Delay In Progression Research Articles

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients

PurposeTANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. MethodsData were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. ResultsData were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. ConclusionWe provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

EE76 Budget Impact of Subcutaneous Infliximab in Comparison to Intravenous Infliximab in the Management of Autoimmune Diseases in Greece

Autoimmune diseases (ADs) are associated with a significant clinical and economic burden. Disease management is often challenging, requiring both delay of diseases progression and improvement of quality of life. Infliximab is an effective choice for ADs management. Subcutaneous (SC) infliximab has the potential to significantly reduce ADs treatment costs, mainly due to avoided hospitalization costs compared to intravenous (IV) infliximab. The aim of this study was to evaluate the Budget Impact (BI) of the introduction of SC infliximab in the Greek formulary for ADs.

Nanomedicines for Therapy of Bladder Cancer

Bladder cancer is one of most common malignant urinary tract tumor types, and transurethral resection of nonmuscle invasive bladder cancer followed by intravesical instillation of immunochemotherapy is the standard treatment approach to minimize recurrence and delay progression of bladder cancer. In general, conventional intravesical immunochemotherapy lacks selectivity for tumor tissues and the effect of drug is reduced with the excretion of urine leading to frequent administration and bladder irritation symptoms. Recently, nanomedicines which adhere to the bladder tumors for a long time, and continuously and efficiently release drug to bladder cancers may overcome all the above problems. Moreover, the advances in nanomedicine based targeted therapy have led to significant improvements in drug efficacy and precision of targeted drug delivery. This review shows the available nano-systems of targeted drug delivery to bladder cancer tissues.

Assessing the Seeds of Disputes in Projects

Purpose: Unlike other projects, disputes are not avoidable on road projects. The study was focused to assess the causes of disputes management practices on road construction project performance under the department of roads. Design/Methodology/Approach: Based on convenient sampling eight (8) construction sites were chosen for the contextual analysis. After the serious audits of accessible writing on the reasons for debates in the development businesses, one set questionnaire study was completed among the principal partners engaged with the road sites to evaluate the reasons for questions. Semi-organized interviews were led with the stakeholders. Findings/Result: The main seeds of disputes were attributed due to Delays in works progress, Design error, Financial failures of contractors, Quality of works, Technical inadequacy of contractors, Payment delays, Semi-structured, Change in scope, Extension of Time (EoT) and Financial difficulties. Claims arising from delay in work progress can be reduced by realistic work schedule with resource deployment plan. The employer should closely monitor the activities with approved work schedule and provide appropriate solution for the issues arises from disputes / claims. Claims arising from delay in payment can be reduced by systematic disbursement of payment or directly payment to the people working groups under contractor. The cash flow management of contractors can be control by control mechanism for the use of mobilization fund on the same project works. Consultants ought to guarantee BOQ and contract periods, determined in the bid archives, are practical and according to existing site conditions. Originality/Value: The study is significant for professionals to overcome identified causes effectively to create zero dispute projects based on real time causes. Paper Type: Research paper

Loss of Cell Fate Determinant LLGL1 Impairs Leukemia Development in Acute Myeloid Leukemia

