The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with ...belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).
A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR).
The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation.
Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil–containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 ...and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval CI, 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
•Belumosudil, a selective ROCK2 inhibitor, was well tolerated in heavily pretreated subjects, with 44% continuing treatment beyond 1 year.•Belumosudil demonstrated efficacy in patients with SR cGVHD, with responses in all organs and after failure of ibrutinib/ruxolitinib.
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Sirtuins are protein deacetylases that play a protective role in cardiovascular diseases (CVDs), as well as many other diseases. Absence of sirtuins can lead to hyperacetylation of both nuclear and ...mitochondrial proteins leading to metabolic dysregulation. The protein post-translational modifications (PTMs) are known to crosstalk among each other to bring about complex phenotypic outcomes. Various PTM types such as acetylation, ubiquitination, and phosphorylation, and so on, drive transcriptional regulation and metabolism, but such crosstalks are poorly understood. We integrated protein-protein interactions (PPI) and PTMs from several databases to integrate information on 1,251 sirtuin-interacting proteins, of which 544 are associated with cardiac diseases. Based on the ∼100,000 PTM sites obtained for sirtuin interactors, we observed that the frequency of PTM sites (83 per protein), as well as PTM types (five per protein), is higher than the global average for human proteome. We found that ∼60-70% PTM sites fall into ordered regions. Approximately 83% of the sirtuin interactors contained at least one competitive crosstalk (
) site, with half of the sites occurring in CVD-associated proteins. A large proportion of identified crosstalk sites were observed for acetylation and ubiquitination competition. We identified 614 proteins containing PTM hotspots (≥5 PTM sites) and 133 proteins containing crosstalk hotspots (≥3 crosstalk sites). We observed that a large proportion of disease-associated sequence variants were found in PTM motifs of CVD proteins. We identified seven proteins (TP53, LMNA, MAPT, ATP2A2, NCL, APEX1, and HIST1H3A) containing disease-associated variants in PTM and crosstalk hotspots. This is the first comprehensive bioinformatics analysis on sirtuin interactors with respect to PTMs and their crosstalks. This study forms a platform for generating interesting hypotheses that can be tested for a deeper mechanistic understanding gained or derived from big-data analytics.
The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis (Six), ...eyes absent (Eya) and dachshund (Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The purpose of the present study was to discriminate the Indian CAD ...patients with or without T2DM by using multiple pathophysiological biomarkers.
Using sensitive multiplex protein assays, we assessed 46 protein markers including cytokines/chemokines, metabolic hormones, adipokines and apolipoproteins for evaluating different pathophysiological conditions of control, T2DM, CAD and T2DM with CAD patients (T2DM_CAD). Network analysis was performed to create protein-protein interaction networks by using significantly (p < 0.05) altered protein markers in each disease using STRING 10.5 database. We used two supervised analysis methods i.e., between class analysis (BCA) and principal component analysis (PCA) to reveals distinct biomarkers profiles. Further, random forest classification (RF) was used to classify the diseases by the panel of markers.
Our two supervised analysis methods BCA and PCA revealed a distinct biomarker profiles and high degree of variability in the marker profiles for T2DM_CAD and CAD. Thereafter, the present study identified multiple potential biomarkers to differentiate T2DM, CAD, and T2DM_CAD patients based on their relative abundance in serum. RF classified T2DM based on the abundance patterns of nine markers i.e., IL-1β, GM-CSF, glucagon, PAI-I, rantes, IP-10, resistin, GIP and Apo-B; CAD by 14 markers i.e., resistin, PDGF-BB, PAI-1, lipocalin-2, leptin, IL-13, eotaxin, GM-CSF, Apo-E, ghrelin, adipsin, GIP, Apo-CII and IP-10; and T2DM _CAD by 12 markers i.e., insulin, resistin, PAI-1, adiponectin, lipocalin-2, GM-CSF, adipsin, leptin, Apo-AII, rantes, IL-6 and ghrelin with respect to the control subjects. Using network analysis, we have identified several cellular network proteins like PTPN1, AKT1, INSR, LEPR, IRS1, IRS2, IL1R2, IL6R, PCSK9 and MYD88, which are responsible for regulating inflammation, insulin resistance, and atherosclerosis.
