Therapeutic Endpoints Research Articles

Clinical and Imaging Characteristics of PRPH2 Retinopathies in a Longitudinal Cohort and Diagnostic Implications.

The purpose of this study was to define genotypic-phenotypic correlations related to PRPH2-associated retinopathies in an observational longitudinal cohort and to improve diagnostic accuracy. Individuals with PRPH2 variants were identified by genetic sequencing of 263 individuals (including 59 families). Ocular examinations with multimodal imaging were evaluated. Two pathogenic/likely pathogenic PRPH2 variants were identified in 22 individuals with retinopathies, low genetic susceptibility to age-related macular degeneration (AMD) and younger age of onset. The mean follow-up was 14 years. One family and 4 independent cases (n = 7) were heterozygous for the variant rs121918563 L185P (p.Leu185Pro). The individuals developed retinopathy compatible with autosomal dominant pattern dystrophy (PD), including adult-onset vitelliform macular dystrophy and butterfly macular dystrophy in their fourth to fifth decades of life, evolving to retinal pigment epithelial (RPE) irregularities and central macular atrophy 20years later. Two families and an independent case (n = 15) had the rs281865373 splice-site variant c.828+3A>T (IVS2+3A>T) presenting as retinal flecks consistent with adult-onset fundus flavimaculatus with macular dystrophy and diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life progressing to extensive atrophy in the sixth to eighth decades. The L185P variant was associated with better visual acuity (VA) during follow-up versus c.828+3A>T variant. Some individuals were initially misdiagnosed with geographic atrophy secondary to AMD. Individuals with the L185P variant had less severe disease with clinical manifestation typical of PD and better VA. More advanced disease with CACD and worse VA were associated with the c.828+3A>T variant. Results contribute to knowledge about genotypic-phenotypic associations of PRPH2 retinopathies and inform clinical and therapeutic end points.

The efficacy and safety of low-dose roxadustat in combination with recombinant human erythropoietin for treating hemodialysis patients with moderate anemia: A retrospective cohort study.

To evaluate the safety and efficacy of low-dose roxadustat combined with low-dose recombinant human erythropoietin (rhEPO) for the treatment of renal anemia in hemodialysis patients. We retrospectively reviewed the medical records of hemodialysis patients with moderate renal anemia between December 2019 and July 2023 from two medical centers. Patients were classified into 3 groups: rhEPO (150-300 IU/kg/week), roxadustat (1.5-2.5 mg/kg thrice weekly), and combination therapy (low-dose (≤1.5 mg/kg thrice weekly) roxadustat in addition to low-dose (≤150 IU/kg per week) rhEPO. After 24 weeks of treatment, the efficacy therapeutic endpoints and the safety endpoints were evaluated. Overall, a total of 158 patients were included: 53 in the rhEPO group, 52 in the roxadustat group, and 53 in the combination group. The median time to achieve Hb response in the combination therapy group was 20 days, which was shorter than that in the roxadustat group (20 vs. 25.5 days, log-rank p=0.027) and the rhEPO group (20 vs. 27 days, log-rank p=0.004). The mean rate of increase in Hb (g/L/month) during the first month of the treatment period was significantly greater in the combination group than in the roxadustat group (15.4 ± 4.7 vs. 11.1 ± 5.7, p=0.038) or in the rhEPO group (15.4 ± 4.7 vs. 10.5 ± 4.3, p=0.026). The incidence and frequency of adverse events were similar among the 3 groups. The combination of low-dose roxadustat and rhEPO appears to have better effects in treating hemodialysis patients with moderate anemia by shortening the hemoglobin response time with minimal adverse effects.