Cell fate determinants and polarity regulators influence the fine balance between self-renewal and differentiation in HSC and leukemic stem cells (LSC). Previously our group provided first evidence that inactivation of the cell fate regulator Llgl1 in murine HSCs leads to alterations in self-renewal, proliferative capacity and differentiation (Heidel et al., 2013). The impact of Llgl1 on malignant transformation and especially acute myeloid leukemia (AML) development had not been investigated in detail. Inactivation of LLGL1 in several human AML cell lines (MOLM13, HEL, MV4;11, HL-60) by CRISPR/Cas9 resulted in decreased proliferation of leukemic cells. Consistently, xenograft studies using LLGL1-depleted human AML cells resulted in delayed disease development compared to non-targeting control (median survival NT-control: 37.5 days vs. LLGL1-KD: 92 days; p=0.0002). Genetic inactivation of LLGL1 in primary AML patient cells resulted in reduced colony formation in vitro and improved survival of recipient mice in a patient-derived xenograft model of AML. To recapitulate these findings in defined model systems of murine AML, we used a conditional Llgl1 knockout mouse model (Klezovitch et al, 2004) and intercrossed it with AML-models harboring different driver mutations: MllAF9 (Cerral et al., 1995) or Flt3ITD/ITD (Lee et al., 2006). Conditional deletion of Llgl1 in MllAF9 knockin mice using an Mx1-Cre-recombinase (Cre+) resulted in significant delay of leukemia development (median survival +/+: 174 days; -/-: 203 days; p=0.0361). To confirm these findings, we investigated a second oncogenic model and induced deletion of Llgl1 in Flt3ITD/ITD knockin mice. Leukemic Flt3ITD/ITD; Llgl1+/+; Cre+ animals (n=12) showed rapid onset of leukemia development, whereas the Flt3ITD/ITD; Llgl1-/-; Cre+ animals (n=25) showed significant delay in leukemia progression (median survival +/+: 38 days; -/-: 51 days; p=0.0005). Llgl1-/- animals show reduced peripheral blast counts (WBC +/+: 332.558 Gpt/l; -/-: 141.083 Gpt/l; p=0.0012) and decreased organ infiltration. Importantly, immunophenotypic analysis of bone marrow (BM) compartments indicated a shift of immature cells towards a more differentiated state. The overall abundance of leukemic Lin-Kit+Sca-1+ (LSK) cells was reduced in Flt3ITD/ITD; Llgl1-/- animals compared to Flt3ITD/ITD; Llgl1+/+ controls (LSK +/+: 13099±3144/106 BMC; -/-: 8117±2810 /106 BMC; p=0.0227). In contrast, we found increased numbers of Lin-Kit+Sca-1+FcgR+CD34+ of leukemic granulocyte-macrophage progenitors (LGMPs: +/+: 8306±1963/106 BMC; -/-: 14755±4783/106 BMC; p=0.0141) upon deletion of Llgl1 in Flt3ITD/ITD animals. These findings indicate that genetic inactivation of Llgl1 results in loss of leukemia stemness and shifts the leukemia stem cell phenotype from HSC-like to GMP-like LSCs. To test for this hypothesis, we performed global transcriptome analysis of sorted LSK cells of Flt3ITD/ITD mice early after genetic deletion of Llgl1. Among the significantly downregulated genes, we found several members of the HoxA-cluster, consistent with the immunophenotypic loss of stemness. Gene-set-enrichment analysis revealed downregulation of leukemia stem cell signatures (Gal et al., 2006) and enrichment of a gene set associated with LGMPs (compared to leukemic-HSC) signatures (Krivtsov et al., 2006). To validate whether loss of Hox-gene expression is relevant for impaired leukemia development, we performed rescue experiments in vivo. LSK cells derived from Flt3ITD/ITD; Llgl1+/+ or Flt3ITD/ITD; Llgl1-/- animals were retrovirally transduced with HoxA9 or empty vector control (eV). When transplanted into sublethally irradiated recipient mice, overexpression of HoxA9 (OE) in Llgl1-/-; Flt3ITD/ITD cells rescued the disease phenotype comparable to Flt3ITD/ITD; Llgl1+/+ cells (median survival +/+;eV: 62.50%; -/-; OE: 55.56%). In contrast, empty vector control Flt3ITD/ITD; Llgl1-/- recipients showed no disease development (median survival -/-; eV: 100%). Taken together our results may provide first evidence for a functional role of Llgl1 in models of AML. In contrast to its function in normal HSCs, deletion of Llgl1 appears to reduce stemness of leukemic stem cells and impair leukemia development in vitro and in vivo. Experiments to assess for the effects of Llgl1 on LSC polarity and cell fate decisions are currently under way.

Genomic Evolution of Patients with Myelodysplastic Syndrome after Hypomethylating Agent Failure

