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B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases., Competing Interests: WR has received consulting fees from IGM Biosciences. DF has received consulting fees from IGM Biosciences, Kyverna Therapeutics, Argenx, Priovant Therapeutics, Pfizer, Biogen, Bristol Meyers Squibb, and Serono. LC has received consulting fees from IGM Biosciences, Kyverna Therapeutics, Mitsubishi Tanabe, Lilly, Janssen, Mediar Therapeutics, and Genentech. LM serves as a member of independent data safety monitoring boards for Boehringer Ingelheim and Celltrion. MD, MH, CS, and RK are employees of IGM Biosciences., (Copyright © 2024 Robinson, Fiorentino, Chung, Moreland, Deodhar, Harler, Saulsbery and Kunder.)

Introduction: Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs)., Methods: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations., Results: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C max ) and area under the concentration-time curve from time 0 to infinity (AUC 0-inf ) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition., Conclusion: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy., Trial Registration: ISRCTN13175485., (© 2024. The Author(s).)

Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows., (© 2024 Genentech, Inc. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

MTBT1466A is a high-affinity TGFβ3-specific humanized IgG1 monoclonal antibody with reduced Fc effector function, currently under investigation in clinical trials as a potential anti-fibrotic therapy. Here, we characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of MTBT1466A in mice and monkeys and predicted the PK/PD of MTBT1466A in humans to guide the selection of the first-in-human (FIH) starting dose. MTBT1466A demonstrated a typical IgG1-like biphasic PK profile in monkeys, and the predicted human clearance of 2.69 mL/day/kg and t 1/2 of 20.4 days are consistent with those expected for a human IgG1 antibody. In a mouse model of bleomycin-induced lung fibrosis, changes in expression of TGFβ3-related genes, serpine1, fibronectin-1, and collagen 1A1 were used as PD biomarkers to determine the minimum pharmacologically active dose of 1 mg/kg. Unlike in the fibrosis mouse model, evidence of target engagement in healthy monkeys was only observed at higher doses. Using a PKPD-guided approach, the recommended FIH dose of 50 mg, IV, provided exposures that were shown to be safe and well tolerated in healthy volunteers. MTBT1466A PK in healthy volunteers was predicted reasonably well using a PK model with allometric scaling of PK parameters from monkey data. Taken together, this work provides insights into the PK/PD behavior of MTBT1466A in preclinical species, and supports the translatability of the preclinical data into the clinic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1β and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development., (© 2023 Genentech, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Aims: BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD., Approach and Results: Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose-proportional increases in exposure. The treatment-emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure-dependent increases in high-density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high-exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low-, medium-, and high-exposure tertiles, respectively, compared with 0.1% with placebo at Day 85., Conclusions: BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. ( ClinicalTrials.gov : NCT03060538)., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations., Aim: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation., Methods: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV 1 )> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed., Results: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful., Conclusions: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns., Australian New Zealand Clinical Trials Registry: ACTRN12619000227190., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC) is the breast cancer subtype with the poorest clinical outcome. The PIM family of kinases has emerged as a factor that is both overexpressed in TNBC and associated with poor outcomes. Preclinical data suggest that TNBC with an elevated MYC expression is sensitive to PIM inhibition. However, clinical observations indicate that the efficacy of PIM inhibitors as single agents may be limited, suggesting the need for combination therapies. Our screening effort identifies PIM and the 20S proteasome inhibition as the most synergistic combination. PIM inhibitors, when combined with proteasome inhibitors, induce significant antitumor effects, including abnormal accumulation of poly-ubiquitinated proteins, increased proteotoxic stress, and the inability of NRF1 to counter loss in proteasome activity. Thus, the identified combination could represent a rational combination therapy against MYC-overexpressing TNBC that is readily translatable to clinical investigations., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Real-time PCR technology has been instrumental in contributing toward biomarker discovery, classification of tumors as well as risk stratification of patients. However, much of its success depends on the quality and quantity of the starting material used for RNA extraction. Clinical samples are most often provided as formalin-fixed and paraffin-embedded, wherein the RNA is extensively degraded, affecting sensitivity. Here, we describe a real-time PCR based assay developed for molecular subgrouping of medulloblastomas that is particularly useful for formalin-fixed, paraffin-embedded (FFPE) samples., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

A meeting was organized to bring together multiple stakeholders involved in the testing and authorization of new medications for juvenile idiopathic arthritis (JIA) to discuss current issues surrounding clinical trials and access to new medications for children and adolescents with JIA. The Childhood Arthritis and Rheumatology Research Alliance invited representatives of regulatory agencies (Food and Drug Administration and European Medicines Agency), and major pharmaceutical companies with JIA-approved products or products in development, patient and parent representatives, representatives of an advocacy organization (Arthritis Foundation), and pediatric rheumatology clinicians/investigators to a 1-day meeting in April 2018. The participants engaged in discussion regarding issues in clinical trials. As the pharmacologic options to treat inflammatory arthritis rapidly expand, registration trial designs to test medications in JIA patients must adapt. Many methodologies successfully used in the recent past are no longer feasible. The pool of patients meeting entry criteria who are willing to participate is shrinking while the number of medications to be tested is growing. Suggested solutions included proposing innovative clinical trial methods to regulatory agencies, as well as open discussions among stakeholders. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critical. Approaches should include open dialog between regulatory agencies, pharmaceutical companies, and other stakeholders to develop and implement novel study designs, including patient and clinician perspectives to define meaningful trial outcomes, and changing existing study plans., (© 2019, American College of Rheumatology.)