CDA Formulations: Potentially the Standard Care of Breast, Lung and Liver Cancers

Breast and lung cancers are very common, which are the top two leading causes of death from cancer. Hepatomas are not as common. But hepatomas are not responding well to therapies currently available. Cancer incidence and mortality keep on increasing ever since these statistics became public records, which are an indication of the failure of the health profession to control cancer. Cancer therapies approved in the past are mostly based on killing of cancer cells which are wrong to solve only a fraction of cancer problems. To effectively solve cancer, we must eliminate all factors contributing to the evolution of cancer. Cancer evolves due to wound unhealing because of the collapse of chemo-surveillance. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs), which are embryonic stem cells to initiate the development of organs and tissues. Methylation enzymes (MEs) play a pivotal role on the regulation of cell replication and differentiation. Because of this pivotal role, MEs are exceptionally subjected to double allosteric regulations, on the individual enzymes by steroid hormone and on the enzyme complex by telomerase and chemo-surveillance. MEs of embryonic stem cells (ESCs) including PSCs are abnormal due to association with telomerase, which are important for the functions of these cells for the development of fetus and wound healing. The build-up of normal stem cells with abnormal MEs is strictly under regulations by contact inhibition, ten-eleven translocator -1 (TET-1) enzyme to direct lineage transitions and chemo-surveillance to destabilize abnormal MEs. When such safety mechanisms fail, clinical symptoms arise. Obviously, the most appropriate solution of diseases due to wound unhealing is to restore safety mechanisms created by the nature. Cell differentiation agent -2 (CDA-2) is our creation of cancer drug to target on abnormal MEs. CDA-2 was approved by the Chinese FDA as an adjuvant to supplement cytotoxic therapy of cancer against breast, non-small cell lung cancers and primary hepatomas in 2004, and as a mono-therapeutic agent for the therapy of myelodysplastic syndromes (MDSs) in 2017. MDSs are diseases attributable entirely to cancer stem cells (CSCs). CDA-2 was the best drug for the therapy of MDSs, and therefore should be considered the standard care of MDSs. Breast, non-small cell lung cancers and primary hepatomas responded well to CDA-2. The therapeutic end point of CDA-2 is the terminal differentiation of cancer cells which cannot make tumor to disappear. Evidently, terminal differentiation of CSCs is the only option to solve CSCs. The solution of CSCs is very critical to the success of cancer therapy. Therefore, CDA formulations are potentially the standard care of breast and lung cancers and primary hepatomas.

Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer.

NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non-small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428), a randomized phase II trial, studied whether midtreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease. Patients fit for concurrent chemoradiation were randomly assigned (1:2) to standard (60 Gy/30 fractions) or FDG-PET-guided adaptive treatment, stratified by substage, primary tumor size, and histology. All patients had midtreatment FDG-PET/CT; adaptive arm patients had an individualized, intensified boost RT dose to residual metabolically active areas. The primary therapeutic end point was 2-year centrally reviewed freedom from local-regional progression (FFLP), defined as no progression in or near the planning target volume and/or regional nodes. FFLP was analyzed on a modified intent-to-treat population at a one-sided Z-test significance level of 0.15. The primary imaging end point was centrally reviewed change in SUVpeak from baseline to midtreatment; its association with FFLP was assessed using the two-sided Wald test on the basis of Cox regression. Of 138 patients enrolled, 127 were eligible. Adaptive-arm patients received a mean 71 Gy in 30 fractions, with mean lung dose 17.9 Gy. There was no significant difference in centrally reviewed 2-year FFLP (59.5% and 54.6% in standard and adaptive arms; P = .66). There were no significant differences in protocol-specified grade 3 toxicities, survival, or progression-free survival (P > .4). Median SUVpeak and metabolic tumor volume (MTV) in the adaptive arm decreased 49% and 54%, from pre-RT to mid-RT PET. However, ΔSUVpeak and ΔMTV were not associated with FFLP (hazard ratios, 0.997; P = .395 and .461). Midtreatment PET-adapted RT dose escalation as given in this study was safe and feasible but did not improve efficacy outcomes.

The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making.