Background: Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the current standard of care for patients with myelodysplastic syndrome (MDS). Though HMAs improve cytopenias and delay progression of disease, most patients eventually lose response to these agents and have poor survival afterwards. This poses significant treatment challenges after HMA failure (HMA-F) and an increased risk of transformation to acute myeloid leukemia. The genomic evolution of patients with MDS at the time of HMA-F has not been previously described. Here, we assess the genomic changes of MDS patients at the time of HMA-F and their effects on the outcomes of MDS patients at the time of HMA-F. Methods: We retrospectively evaluated all patients with MDS seen at a single tertiary cancer center from July 2017 to July 2021 and identified those who were previously untreated and later developed HMA-F. Bone marrow (BM) data was assessed at diagnosis and at the time of HMA-F. Genomic DNA was extracted from whole BM aspirate samples and subject to 81-gene target PCR-based sequencing using a next-generation sequencing platform. Survival data was updated in May 2022. The Kaplan-Meier method and Cox proportional hazards model were used for time-to-event data analysis. The number of metaphases for each unique karyotypic aberration combinations were used to compute the proportions of cytogenetic clones. All the analysis was performed in R 4.0.3. Results: Out of 799 untreated MDS patients, 147 patients (32%) developed HMA-F with a median follow-up time of 44.0 months from diagnosis. Paired cytogenetic and molecular data were available in 128 and 75 patients, respectively. The median overall survival (mOS) since diagnosis (hazard ratio (HR) 1.65, p=0.033) and HMA-F (HR 1.95, p=0.004, Figure A) was inferior for individuals with decreasing number of clones at the time of HMA-F with no statistically significant differences in the time to HMA-F. Gain and/or loss of cytogenetic abnormalities at the time of HMA-F resulted in a shorter mOS (HR 2.35, p<0.001), time to HMA-F (HR 1.65, p=0.033) and mOS since HMA-F (HR 2.89, p<0.001). A change in the dominant cytogenetic clone by the number of metaphases at the time of HMA-F resulted in inferior mOS since diagnosis (HR 2.28, p<0.001), time to HMA-F (HR 1.89, p=0.005), and mOS since HMA-F (HR 2.45, p<0.001). Interestingly, most patients who had gain and/or loss of karyotypic abnormalities and a change in the dominant cytogenetic clone had mutations in TP53. Regarding mutations, there were no statistically significant differences in mOS and time to HMA-F by the gain and/or loss of new mutations at the time of HMA-F. However, the change of the dominant mutation by variant allele frequency resulted in improved mOS from diagnosis (HR 0.47, p=0.02), time to HMA-F (HR 0.46, p=0.02), and mOS since HMA-F (HR 0.55, p=0.072, Figure B). Of note, most TP53-mutated patients had no changes in mutations at the time of HMA-F. Conclusions: Patients with HMA-F MDS have poorer outcomes with a decreasing number of cytogenetic clones, gain and/or loss of karyotypic aberrations, or a change in the dominant clone by the number of metaphases at the time of HMA-F. However, the gain or loss of mutations on next-generation sequencing appear to have no impact on survival outcomes, though a change in the dominant mutation by variant allele frequency appears to be protective. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EXTH-08. DEVELOPMENT OF NOVEL HISTONE DEMETHYLASE INHIBITOR AGAINST DIPG

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of most the devastating pediatric brain tumors, and virtually all patients die within two years after diagnosis. It has been shown that targeted inhibition of JMJD3 demethylase activity by GSK-J4 results in restored K27 methylation and a significant delay of tumor progression and prolonged animal survival in intracranial DIPG patient-derived xenograft (PDX) models. Because of its promising anti-tumor activities, GSK-J4 has been used to treat many kinds of tumors in preclinical models including leukemia, lymphoma, neuroblastoma, prostate, and gastric cancer, and DIPG; however, GSK-J4 is not yet in clinical development. The major challenge for GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted in vivo to the active drug GSK-J1, which has restricted cellular and brain permeability. Hypothesis: We hypothesize that development of a stable GSK- J1 analog that offers good cellular and brain transport is essential to improving in vivo efficacy and is required for clinical application of this class of compounds. METHODS We developed a novel alcohol derivative of GSK-J1, UR-8, as a lead anti-cancer agent through our screening and drug development activities. RESULTS UR-8 has demonstrated selective cytotoxic activity against human K27M DIPG cells in vitro and apparently transported the brain to a useful extent based on its in vivo bio-distribution and effectiveness. CONCLUSION UR-8 showed greater anti-tumor activity and survival benefit than that obtained by GSK-J4 treatment in intracranial DIPG PDX models.

