient population. We aimed to perform a cluster analysis among GCA to identify clusters and evaluate their prognostic value. In a multicenter cohort study, we performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with 283 GCA patients' characteristics to generate clusters and assess incidence of relapse, cardiovascular events and death. Three clusters were identified: "Vascular relapsing profile" (23.0%), "Typical GCA profile" (47.7%), and "Ophthalmologic elderly profile" (29.3%). The "Vascular relapsing profile" cluster included younger patients with more frequent relapses and cardiovascular events, particularly thoracic aortic aneurysms. The "Typical GCA profile" was the largest, with classic cranial manifestations and frequently associated polymyalgia rheumatica. The "Ophthalmologic elderly profile" had the oldest patients with more visual loss and the highest mortality rate. Our findings underline the varied prognostic landscape within GCA, emphasizing the poor cardiovascular prognosis of younger patients with LV involvement and the higher mortality among elderly patients. This reinforces the need for further research regarding the screening of aortic abnormalities and whether those patients might benefit from intensive treatment with biotherapy and cardiovascular risk factors management.