While some model-informed drug development frameworks are well recognized as enabling clinical trials, the value of disease progression modeling (DPM) in impacting medical product development has yet to be fully realized. The Clinical Trials Transformation Initiative assembled a diverse project team from across the patient, academic, regulatory, and industry sectors of practice to advance the use of DPM for decision making in clinical trials and medical product development. This team conducted a scoping review to explore current applications of DPM and convened a multi-stakeholder expert meeting to discuss its value in medical product development. In this article, we present the scoping review and expert meeting output and propose key questions that medical product developers and regulators may use to inform clinical development strategy, appreciate the therapeutic context and endpoint selection, and optimize trial design with disease progression models. By expanding awareness of the unique value of DPM, this article does not aim to be technical in nature but rather aims to highlight the potential of DPM to improve the quality and efficiency of medical product development.

7993 Thienopyrimidine-Based Estrogen Receptor Modulators Adopt Unique Ligand Binding Poses to Elicit Anti-Proliferative Activities in ER+ Breast Cancer Cells

Abstract Disclosure: E.C. Fink: None. S.L. Mateus: None. N. Meganathan: None. V.K. Sammeta: None. J.D. Norris: None. D.P. McDonnell: None. T. Willson: None. S.W. Fanning: None. One in eight women will be diagnosed with breast cancer in their lifetimes. Estrogen receptor alpha (ER) drives breast cancer pathology and is expressed in approximately seventy percent of tumors. Hormone therapies are used to treat and prevent the metastasis of ER+ breast cancers and these patients have favorable 5-year survivals. However, most breast cancer patient deaths are ER+. While the next generation of antiestrogens have shown promise in the advanced setting, more work needs to be done to fully address these mortalities. ER is a ligand-dependent master transcriptional regulator, whereby ligand-specific ER conformational ensembles redirect multiple programs to produce oncogenic or therapeutic endpoints. To better understand ER structure-activity relationships, we have developed new antiestrogenic small molecules based on a thienopyrimidine scaffold. Comprehensive structural, ER activity, and cancer endpoint profiling shows that these new molecules adopt a unique ligand binding pose, which perturbs new structural elements within the orthosteric hormone binding pocket. These molecules downregulate ER target genes and halt the proliferation of ER+ breast cancer cells. Presentation: 6/3/2024

Fluid biomarkers of chronic traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which iscommonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted.

The intestinal mucin isoform landscape reveals region-specific biomarker panels for inflammatory bowel disease patient stratification.

Mucosal healing is considered as a key therapeutic endpoint in inflammatory bowel diseases (IBD) and comprises endoscopic improvement of inflammation without taking barrier healing into account. Mucins are critical components of the mucosal barrier function that give rise to structurally diverse isoforms. Unraveling disease-associated mucin isoforms that could act as an indication for barrier function would greatly enhance IBD management. We present the intestinal mucin RNA isoform landscape in IBD and control patients using a targeted mucin isoform sequencing approach on a discovery cohort (n = 106). Random Forest modeling (n = 1683 samples) with external validation (n = 130 samples) identified unique mucin RNA isoform panels that accurately stratified IBD patients in multiple subpopulations based on inflammation, IBD subtype (Crohn's disease (CD), ulcerative colitis (UC)), and anatomical location of the intestinal tract (i.e. ileum, proximal colon, distal colon, rectum). Particularly, the mucin RNA isoform panels obtained from the inflamed UC and CD distal colon showed high performance in distinguishing inflamed biopsies from their control counterparts (AUC of 93.3% and 91.1% in the training, 95.0% and 96.0% in the test, and 89.5% and 78.3% in the external validation datasets, respectively). Furthermore, the differentially expressed MUC4 (PB.1238.363), MUC5AC (PB.2811.15), MUC16 (ENST00000397910.8) and MUC1 (ENST00000462317.5, ENST00000620103.4) RNA isoforms frequently occurred throughout the different panels highlighting their role in IBD pathogenesis. We unveiled region-specific mucin RNA isoform panels capturing the heterogeneity of the IBD patient population and showing great potential to indicate barrier function in IBD patients.

Common functional mechanisms underlying dynamic brain network changes across five general anesthetics: A rat fMRI study.