The relationship between depression symptoms and academic performance among first-year undergraduate students at a South African university: a cross-sectional study

Background:South African universities face a challenge of low throughput rates, with most students failing to complete their studies within the minimum regulatory time. Literature has begun to investigate the contribution of well-being, including mental health, with depression among students being one of the most common mental disorders explored. However, locally relevant research exploring associations between depression and academic performance has been limited. This research hypothesizes that the presence of depression symptoms, when controlling for key socio-demographic factors, has an adverse impact on student academic outcomes and contributes to the delay in the academic progression of students.Methods:The study used a cross-sectional design. Data were collected in 2019 from first-time, first-year undergraduate students using a self-administered online questionnaire. In total, 1,642 students completed the survey. The Patient Health Questionnaire-9 (PHQ-9) was used to screen for depression symptoms. Data on students’ academic performance were obtained from institutional records. Bivariate and multivariate regression analyses were used to examine associations between depression symptoms and academic performance.Results:Most participants (76%) successfully progressed (meeting the requirements to proceed to the second year of university study). Of the participants, 10% displayed symptoms of severe depression. The likelihood of progression delay (not meeting the academic requirements to proceed to the second year of university study) increased with the severity of depression symptoms. Moderate depression symptoms nearly doubled the adjusted odds of progression delay (aOR = 1.98, 95% CI: 1.30-3.00, p = 0.001). The likelihood of progression delay was nearly tripled by moderate severe depression symptoms (aOR = 2.70, 95% CI:1.70–4.36, p < 0.001) and severe depression symptoms (aOR = 2.59, 95% CI:1.54–4.36, p < 0.001). The model controlled for field of study, financial aid support as well as sex and race.Conclusion:Higher levels of depression symptoms among first-year university students are associated with a greater likelihood of progression delay and may contribute to the low throughput rates currently seen in South African universities. It is important for students, universities and government departments to recognize student mental wellness needs and how these can be met.

Dispersive silicon–nitride optical phased array incorporating arrayed waveguide delay lines for passive line beam scanning

As optical phased arrays (OPAs), used as solid-state beam scanning elements, swiftly stride towards higher efficiency and faster scanning speed, the line beam scanner is emerging as a viable substitute for its counterpart relying on point-beam-incorporated raster scanning. However, line-beam scanners require active phase shifters for beam scanning; thus, they consume more power and have complex device designs. This study proposes and demonstrates a dispersive silicon–nitride OPA that allows for passive wavelength-tuned steering of a line beam with an elongated vertical beamwidth. To steer the line beam passively covering the two-dimensional field of view, we deployed an array of delay lines with progressive delay lengths across adjacent channels. Furthermore, adiabatic tapers that allow precise effective array aperture adjustment are used as emitter elements to flexibly realize different vertical beamwidths. Combinations of different delay-length differences and taper tip-widths resulted in beam coverage (lateral × vertical) ranging from 6.3° × 19° to 23.8° × 40° by tuning the wavelength from 1530 to 1600 nm. The main lobe emission throughput was as small as − 2.8 dB. To the best of our knowledge, the embodied OPA is the first demonstration of a passive line beam scanner facilitating an adjustable beam coverage with quick operation and enhanced efficiency.

Small lymphocytic lymphoma presenting as chronic diffuse lip swelling.

Although rare, small lymphocytic lymphoma can present as chronic lip swelling and papules, thus mimicking the features of orofacial granulomatosis, a chronic inflammatory disorder characterized by subepithelial noncaseating granulomas, or papular mucinosis, characterized by localized dermal mucin deposition of mucin. When assessing lip swelling, one must carefully consider the clinical clues and have a low threshold to perform a diagnostic tissue biopsy, preventing delays in treatment or progression of the lymphoma.

Doxorubicin for treatment of histiocytic sarcoma in dogs: 31 cases (2003-2017).

To evaluate the efficacy of doxorubicin for treatment of histiocytic sarcoma (HS) in dogs, whether administered as the sole treatment or as an adjunct to surgery or radiation therapy. 31 client-owned dogs with localized or disseminated HS examined between 2003 and 2017. Medical records were reviewed retrospectively, and data were collected. The Kaplan-Meier method was used to estimate time-to-progression from the date of first doxorubicin administration and survival time from initial diagnosis. Factors that could be associated with poorer outcomes with doxorubicin treatment were analyzed with log-rank tests. The objective response rate (ORR) was 26%. When stratified by disease status, dogs with localized and disseminated forms experienced 43% and 21% ORRs, respectively. Median time to progression after initiating doxorubicin treatment (n = 30 dogs) was 42 days. Median survival time from initial diagnosis to death (n = 29 dogs) was 169 days. Complete responses were obtained in only 2 dogs that had localized disease and received multimodality therapy. Benefits of doxorubicin administration in canine HS are modest, with a limited ORR and delay in tumor progression, and are comparable to effects attained with other single-agent regimens.

