bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Characteristics of Light Chain Amyloidosis in an Underserved Patient Population
Authors: Samuel Nina , Shah Nishi
Published: December 2023

Background

Primary or light chain (AL) amyloidosis is the most common form of systemic amyloidosis in which insoluble fibrils are deposited in various tissues and can ultimately lead to multi-organ failure. It is commonly linked to plasma cell dyscrasias which lead to the overproduction and deposition of immunoglobin proteins. Due to multi-organ involvement and difficulty in diagnosing patients with light chain amyloidosis, these patients are faced with greater challenges present with extensive disease especially in an underserved patient population in the Bronx. Our aim was to report clinical characteristics of patients at a tertiary care center in the Bronx

Methods

A retrospective analysis of 29 patients with AL amyloidosis were evaluated at Montefiore Medical Center from 2008 until 2023 was performed to determine demographics, clinical characteristics, and outcome measures. Patient demographics such as age, sex, and race/ethnicity as well as organ involvement, mode of diagnosis, and disease staging were determined. The Mayo 2004 staging system was used for staging at the time of diagnosis.

Results

29 patients with AL amyloidosis were identified at Montefiore Medical center from 2008-2023, the median age of diagnosis was 63 (range 36-87). There were 18 men (62%) and 11 women (38%). Most of the female and male patients were black with 5 (45%) and 9 (50%) respectively. One third of the population were Hispanic. Out of all the patients, 11 (38%) had positive bone marrow biopsies at time of diagnosis and the most common organ involvement was cardiac with 21 patients at 72% of the data set. 11 had renal involvement (38%) and 9 (31%) had involvement of the gastrointestinal tract. 11 of the patients were stage 3 disease (38%) and 9 patients had stage 1 and 2 disease (31%) each. Majority of patients had lambda light chain involvement (55%). 2 patients had concurrent TTR amyloidosis. In terms of follow-up, 4 patients have died while 4 patients have been lost to follow-up.

Conclusion

Our study reports the extensive organ involvement in our patient population. A third of the patients present with Stage III AL amyloidosis with most patients having cardiac involvement. We aim to report specific outcomes for this patient population at the meeting.
Trials in Progress: A Phase I/II Clinical Trial of Off the Shelf Universal Donor Natural Killer Cells Combined with Chemotherapy for Treatment of Relapsed/Refractory Acute Myeloid Leukemia (KARMA)
Authors: Lamb Margaret , Guinipero Terri L. , Lee Dean Anthony
Published: December 2023

Background and Significance: Natural killer (NK) cells are cytotoxic lymphocytes that play a key role in recognizing malignant cells. In AML, qualitative and quantitative dysfunction of innate NK cells portends a poor prognosis and adoptive NK cell therapy has been shown to be safe and effective with minimal risk for GVHD (Ciurea et al. 2022; Silla et al. 2021). To circumvent cost and logistics restraints of per patient manufacture of NK cells, we developed a universal donor (UD) NK cell bank for “off-the-shelf” NK cells (UD FC21-NK cells). Donors with optimal NK cell characteristics are identified through the National Marrow Donor Program, and peripheral blood NK cells are expanded for two weeks by co-culture with irradiated K562 feeder cells expressing 4-1BB ligand and membrane bound IL-21 as previously described (Denman et al. 2012). We seek to study the safety and efficacy of multiple doses of UD FC21-NK cells combined with fludarabine and cytarabine (FLA) chemotherapy in patients with relapsed or refractory AML.

Study Design and Methods: This open label, single-center phase I/II study will include a dose escalation phase to establish safety and determine the recommended phase II dose followed by an expansion phase to estimate efficacy (complete response rate and MRD negative response rate). Up to 20 patients ages 18-25 with relapsed or refractory AML, including isolated extramedullary disease, will be enrolled. Exclusion criteria include active GVHD, uncontrolled infections, hematopoietic stem cell transplant within 3 months of enrollment, and donor lymphocyte infusion within 30 days of enrollment. Patients will undergo FLA chemotherapy followed by six doses of UD FC21-NK cells given thrice weekly for two weeks (Figure 1). Dose levels include 1 x 10 7 UD FC21-NK cells/kg/dose, 3 x 10 7 UD FC21-NK cells/kg/dose, and 1 x 10 8 UD FC21-NK cells/kg/dose. Patients may receive up to 2 cycles if they do not achieve a CR after cycle 1 or if necessary to bridge to transplant. Peripheral blood samples will be drawn weekly for immune correlatives including in vivo NK cell expansion and persistence. The trial is currently open to enrollment to adult patients with the intent to expand to pediatrics after demonstrating preliminary safety. Clinical trial information: NCT05503134
Examining Racial Disparities in Multiple Myeloma Research and Treatment
Authors: Petit Ryan , Cusnir Mike
Published: December 2023