We have identified three distinct sets of serum markers for diabetes, CAD and diabetes associated with CAD in Indian patients using nonparametric-based machine learning approach. These multiple marker classifiers may be useful for monitoring progression from a healthy person to T2DM and T2DM to T2DM_CAD. However, these findings need to be further confirmed in the future studies with large number of samples.
Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 ...Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D.
•Chronic graft-versus-host disease (cGVHD) is a common complication of hematopoietic cell transplantation.•cGVHD is an area of unmet need, as shown by treatment cycling and healthcare cost and ...resource utilization (HCRU).•This study quantifies US cGVHD prevalence, treatment patterns, and HCRU.•Use of therapies is variable for patients progressing past the first line of therapy.•This highlights the need for evidence-based treatment to address unmet needs.
Chronic graft-versus-host disease (cGVHD) is a complication of hematopoietic cell transplantation (HCT). Although the clinical outcomes of cGVHD are well documented, few studies have assessed treatment practices outside of clinical trials. The present study aimed to quantify the prevalence of cGVHD, examine provider prescribing patterns, and evaluate the healthcare cost and resource utilization (HCRU) in a US cGVHD population. We analyzed anonymized claims from the Medicare Fee-for-Service (FFS) 5% sample for beneficiaries enrolled between 2013 and 2016 and PharMetrics commercial 2013 to 2018 databases to identify cGVHD in allogeneic HCT recipients. cGVHD was identified based on International Classification of Diseases Ninth/Tenth Revision diagnosis codes for cGVHD or unspecified GVHD with a first diagnosis >180 days post-HCT or a maintained unspecified GVHD diagnosis for >12 months postindex of unspecified GVHD diagnosis. Longitudinal and line of therapy (LOT) analyses were based on the PharMetrics dataset for 2013 to 2018. Healthcare costs were calculated by adding the inpatient, outpatient, and pharmacy insurer and beneficiary paid amounts for the commercially insured population. Total HCRU was assessed using the number of inpatient and outpatient visits following the initial cGVHD diagnosis. In 2016, the projected prevalence of cGVHD in the United States based on the Medicare FFS and PharMetrics commercial databases was 14,017 individual patients. Within 3 years after undergoing allogeneic HCT, 42% of patients developed cGVHD; 66% of the cGVHD patients had a prior diagnosis of acute GVHD. The majority of cGVHD patients received at least one systemic therapy; 71% and 47% of cGVHD patients progressed to a second and third LOT, respectively. A total of 24 unique therapeutic agents and more than 150 combinations were used in the second and third LOTs. Corticosteroids and corticosteroid combination therapy were the most common forms of treatment across all examined LOTs. Furthermore, the most commonly used agents in the first LOT, second LOT, and third LOT were corticosteroids only, calcineurin inhibitors only, and corticosteroids only, respectively. In the 12 months postdiagnosis, cGVHD patients had an average of 21.0 cGVHD-related inpatient and outpatient visits (2.8 inpatient and 18.2 outpatient visits). A significant proportion of allogeneic HCT recipients continue to develop cGVHD, and despite advances in the understanding of cGVHD, corticosteroids remain the mainstay of therapy. Patients often progress beyond the first LOT, at which time the utilization of systemic therapies is highly variable, demonstrating the need for evidence-based treatment approaches.
This paper presents a new extension of the hesitant fuzzy linguistic term set (HFLTS) called intuitionistic fuzzy confidence-based HFLTS that associates an intuitionistic fuzzy value (IFV) with each ...linguistic term. The resulting term set is termed as intuitionistic fuzzy confidence hesitant fuzzy linguistic term set (IFCHFLTS). The previous studies on the linguistic decision making have emphasized little upon the preference and non-preference for each of the linguistic terms. This information, however, is crucial in multi-criteria decision making under uncertainty. In this regard, we find IFV particularly useful for qualifying each of the linguistic terms with the agent’s degree of preference, non-preference, and hesitation values. Besides, a new aggregation operator named intuitionistic fuzzy confidence linguistic simple weighted geometry (IFCLSWG) is also proposed to fuse decision makers’ linguistic preferences. Further, the criteria weights are estimated using a new method called intuitionistic fuzzy confidence linguistic standard variance. An approach is also suggested for ranking the given alternatives by adapting VIKOR under the proposed IFCHFLTS context. Finally, the practicality and usefulness of the proposal are demonstrated through two real-world problems in green supplier selection for manufacturing industry, and medical diagnosis. The strengths and weaknesses of the proposal are also highlighted by drawing upon a comparison with similar methods.