Manipulating the nature of embryonic mitotic waves

Early embryogenesis is characterized by rapid and synchronous cleavage divisions, which are often controlled by wave-like patterns of Cdk1 activity. Two mechanisms have been proposed for mitotic waves: sweep and trigger waves.1,2 The two mechanisms give rise to different wave speeds, dependencies on physical and molecular parameters, and spatial profiles of Cdk1 activity: upward sweeping gradients versus traveling wavefronts. Both mechanisms hinge on the transient bistability governing the cell cycle and are differentiated by the speed of the cell-cycle progression: sweep and trigger waves arise for rapid and slow drives, respectively. Here, using quantitative imaging of Cdk1 activity and theory, we illustrate that sweep waves are the dominant mechanism in Drosophila embryos and test two fundamental predictions on the transition from sweep to trigger waves. We demonstrate that sweep waves can be turned into trigger waves if the cell cycle is slowed down genetically or if significant delays in the cell-cycle progression are introduced across the embryo by altering nuclear density. Our genetic experiments demonstrate that Polo kinase is a major rate-limiting regulator of the blastoderm divisions, and genetic perturbations reducing its activity can induce the transition from sweep to trigger waves. Furthermore, we show that changes in temperature cause an essentially uniform slowdown of interphase and mitosis. That results in sweep waves being observed across a wide temperature range despite the cell-cycle durations being significantly different. Collectively, our combination of theory and experiments elucidates the nature of mitotic waves in Drosophila embryogenesis, their control mechanisms, and their mutual transitions.

Genistein improves renal disease in a mouse model of nephropathic cystinosis: a comparison study with cysteamine.

Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns-/- female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14months. Genistein (160mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16months, Ctns-/- mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.

The paradigm and future value of the metaverse for the intervention of cognitive decline.

Cognitive decline is a gradual neurodegenerative process that is affected by genetic and environmental factors. The doctor-patient relationship in the healthcare for cognitive decline is in a "shallow" medical world. With the development of data science, virtual reality, artificial intelligence, and digital twin, the introduction of the concept of the metaverse in medicine has brought alternative and complementary strategies in the intervention of cognitive decline. This article technically analyzes the application scenarios and paradigms of the metaverse in medicine in the field of mental health, such as hospital management, diagnosis, prediction, prevention, rehabilitation, progression delay, assisting life, companionship, and supervision. The metaverse in medicine has made primary progress in education, immersive consultation, dental disease, and Parkinson's disease, bringing revolutionary prospects for non-pharmacological complementary treatment of cognitive decline and other mental problems. In particular, with the demand for non-face-to-face communication generated by the global COVID-19 epidemic, the needs for uncontactable healthcare service for the elderly have increased. The paradigm of self-monitoring, self-healing, and healthcare experienced by the elderly through the metaverse in medicine, especially from meta-platform, meta-community, and meta-hospital, will be generated, which will reconstruct the service modes for the elderly people. The future map of the metaverse in medicine is huge, which depends on the co-construction of community partners.

A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease

BackgroundTolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.MethodsA model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death.ResultsWhen treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively.ConclusionsThe model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.

Objective perimetry and progression of multiple sclerosis.

IntroductionWe re-examined the per-region response amplitudes and delays obtained from multifocal pupillographic objective perimetry (mfPOP) after 10 years in 44 persons living with multiple sclerosis (PwMS), both to examine which parts of the visual field had progressed in terms of response properties and to examine if the baseline data could predict the overall progression of disease.MethodsExpanded Disability Status Scale (EDSS) scores were assessed in 2009 and 2019. Both eyes of each participant were concurrently tested at 44 locations/eye on both occasions. Several measures of clinical progression were examined, using logistic regression to determine the odds of progression.ResultsAt the second examination the 44 PwMS (31 females) were aged 61.0 ± 12.2 y. Mean EDSS had not changed significantly (3.69 ± 1.23 in 2009, 3.81 ± 2.00 in 2019). mfPOP delay increased progressively from inferior to superior regions of the visual fields while amplitudes demonstrated a temporal to nasal gradient. The mean of the 3 most delayed visual field regions was correlated with progression of MS by 2019 (p = 0.023). Logistic regression indicated a significant association between delay and odds of progression (p = 0.045): an individual with 3 regions at least 1 SD (40 ms) slower than the mean in 2009 had 2.05× (±SE: 1.43× to 2.95×) the odds of progression by 2019. A 1 SD shorter delay was associated with 2.05× lower odds of progression. Amplitude changes were not predictive of progression.SignificancemfPOP may provide a rapid, convenient method of monitoring and predicting MS progression.