Multiple myeloma (MM) is a disease which occurs in all races, geographic locations, and ethnicities, however the burden of this cancer is especially prominent in the African American/Black population with prevalence estimated to be as high as two to three times that of the White population. As a result MM is the most common hematological malignancy in Black patients. Despite a higher disease burden, this population suffers disproportionate rates of mortality. From 2017-2022 Black men had a 6% higher incidence rate than White men, but a 19% higher mortality rate. This disparity in outcomes between ethnic groups is likely multifactorial. Some explanations include novel therapy underutilization, or prevalence of comorbid conditions. It may also be attributable to biological differences, such as an increase rate of immunoglobin A disease, and an increased rate of chromosome 14 translocations. There may as a result be a heterogenous response to novel MM therapy. Unfortunately, clinical trial participation of Black patients has been significantly underrepresented. Studies that sought to analyze the results of novel therapy trials in this population found a trend towards decreased efficacy, however, were unable to reach significance due to insufficient study participation.

We conducted a pooled analysis of interventional phase III clinical trials obtained from ClinicalTrials.gov data from 01/01/2000 to 12/31/2022. Studies who did not include racial/ethnicity data were excluded. There were 34 trials included in total that met this criteria and included in this analysis. There were 16,405 total enrolled patients analyzed. 13,618 (83.01%) were White, 1,255 (9.21%) were Asian, 777 (4.74%) were Black/African American, and 454 (2.7%) identified as Hispanic, with the remaining identified as other. Study participation was analyzed over time. Percentage of patients enrolled by year showed a negative correlation in Black/African Americans over the analyzed period.

Our analysis suggests greater efforts need to be made to ensure the enrollment of a more diverse and representative MM population. Although this disease is roughly twice as prevalent in Black populations, clinical trial study participation since 2003 involved 18-times more White than Black patients. Despite ongoing recognition of this problem, study participation in MM has continued to remain largely homogenous. Interventions that may improve this problem include fostering and rebuilding trust in the clinical trial system that was damaged from historical abuses, expanding clinical sites to more diverse areas, expanding/revising eligibility criteria, and employing changes to enrollment techniques that better represent the demographics of the population intended to treat. Ultimately, the clinical trials for an intervention should appropriately reflect the population who will use it, otherwise these novel treatments may have unexpected heterogeneity in efficacy and safety once employed clinically.
Inhibition of NOTCH4 Sensitizes FLT3/ITD Acute Myeloid Leukemia Cells to FLT3 Tyrosine Kinase Inhibition
Authors: Zhu Ruiqi , Shirley Courtney , Chu Haihua , Li Li , Nguyen Bao , Seo Jaesung , Seale Tessa , Duffield Amy , Staudt Louis M. , Levis Mark J. , Hu Yu , Small Donald
Published: December 2023

Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cell lines, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or g-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cell lines and patient samples. NOTCH4 inhibition also sensitized TKI-resistant FLT3/ITD cell lines to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in the expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML patients with FLT3/ITD mutations.
Demographic Disparities in Clinical Trial Enrollment of US Patients with Newly-Diagnosed Multiple Myeloma
Authors: Costa Bruno Almeida , Debnath Neha , Costa Thomaz Alexandre , Bertasi Raphael , Mouhieddine Tarek H. , Nath Karthik , Rossi Adriana C
Published: December 2023

Background: Racial, ethnic and gender disparities impact the real-world reproducibility of clinical trials leading to drug approvals for hematologic malignancies. Interestingly, a prior abstract (Boisclair et al., 2022) has shown an equitable enrollment between US demographic groups in frontline trials for newly-diagnosed non-Hodgkin lymphoma. Although disparities in multiple myeloma (MM) trial participation have been oftentimes demonstrated, prior studies (Kanapuru et al., 2022; Alqazaqi et al., 2022) predominantly involved patients with relapsed/refractory MM (RRMM). To further assess this gap, we conducted a cross-sectional analysis of US demographic representation in phase II or III trials for newly-diagnosed MM (NDMM).