Genome-wide expression profiling studies have identified four core molecular subgroups of medulloblastoma: WNT, SHH, Group 3 and Group 4. Molecular markers are necessary for accurate risk stratification in the non-WNT subgroups due to the underlying heterogeneity in genetic alterations and overall survival. MiR-204 expression was evaluated in molecularly classified 260 medulloblastomas from an Indian cohort and in 763 medulloblastomas from the MAGIC cohort, SickKids, Canada. Low expression of miR-204 in the Group 3 / Group 4 tumors identify a highly aggressive subset of tumors having poor overall survival, in the two independent cohorts of medulloblastomas. Downregulation of miR-204 expression correlates with poor survival within the Group 4 as well indicating it as a valuable risk-stratification marker in the subgroup. Restoration of miR-204 expression in multiple medulloblastoma cell lines was found to inhibit their anchorage-independent growth, invasion potential and tumorigenicity. IGF2R was identified as a novel target of miR-204. MiR-204 expression resulted in downregulation of both M6PR and IGF2R that transport lysosomal proteases from the Golgi apparatus to the lysosomes. Consistent with this finding, miR-204 expression resulted in reduction in the levels of the lysosomal proteases in medulloblastoma cells. MiR-204 expression also resulted in inhibition of autophagy that is known to be dependent on the lysosomal degradation pathway and LC3B, a known miR-204 target. Treatment with HDAC inhibitors resulted in upregulation of miR-204 expression in medulloblastoma cells, suggesting therapeutic role for these inhibitors in the treatment of medulloblastomas. In summary, miR-204 is not only a valuable risk stratification marker in the combined cohort of Group 3 / Group 4 medulloblastomas as well as in the Group 4 itself, that has paucity of good prognostication markers, but also has therapeutic potential as indicated by its tumor suppressive effect on medulloblastoma cells.

Background: The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis., Methods: The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670., Findings: Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p<0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group., Interpretation: Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified., Funding: Galapagos and Gilead Sciences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

Background: Medulloblastoma has recently been found to consist of 4 molecularly and clinically distinct subgroups: WNT, Sonce hedgehog (SHH), Group 3, and Group 4. Deregulated microRNA expression is known to contribute to pathogenesis and has been shown to have diagnostic and prognostic potential in the classification of various cancers., Methods: Molecular subgrouping and microRNA expression analysis of 44 frozen and 59 formalin-fixed paraffin embedded medulloblastomas from an Indian cohort were carried out by real-time RT-PCR assay., Results: The differential expression of 9 microRNAs in the 4 molecular subgroups was validated in a set of 101 medulloblastomas. The tumors in the WNT subgroup showed significant (P < .0001) overexpression of miR-193a-3p, miR-224, miR-148a, miR-23b, and miR-365. Reliable classification of medulloblastomas into the 4 molecular subgroups was obtained using a set of 12 protein-coding genes and 9 microRNAs as markers in a real-time RT-PCR assay with an accuracy of 97% as judged by the Prediction Analysis of Microarrays. Age at diagnosis, histology, gender-related incidence, and the relative survival rates of the 4 molecular subgroups in the present Indian cohort were found to be similar to those reported for medulloblastomas from the American and European subcontinent. Non-WNT, non-SHH medulloblastomas underexpressing miR-592 or overexpressing miR-182 were found to have significantly inferior survival rates, indicating utility of these miRNAs as markers for risk stratification., Conclusions: The microRNA based real-time PCR assay is rapid, simple, inexpensive, and useful for molecular classification and risk stratification of medulloblastomas, in particular formalin-fixed paraffin embedded tissues, wherein the expression profile of protein-coding genes is often less reliable due to RNA fragmentation.