Reversible loss of consciousness is the primary therapeutic endpoint of general anesthesia; however, the drug-invariant mechanisms underlying anesthetic-induced unconsciousness are still unclear. This study aimed to investigate the static, dynamic, topological and organizational changes in functional brain network induced by five clinically-used general anesthetics in the rat brain. Male Sprague-Dawley rats (n = 57) were randomly allocated to received propofol, isoflurane, ketamine, dexmedetomidine, or combined isoflurane plus dexmedetomidine anesthesia. Resting-state functional magnetic resonance images were acquired under general anesthesia and analyzed for changes in dynamic functional brain networks compared to the awake state. Different general anesthetics induced distinct patterns of functional connectivity inhibition within brain-wide networks, resulting in multi-level network reorganization primarily by impairing the functional connectivity of cortico-subcortical networks as well as by reducing information transmission capacity, intrinsic connectivity, and network architecture stability of subcortical regions. Conversely, functional connectivity and topological properties were preserved within cortico-cortical networks, albeit with fewer dynamic fluctuations under general anesthesia. Our findings highlighted the effects of different general anesthetics on functional brain network reorganization, which might shed light on the drug-invariant mechanism of anesthetic-induced unconsciousness.

Relationship between depression and sex steroid hormone among women with epilepsy.

Sex steroid hormones are emerging significant biomarkers of depression among Women with Epilepsy (WWE) with promising prognostic potential and therapeutic end point. Therefore, the study is aimed at exploring the association between sex steroids hormones, Anti-seizure Medication (ASM) and depression among WWE. A baseline questionnaire was used to obtain socio-demographics and clinical characteristic from one hundred and twelve (112) WWE and 50 age matched healthy control. The diagnosis of epilepsy and Electroencephalography (EEG) description was based on 2017 International League Against Epilepsy (ILAE) criteria. Blood samples were collected from cases and control during Luteal Phase (LP) and Follicular Phase (FP). The Zung Self-Rating Depression Scale (ZSRDS) was used to assess depression. The prevalence of depression among WWE is 18.8%, with a significant difference between the level of formal education (p0.000), age (p0.000), and mean ZSRDS (p0.000) among cases and control. There is a statistical difference in hormonal levels between cases and control with regards to higher testosterone [3.28 ± 9.99 vs. 0.31 ± 0.30; p0.037], lower FP prolactin [16.37 ± 20.14 vs. 17.20 ± 7.44; p0.778], and lower LP prolactin [15.74 ± 18.22 vs. 17.67 ± 7.27; p0.473]. Testosterone (p0.024), FP Follicle Stimulating Hormone (FSH) (p0.009), FP Estradiol (p0.006), LP FSH (p0.031), LP Progesterone (p0.023), and LP Prolactin (p0.000) were associated with depression. However, only prolactin (p0.042) and testosterone (p0.000) predicts depression among WWE. There was higher mean depression score, lower prolactin and higher testosterone level among cases compared to control. Furthermore, there was lower prolactin and higher testosterone level in Carbamazepine (CBZ) group compared to Levetiracetam (LEV) groups.

Evaluation of Simplified Geboes Score in Ulcerative Colitis

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of unknown etiology characterized by a relapsing and remitting course. Assessment of disease activity is based on combination of clinical features, endoscopic scoring and histological scoring. Over the years, Histological healing has replaced mucosal healing as the therapeutic endpoint in UC. Various histological parameters have their own significance in predicting treatment outcomes and prognosis. Many histologic scoring systems have been proposed with one such validated score being Geboes score. However, in view of its complexity to use the Simplified Geboes Score (SGS) was developed in 2016. Aim & Objectives: To assess the interobserver agreement of SGS in ulcerative colitis. Methods: This was retrospective study of 6 years duration. Relevant clinical and endoscopic details were documented. 41 cases of UC were included in the study. The SGS scoring was done by two pathologists independently. Agreement for individual grades of SGS and for the detection of Histologic activity (score >3.1) was compared between both pathologists using Cohen’s kappa coefficient. Results: Majority of the patients were in the age group of 15-72 years with male preponderance. Left sided colon was more commonly involved with loose stools being most common symptom. Cohen’s test showed moderate to good agreement for individual grades and good agreement for Histologic activity. Conclusion: The SGS is simple to use and shows good interobserver agreement for histological activity and moderate to good agreement for individual parameter. Therefore, it can be adopted for routine reporting of all biopsies in ulcerative colitis. Keywords: Histological healing, Mucosal healing, Simplified Geboes Score, Ulcerative colitis

Current Concepts for the Treatment of Peri-implant Disease.