Methods: Clinicaltrials.gov was searched for completed NDMM trials with a recruitment period between 01/01/2007-12/31/2020. Studies limited to phase I data (n=10), enrolling <30 patients (n=35), including RRMM or other malignancies (n=18), and/or recruiting outside the US (n=93) were excluded. We subdivided patients according to gender, race, and ethnicity. For each subgroup, total new cases of MM from 2007-2020 were identified via the Surveillance, Epidemiology and End Results (SEER) Cancer Statistics Explorer Network, with subsequent calculation of a trial enrollment fraction (TEF; number of trial enrollees divided by incident US cases). Pearson's chi-square test was used to compare TEF between subgroups, yielding odds ratio (OR) and 95% confidence interval (95%CI) values, with P<0.05 deemed significant.

Results: Among the 194 trials found on initial review, 25 met the established criteria for inclusion (Figure 1). All studies (n=3,559) described the participants' gender, while only 18 (72%; n=3,129) reported race and 9 (36%; n=2,319) reported ethnicity. Overall, women showed a significantly lower TEF compared to men (OR, 0.88; 95%CI, 0.82-0.94; P<0.001). When compared to White Americans, TEF was significantly lower for African Americans (OR, 0.71; 95%CI, 0.64-0.78; P<0.001) and Asian Americans/Pacific Islanders (AAPIs; OR, 0.64; 95%CI, 0.22-0.41; P<0.001). In studies reporting ethnicity, TEF was significantly lower for Hispanics compared to non-Hispanics (OR, 0.18; 95%CI, 0.14-0.24; P<0.001).

Conclusion: Our cross-sectional analysis reveals an underrepresentation of women, African Americans, AAPIs, and Hispanics in NDMM trials conducted around the US. These findings are complementary to the enrollment disparities previously shown in RRMM trials. Through the implementation of a comprehensive diversity plan, MM trials must include a more inclusive representation of the US population affected by this blood cancer. Such an approach will not only enhance the external validity of these trials but also mitigate the impact of ascertainment bias and promote healthcare equity.
Erythrocyte Intracellular Adenosine Regulates Oxygen Release Combating Tissue Hypoxia, Inflammation and Fibrosis
Authors: Chen Changhan , Xie Tingting , Zhang Yujin , Wang Yiyan , Yu Fang , Lin Lizhen , Zhang Weiru , Brown Benjamin C. , Zhang Xin , Kellems Rodney E. , D'Alessandro Angelo , Xia Yang
Published: December 2023

Hypoxia is considered a common cause of myriad diseases and drives tissue damage and progression. Erythrocytes are vital under hypoxia since they can sense and act rapidly to hypoxia by promoting metabolomic reprogramming and oxygen (O 2) release. Adenosine monophosphate deaminase 3 (AMPD3) is highly enriched in erythrocytes and plays an important role in maintaining erythrocyte intracellular purine homeostasis. However, how it senses and regulates oxygen release remains poorly understood. Here we report that genetic ablation of AMPD3 led to more O 2 release from erythrocytes, resulting in less tissue hypoxia, damage, inflammation and fibrosis in two independent pathological hypoxia models including Angiotensin II infusion and unilateral ureteric obstruction (UUO) models. Metabolically, untargeted high-throughput metabolomic profiling in erythrocytes revealed that nucleotides including AMP, ADP and ATP levels were significantly increased in WT mice and further elevated in Ampd3 -/-mice. Isotopically adenosine flux experiment demonstrated that adenosine was rapidly and largely converted to AMP. At molecular level, we further demonstrated that hypoxia-induced AMPD3 activity as a compensatory mechanism led to accumulation of AMP, subsequently inducing AMP kinase (AMPK)-dependent metabolic reprogramming by inducing bisphosphoglycerate mutase (BPGM), which shifts glycolysis toward erythroid unique Rapoport-Leubering Shunt (RSL) to promote 2,3-BPG production, O 2 delivery and anti-ROS capacity to mitigate tissue hypoxia, dysfunction, inflammation and fibrosis. At cellular level, we revealed that hypoxia directly inhibited AMPD3, leading to activation of AMPK by lowering ROS in both cultured primary human and murine erythrocytes. Finally, we conducted human translational studies demonstrating that the production of 2,3-BPG, BPGM activity, p-AMPK level, and P50 were increased, while AMPD3 activity was decreased in patients with chronic kidney disease (a common pathological condition) compared with normal controls. Altogether, eAMPD3is a previously unrecognized master intracellular purinergic componentsensing hypoxia and promoting adaptative metabolic reprogramming tomitigate tissue hypoxia, insufficient energy, tissue damage and fibrosis by enhancing O 2 delivery and antioxidative stress capacity in a positive feedforward manner.
Tranexamic Acid for Trauma Care: An Updated Meta-Analysis of Mortality and Thromboembolic Events in Severely Injured Patients
Authors: Shafique Nouman , Akbar Usman Ali , Umer Ahmed Muaaz , Kumar Besham , Muhibullah Fnu , Siddiqui Fakeha , Vikash Sindhu , Nethagani Sanjana , Rizwan Umer
Published: December 2023