MDS-407 Disease Characteristics and Outcomes of Hypomethylating Agent Failure in Patients With Myelodysplastic Syndromes

Hypomethylating agents (HMA) improve cytopenias and delay progression of myelodysplastic syndromes (MDS), but most patients eventually lose their response. Although patients with HMA failure (HMA-F) pose significant treatment challenges with dismal outcomes, the clinicopathologic characteristics of MDS patients at the time of HMA-F are still poorly understood. We retrospectively evaluated 135 untreated patients with MDS diagnosed between 2017-2021 who later developed HMA-F. Pt characteristics, laboratory values, and bone marrow (BM) data, including cytogenetics and next generation sequencing, were assessed at both diagnosis and the time of HMA-F. The median age was 70 at diagnosis, with therapy-related MDS (t-MDS) in 39%. Most patients had higher-risk MDS with IPSS-R high (30%) or very high (42%) disease, and complex karyotype was seen in 47%. The median number of mutations identified was 2 with TP53 (46%) and ASXL1 (21%) the most frequently discovered mutations. Regarding treatment, 67% received HMA monotherapy and 33% received HMA in combination with various agents. The median number of cycles of HMAs received was 7 (range: 1-37). At the time of HMA-F, patients presented with higher BM blasts (p<0.001), lower platelet counts (p<0.001), and more cytogenetic abnormalities (p=0.002) and mutations (p<0.001) than at diagnosis. The median time from diagnosis to HMA-F was 10.6 mo, and the median overall survival (mOS) from HMA-F was 6.5 mo. Survival was well-stratified by both IPSS-R at diagnosis (p=0.066) and at HMA-F (17.8 mo in lower-risk vs 3.8 mo in higher-risk MDS, p<0.001). There was no difference in mOS from HMA-F by number of HMA cycles, response to HMA, and treatment regimen at HMA-F; however, in patients with higher-risk MDS, stem cell transplantation (p<0.001) was associated with improved mOS and upfront HMA combination therapy (p=0.008) with inferior survival. Patients with HMA-F MDS have high-risk features which are often therapy-related. At the time of HMA-F, patients present with higher BM blasts, worsening thrombocytopenia, and more genomic aberrations. Unfortunately, after failure of HMA, patients have poor prognosis. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy.

RADIOGRAPHIC COMPARATIVE REGENERATIVE EFFECTS OF HYALURONATE AND PIROXICAM IN OSTEOARTHRITIS MODELS OF RATS

Background: Osteoarthritis is the most common degenerative joint disease that affects commonly in old age. Standard treatment of this disease is still underdeveloped, however multiple drug groups delay progression or reduce the symptoms. Objective of this study was to assess and compare the regenerative effects of hyaluronate and piroxicam in a rat model of osteoarthritis at the radiographic level. Methods: This laboratory-based randomized trial was conducted at Department of Pharmacology Army Medical College, Rawalpindi, from May to July 2019. Resection of the medial meniscus and anterior cruciate ligament resulted in osteoarthritis in the right knee joints of 24 rats. They were separated into 3 groups of 8 rats each. For 4 weeks, groups I, II, and III received intra-articular saline, hyaluronate, and piroxicam, respectively. After one week, radiographs of the anaesthetized rats’ matching knee joints were collected. Results: Comparison of radiograph of control group with drug treated group confirmed regenerative effects of hyaluronate and piroxicam (p=0.001). However comparison of hyaluronate and piroxicam treated groups had p=0.335 that professed both drug have equal regenerative effects in rat model of osteoarthritis. Conclusion: In a rat model of osteoarthritis, intra-articular injection of hyaluronate acid and piroxicam had regenerating benefits at the radiological level. Both administered medicines had similar regeneration effects. Pak J Physiol 2022;18(3):19–22

Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer

Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.

A Peculiar Wide Complex Tachycardia During Flecainide Treatment.

A Peculiar Wide Complex Tachycardia During Flecainide Treatment.