Peri-implant diseases are defined as bacterial plaque-induced inflammatory conditions affecting implant-surrounding tissues and are classified as peri-implant mucositis and peri-implantitis. Peri-implant mucositis is characterized by an inflammatory lesion that resides in the soft tissue compartment, whereas at peri-implantitis sites the lesions also feature progressive loss of implant-supporting bone. Inflammation resolution and disease progression arrestment are the main therapeutic endpoints of the treatment of peri-implant diseases. The present position paper displays the current evidence and clinical recommendations of the European Association for Osseointegration for the treatment of peri-implant diseases. Mechanical biofilm removal along with the reinforcement of patient-administered oral hygiene is considered the standard treatment for managing peri-implant mucositis. It is recommended to assess the outcomes of peri-implant mucositis treatment 2 to 3 months after therapy, and repeated intervention should be considered in the absence of treatment success. Peri-implantitis treatment should follow a stepwise treatment approach, starting with nonsurgical treatment followed by surgical intervention, if that is not sufficient. Surgical peri-implantitis therapies include nonreconstructive, reconstructive, and combined treatment modalities. Implantoplasty may be advocated for the treatment of supracrestal peri-implant defects, whereas reconstructive therapy is indicated at peri-implantitis sites featuring intraosseous defects with a depth ≥ 3 mm. Adjunctive reconstructive measures may be beneficial in enhancing radiographic defect fill and maintaining postoperative soft tissue levels, which may have a great impact in esthetic cases. The adjunctive use of systemic antibiotics during surgical therapy does not seem to improve the clinical outcomes. Regular supportive peri-implant therapy with biofilm removal should be an integral part of the treatment protocol for peri-implant diseases. In the presence of advanced bone loss around implants that do not play a strategic role in masticatory function, implant removal may be considered immediately.

Pediatric Patients with Eosinophilic Esophagitis and Their Parents Identify Symptoms as the Most Important Treatment Outcome

Introduction: Given the lack of data, we aimed to explore which therapeutic endpoints pediatric patients with eosinophilic esophagitis (EoE) and their parents consider to be relevant. Methods: We created an educational brochure on EoE and a questionnaire, both of which were content-validated by pediatric patients and parents. Validated documents were sent to 112 patients and parents. They ranked the importance (5 levels) of short (during next 3 months) and long-term (≥1 year) treatment effect on symptoms, quality of life, endoscopic inflammation, stricture formation, histological inflammation, and fibrosis. Results: A total of 45 parents and 30 pediatric patients ≥11 years completed the questionnaires. Pediatric patients identified improvement in the following domains as most important in the short- and long-term, respectively: symptoms (73% vs. 77%), QoL (53% vs. 57%), histologic inflammation (47% vs. 50%), histologic fibrosis (40% vs. 33%), endoscopic inflammation (47% vs. 40%), and strictures (33% vs. 40%). Parents of children ≥11 years old classified improvement in the following domains as most important in the short- and long-term, respectively: symptoms (70% vs. 83%), QoL (63% vs. 80%), histologic inflammation (67% vs. 77%), histologic fibrosis (47% vs. 63%), endoscopic inflammation (77% vs. 80%), and strictures (40% vs. 53%). Agreement between caregiver and children on the short-term importance of treatment outcomes was as follows: symptoms (77%), QoL (40%), histologic inflammation and fibrosis (47% and 43%), endoscopic inflammation and strictures (50% and 40%). Conclusion: Pediatric patients and parents attributed most importance to improvement in symptoms and QoL. Agreement between parents and patients regarding therapy goals is limited.

Clinical and ultrasonographic evaluation of efficacy and safety of intralesional injection of autologous platelet-rich plasma in morphea: A comparative case series.