Introduction : Tranexamic Acid (TXA) is an anti-fibrinolytic agent that inhibits fibrinolysis and prevents blood clot breakdown. Widely used to manage hemorrhage in various clinical scenarios, including trauma, menorrhagia, bleeding in hemophilia, cardiac surgery, and orthopedic surgery, its impact on morbidity and mortality in severely injured patients necessitates an updated systematic review and meta-analysis. Our study aimed to evaluate the association of TXA with mortality and thromboembolic events in trauma patients.

Methods: We conducted a comprehensive literature search on PubMed, EMBASE, CENTRAL, and Google Scholar up to July 2023, focusing on randomized controlled trials (RCTs) involving adult trauma patients receiving Tranexamic Acid (TXA) compared to standard care or placebo. Primary outcomes included mortality rates and thromboembolic event incidence. Statistical analyses used Review Manager Software (RevMan, version 5.3) with the Mantel-Haenszel random-effect model.

Results : A total of 8 randomized controlled trials (RCTs) with 36,416 patients were included in this meta-analysis, comparing Tranexamic Acid (TXA) to control (placebo or standard care). The mean age of the included patients was 39 years. The analysis focused on various patient categories, including multiple trauma versus predominantly traumatic brain injury (TBI) patients, severely injured ( Injury Severity Score ,ISS ≥ 16, massive transfusion requirement, signs of shock) versus non-severely injured patients, blunt versus penetrating versus burn trauma, in-hospital versus prehospital TXA administration, and TXA administration within 3 hours versus beyond 3 hours of injury. The meta-analysis showed that TXA administration was not significantly associated with mortality (odds ratio: 0.98, 95% CI: 0.76 to 1.27, p = 0.89), with moderate heterogeneity observed (I 2 = 56%). However, TXA use demonstrated a significant reduction in the incidence of thromboembolic events (odds ratio: 0.90, 95% CI: 0.84 to 0.95, p = 0.0002), with no significant heterogeneity (I 2 = 0%). (Figure 1 & 2)

Conclusion TXA administration was not significantly associated with mortality in patients with significant trauma; however, it significantly reduced thromboembolic events, suggesting its potential benefit in preventing such complications. Further research is needed to explore its efficacy and safety in specific patient categories and administration settings to optimize its use in trauma care.
Incidence, Clinical Features, and Outcomes of Large Granular Lymphocyte Leukemia
Authors: Budhathoki Pravash , Shah Anish , Karki Ujjwal , Neupane Niraj , Shah Sabita , Kariamanickam Karthickrajkumar
Published: December 2023

Introduction: -

Large Granular Lymphocyte (LGL) leukemia is a rare and diverse hematologic disorder characterized by the clonal proliferation of large granular lymphocytes in the peripheral blood and bone marrow. Despite its rarity, population-based studies on LGL leukemia remain limited. This study aims to comprehensively analyze clinical characteristics and outcomes among patients with LGL leukemia.

Methods: -

We utilized the Surveillance, Epidemiology, and End Results (SEER) database 17 registry to identify patients diagnosed with large granular lymphocytic leukemia between 2000-2020. Data analysis was conducted using SEER*Stat version 8.4.1.2 and STATA. Univariate survival analysis was done using a Kaplan Meir plot with a log-rank test, and the Cox proportion hazard regression model was used for multivariate survival analysis.