A great number of glacial lakes have appeared in many mountain regions across the world during the last half-century due to receding of glaciers and global warming. In the present study, glacial lake ...outburst flood (GLOF) risk assessment has been carried out in the Teesta river basin located in the Sikkim state of India. First, the study focuses on accurate mapping of the glaciers and glacial lakes using multispectral satellite images of Landsat and Indian Remote Sensing satellites. For glacier mapping, normalized difference snow index (NDSI) image and slope map of the area have been utilized. NDSI approach can identify glaciers covered with clean snow but debris-covered glaciers cannot be mapped using NDSI method alone. For the present study, slope map has been utilized along with the NDSI approach to delineate glaciers manually. Glacial lakes have been mapped by supervised maximum likelihood classification and normalized difference water index followed by manual editing afterwards using Google Earth images. Second, the first proper inventory of glacial lakes for Teesta basin has been compiled containing information of 143 glacial lakes. Third, analysis of these lakes has been carried out for identification of potentially dangerous lakes. Vulnerable lakes have been identified on the basis of parameters like surface area, position with respect to parent glacier, growth since 2009, slope, distance from the outlet of the basin, presence of supraglacial lakes, presence of other lakes in downstream, condition of moraine, condition of the terrain around them, etc. From these criterions, in total, 18 lakes have been identified as potentially dangerous glacial lakes. Out of these 18 lakes, further analysis has been carried out for the identification of the most vulnerable lake. Lake 140 comes out to be the most vulnerable for a GLOF event. Lastly, for this potentially dangerous lake, different dam break parameters have been generated using satellite data and digital elevation model. The volume and depth have been computed using empirical formulae, and other parameters such as cross-sections from the lake to outlet etc. have been prepared in ArcGIS 9.3. The GLOF which can be triggered by Lake 140 was modelled and simulated using MIKE-11 software's hydrodynamic module. As a result, flood values and hydrograph have been obtained. The flood at lake site comes out to be 2611.136 cumec which get mitigated to 1417.844 cumec at the outlet.
To determine the prevalence of sarcopenia obesity (SO) in healthy Indian adults and delineate the relative impact of the 3 indices of obesity body mass index (BMI), waist circumference (WC), fat mass ...percent (FM%) with regards to inter-definitional agreement and their relationship with usual gait speed (GS).
Apparently healthy adults (aged ≥ 20 years) with no background history of comorbidities were enrolled from the community by door-to-door survey. Following blood investigations, individuals with biochemical abnormalities were excluded. Enrolled participants underwent dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined according to EWGSOP2 consensus based on indigenous cut-offs obtained from the Sarcopenia-Chandigarh Urban Bone Epidemiological Study (Sarco-CUBES). Obesity was defined based on BMI (≥ 25.0 kg/m2) or WC (> 90 cm in men, > 80 cm in women) or DXA-derived FM% (> 32% in men, > 40% in women).
Data of 804 participants were analyzed after exclusion. The mean ± SD for BMI, WC, and FM% were 26.5 ± 2.7 kg/m2, 86.8 ± 9.6, and 34.7 ± 7.3%, respectively. Prevalence of sarcopenia was 3.2%. Based on BMI, WC, and FM%, the prevalence of SO in elderly subjects (≥65 years) was 5.4%, 5.4%, and 6.3%, respectively. Using Cohen’s kappa, inter-definitional agreement between the 3 groups was ‘almost perfect’. FM%, and not BMI/WC, emerged as a significant predictor of GS on multiple linear regression analysis.
The prevalence of SO in healthy elderly Indian adults is 5.4%–6.3%. Either BMI/WC/FM% can be used to correctly identify individuals with SO.
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