To evaluate the efficacy and safety of platelet-rich plasma to restore skin changes in morphea by ultrasound and Localized Scleroderma Cutaneous Assessment Tool. Nine morphea patients (21 lesions) were diagnosed clinically and by histopathology. Intradermal platelet-rich plasma was injected into morphea lesion once weekly for 12 sessions. The disease severity and damage were evaluated at baseline, after the last session (3 months later), and at 6 months follow-up using the LoSCAT and a high-resolution ultrasound. The healthy corresponding side was considered as a control. The Localized Scleroderma Cutaneous Assessment Tool score showed a significant improvement starting from 13 ± 7.28 up to 7.33 ± 6.82 after the therapeutic endpoint, reaching to 6.44 ± 7.09 after 6 months of follow-up with p value = 0.008 and 0.014, respectively. There was a significant positive correlation between the duration of the lesion and the improvement assessed by the ultrasound, with p value = 0.01. Regarding adverse effects, all patients reported having pain during platelet-rich plasma injection; transient edema of the face was reported by four patients (45%), and only two patients showed transient erythema. Autologous platelet-rich plasma is a safe technique with great aesthetic outcomes for filling up the contour defects and correcting both hyper and hypopigmentation, in addition to softening the indurated lesions.

Deep mucosal healing in ulcerative colitis: how deep is better?

Ulcerative colitis (UC), characterized by its recurrent nature, imposes a significant disease burden and compromises the quality of life. Emerging evidence suggests that achieving clinical remission is not sufficient for long-term remission. In pursuit of a favorable prognosis, mucosal healing (MH) has been defined as the target of therapies in UC. This paradigm shift has given rise to the formulation of diverse endoscopic and histological scoring systems, providing distinct definitions for MH. Endoscopic remission (ER) has been widely employed in clinical practice, but it is susceptible to subjective factors related to endoscopists. And there's growing evidence that histological remission (HR) might be associated with a lower risk of disease flares, but the incorporation of HR as a routine therapeutic endpoint remains a debate. The integration of advanced technology has further enriched the definition of deep MH. Up to now, a universal standardized definition for deep MH in clinical practice is currently lacking. This review will focus on the definition of deep MH, from different dimensions, and analyze strengths and limitations, respectively. Subsequent multiple large-scale trials are needed to validate the concept of deep MH, offering valuable insights into potential benefits for UC patients.

Rate and durability of the clearance of HBsAg in Alaska Native persons with long-term HBV infection: 1982-2019.

A functional cure and therapeutic end point of chronic HBV infection is defined as the clearance of HBsAg from serum. Little is known about the long-term durability of HBsAg loss in the Alaskan Native population. We performed a retrospective cohort study of Alaska Native patients with chronic HBV-monoinfection from January 1982 through December 2019. The original group in this cohort was identified during a 1982 to 1987 population-based screening for 3 HBV serologic markers in 53,000 Alaska Native persons. With close to 32,000 years of follow-up, we assessed the frequency and duration of HBsAg seroclearance (HBsAg-negative for > 6mo). We examined factors associated with HBsAg clearance and followed persons for a median of 13.1 years afterward to assess the durability of HBsAg clearance. Among 1079 persons with an average length of follow-up of 33 years, 260 (24%) cleared HBsAg at a constant rate of 0.82% per person/per year. Of the 260 persons who cleared, 249 (96%) remained HBsAg-negative, while 11 persons had ≥ 2 transient HBsAg-positive results in subsequent follow-up. Of the patients with chronic HBV monoinfection, 0.82% of people per year achieved a functional cure. HBsAg seroclearance was durable for treated and nontreated patients and lasted, on average, over 13 years without seroreversion.

Regulatory Framework, Challenges, and Initial Strategic Planning for Advanced Therapy Products (PTAs) Development in Brazil.