Background: In resource-poor settings, the management of neuromyelitis optica (NMO) and NMO spectrum (NMOS) disorders is limited because of delayed diagnosis and financial constraints., Aim: To device a cost-effective strategy for the management of NMO and related disorders in India., Materials and Methods: A cost-effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients., Results: Forty-five patients (65%) had a relapse from the onset and included NMO (n = 20), recurrent transverse myelitis (RTM; n = 10), and recurrent optic neuritis (ROPN; n = 15). In 38 (84.4%) patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5), NMO (n = 1), and RTM (n = 1). They had a second attack after a median interval of 1 ± 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM), of which 20 (80%) remained ambulant at follow-up of 3 ± 1.9 years. Twelve patients (17%) with median expanded disability status scale (EDSS) of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%). Irrespective of the NMO-IgG status, the treatment compliant patients (44.4%) showed significant improvement in EDSS (P ≤ 0.001)., Conclusions: Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set-up. NMO and NMOS disorders contributed to 14.9% (45/303) of all demyelinating disorders in our registry.

Background: Vitamin D deficiency is widely prevalent in India. The association between vitamin D status and multiple sclerosis (MS) has not been previously studied in Indians., Objective: The objective of this paper is to determine whether vitamin D status is associated with MS in India., Methods: In this study 110 MS patients and 108 matched controls were included. Serum 25-hydroxyvitamin D (25(OH)D) was measured in 63 patients in relapse, 77 patients in remission and all controls. Quantity of sun exposure in childhood and body mass index (BMI) were calculated. Patients and controls were genotyped for HLA-DRB1*1501., Results: Patients had significantly lower 25(OH)D levels than matched controls (p = 0.003), and patients in relapse had a significantly lower vitamin D level as compared to those in remission (p = 0.001). Vitamin D deficiency (< 50 nmol/l) was seen in a higher proportion of cases (71.8%) than controls (53.7%) (p = 0.01). Higher quartiles of vitamin D (> 58 nmol/l) showed an inverse relationship with MS (OR = 0.28, CI = 0.11-0.68, p= 0.005). This effect persisted after adjusting for sun exposure., Conclusion: The results of our study indicated that serum 25(OH)D shows an inverse relationship with MS in the Indian population. Reverse causality cannot be excluded.

Plastic bronchitis (PB) is a pathologic condition in which airway casts develop in the tracheobronchial tree causing airway obstruction. There is no standard treatment strategy for this uncommon condition. We report an index patient treated using an emerging multimodal strategy of directly instilled and inhaled tissue plasminogen activator (t-PA) as well as 13 other cases of PB at our institution between 2000 and 2012. The majority of cases (n = 8) occurred in patients with congenital heart disease. Clinical presentations, treatments used, histopathology of the casts, and patient outcomes are reviewed. Further discussion is focused on the epidemiology of plastic bronchitis and a systematic approach to the histologic classification of casts. Comorbid conditions identified in this study included congenital heart disease (8), pneumonia (3), and asthma (2). Our institutional prevalence rate was 6.8 per 100,000 patients, and our case fatality rate was 7%.

A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated receptor activity. Importantly, this signature also predicted the ability of an ERRα antagonist, XCT790, to inhibit proliferation in cellular models of breast cancer. Using a chemical genomic approach, it was determined that activation of the Her2/IGF-1R signaling pathways and subsequent C-MYC stabilization upregulate the expression of peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1β), an obligate cofactor for ERRα activity. PGC-1β knockdown in breast cancer cells impaired ERRα signaling and reduced cell proliferation, implicating a functional role for PGC-1β/ERRα in the pathogenesis of breast cancers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aim: Medulloblastoma is a malignant brain tumor that occurs predominantly in children. Current risk stratification based on clinical parameters is inadequate for accurate prognostication. MicroRNA expression is known to be deregulated in various cancers and has been found to be useful in predicting tumor behavior. In order to get a better understanding of medulloblastoma biology, miRNA profiling of medulloblastomas was carried out in parallel with expression profiling of protein-coding genes., Materials and Methods: miRNA profiling of medulloblastomas was carried out using Taqman Low Density Array v 1.0 having 365 human microRNAs. In parallel, genome-wide expression profiling of protein-coding genes was carried out using Affymetrix gene 1.0 ST arrays., Results: Both the profiling studies identified four molecular subtypes of medulloblastomas. Expression levels of select protein-coding genes and miRNAs could classify an independent set of medulloblastomas. Twelve of 31 medulloblastomas were found to overexpress genes belonging to the canonical WNT signaling pathway and carry a mutation in CTNNB1 gene. A number of miRNAs like miR-193a, miR-224/miR-452 cluster, miR-182/miR-183/miR-96 cluster, and miR-148a having potential tumor/metastasis suppressive activity were found to be overexpressed in the WNT signaling associated medulloblastomas. Exogenous expression of miR-193a and miR-224, two miRNAs that have the highest WNT pathway specific upregulation, was found to inhibit proliferation, increase radiation sensitivity and reduce anchorage-independent growth of medulloblastoma cells., Conclusion: Expression level of tumor/metastasis suppressive miRNAs in the WNT signaling associated medulloblastomas is likely to determine their response to treatment, and thus, these miRNAs would be important biomarkers for risk stratification within the WNT signaling associated medulloblastomas.