Advanced Therapies are a class of innovative complex biological products used for therapeutic purposes, encompassing cell therapy, tissue engineering, and gene therapy products. These are promising therapeutic strategies for several complex diseases with low or non-existent therapeutic alternatives. The proper transposition of basic research in this area into medicinal products must comply with regulatory requirements. Here we review the main regulatory recommendations, emphasizing on the Brazilian regulation. The critical points are the manufacturing process, challenges in characterizing the product, development of non-clinical trials, lack of adequate animal models representative of the clinical situation, and absence of valid and measurable therapeutic endpoints. Based on that, we propose a framework for strategic planning of pre-clinical studies in this field. The detailed example involves producing a nonviral vector-based gene editing product, but the regulations and methods may be extrapolated for developing different types of advanced therapies.

Effectiveness of a treat-to-target strategy in patients with moderate to severely active rheumatoid arthritis treated with abatacept

BackgroundTo compare a treat-to-target (T2T) approach and routine care (RC) in adults with active to severely active rheumatoid arthritis (RA) initiating subcutaneous abatacept.MethodsA 12-month cluster-randomized trial in active RA patients treated with abatacept was conducted. Physicians were randomized to RC or T2T with a primary endpoint of achieving sustained Clinical Disease Activity Index (CDAI) low disease activity (LDA) at two consecutive assessments approximately 3 months apart. Additional outcomes included Simple Disease Activity Index (SDAI), Disease Activity Score 28-CRP (DAS28-CRP), Routine Assessment of Patient Index Data 3 (RAPID3), and the Health Assessment Questionnaire-Disability Index (HAQ-DI). Time to achieve therapeutic endpoints was assessed with survival analysis.ResultsAmong the 284 enrolled patients, 130 were in the T2T group and 154 in RC. Primary endpoint was achieved by 36.9% and 40.3% of patients in T2T and RC groups, respectively. No significant between-group differences were observed in the odds of achieving secondary outcomes, except for a higher likelihood of CDAI LDA in the T2T group vs. RC (odds ratio [95% confidence interval]: 1.33 [1.03–1.71], p = 0.0263). Compared with RC, patients in the T2T group achieved SDAI remission significantly faster (Kaplan–Meier-estimated mean [standard error]: 14.0 [0.6] vs. 19.3 [0.8] months, p = 0.0428) with a trend toward faster achievement of CDAI LDA/remission, DAS28-CRP remission, and HAQ-DI minimum clinically important difference.ConclusionsPatients managed per T2T and those under RC experienced significant improvements in RA disease activity at 12 months of abatacept treatment. T2T was associated with higher odds of CDAI LDA and a shorter time to achieving therapeutic endpoints.Trial registrationName of the registry: ClinicalTrials.gov.Trial registrations: NCT03274141.Date of registration: September 6, 2017.

Trim33 masks a non-transcriptional function of E2f4 in replication fork progression

Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql. Replicative stress blunts Trim33-dependent ubiquitination of E2f4, which stimulates transient Recql recruitment to chromatin and facilitates recovery of DNA synthesis. In contrast, deletion of Trim33 induces chronic genome-wide recruitment of Recql and strongly accelerates DNA replication under stress, compromising checkpoint signaling and DNA repair. Depletion of Trim33 in Myc-overexpressing cells leads to accumulation of replication-associated DNA damage and delays Myc-driven tumorigenesis. We propose that the Trim33-E2f4-Recql axis controls progression of DNA replication forks along transcriptionally active chromatin to maintain genome integrity.

Modern aspects of infusion therapy: review

The infusion therapy is a routine procedure of the nowadays perioperative period and critical patient treatment. But there are controversial questions about the quantity, quality, start and duration of infusion therapy, which are under discussion. Modern infusion therapy includes intravenous administration of crystalloid solutions and more rarely colloid solutions. The type, amount and rate of infusion fluid depends on the indication for infusion therapy and the specific requirements of the patient. Nowadays colloidal solutions have limited indications. Crystalloid solutions are used for infusion therapy of patients with hypovolemia or dehydration, correction of free water deficiency, correction of electrolyte disorders, replenishment of ongoing fluid losses and replacement for patients who unable to drink water orally. All patients should be monitored with combination of clinical parameters and laboratory tests. Therapeutic endpoints should be determined. The moment these endpoints are achieved fluid therapy should be appropriately de-escalated in order to avoid overhydration.