Results: -

We identified a total of 2,589 LGL leukemia cases during the study period. The calculated incidence of LGL leukemia was 0.14 cases per 1,000,000 individuals (range: 0.14 - 0.15). Male patients exhibited a higher incidence rate ratio of 1.19 (95% CI: 1.11 - 1.27, p < 0.01) than females. However, females tended to be diagnosed younger than males (67 vs. 68, p < 0.01). Most cases were observed in the White population (83%) compared to other racial groups. The median age at diagnosis was 67 years (ranging from 7 to 85 years). Patients aged above 70 years showed the highest incidence of LGL leukemia (0.80) in contrast to those aged 45-54 years (0.30) and 55-64 years (0.63). Notably, there was a significant increasing trend in LGL leukemia incidence, with an incidence rate ratio of 13.50 (95% CI: 10.5-17.6, p < 0.001) in the period 2015-2019 compared to 2000-2004.

Approximately 32.7% of patients received chemotherapy; the median time from diagnosis to treatment was one month. The survival rates at 12, 36, and 60 months for LGL leukemia patients were 88.9%, 76.5%, and 66.5%, respectively, with a median follow-up of 40 months. Multivariate analysis revealed that females had a more favorable survival outcome than males (HR: 0.78, 95% CI: - 0.64 - 0.97, p: 0.02). Moreover, patients who underwent chemotherapy exhibited better survival than those who did not (HR: 0.72, 95% CI: 0.56 - 0.93, p: 0.01). Elderly patients above 60 years of age had poorer survival rates (HR: 3.1, 95% CI: 2.34 - 4.01, p < 0.01), and no significant difference in outcomes was observed based on the timing of chemotherapy initiation from the time of diagnosis.

Conclusion: -

This study represents the most extensive and most recent population-based investigation of LGL leukemia. The findings highlight the potential benefits of chemotherapy in improving survival and indicate better outcomes in female patients. Further research is warranted to validate these promising results and gain deeper insights into the management and prognosis of LGL leukemia.
Hypertension and Related-Disorders in Hodgkin Lymphoma Patients Identified from Epic Cosmos System
Authors: Mariano John , Gleber Conrad , Casulo Carla
Published: December 2023

Recent advancements in Hodgkin lymphoma (HL) treatment have significantly improved disease-free survival rates. However, survivors face a higher burden of long-term comorbidities and non-oncologic mortality compared to their peers. Studying survivorship has been challenging due to the time required for comorbidities to develop, patient loss to follow-up, variable disease-specific treatments, and variations across age groups of survivors. In this context, the Cosmos system offers a validated population-based informatics approach to establishing observational relationships between therapy and longitudinal non-oncologic outcomes, with the potential to enhance clinical care.

Cosmos, a data science tool based on the Epic Electronic Medical Record (EMR) system, utilizes a HIPAA-defined limited centralized data set from various US health care systems. At the time of this submission, the data set encompasses 152,450,619 patients. A query population of 89,963 HL patients with more than one face-to-face encounter within any two-year period during the query interval was established. Validated associated ICD-10 diagnoses were assessed within the Cosmos system.

The query revealed that HL patients had a median age of 56, with a male predominance (51.8%), and 35% were diagnosed between the ages of 15 and 39. Staging information was available for only 10% of patients. The most common comorbid diagnoses defined by ICD-10 were essential hypertension (45.4%), hyperlipidemia (36.1%), anemia (32.1%), GERD (32.1%), shortness of breath (31.4%), fatigue (30.1%), non-HL (30%), cough (26.3%), and anxiety (25.6%).

Further assessment of hypertension and associated disorders was conducted by querying Epic grouper terms in comparison to the general Cosmos population. The HL population had a higher prevalence of hypertension (46.1% vs. 24.5%), chronic kidney disease (14.9% vs. 5%), hypertensive renal disease (10.1% vs. 3.1%), hyperlipidemia (44% vs. 21.1%), coronary artery disease (20.7% vs. 6.2%), ischemic or unspecified stroke (4.4% vs. 1.6%), and myocardial infarction (9.6% vs. 2.8%). Notably, death dates were documented for 12.5% of the HL population (compared to 3% in the general Cosmos population), but cause of death information was limited (0.028%).

EMR informatics presents a powerful tool for rapidly generating real-time observational data, which can inform focused studies and interventions. Such data is crucial for understanding trends in treatment-related morbidity and mortality in diseases like HL, which can impact future health in survivorship. This study suggests that hypertension and related disorders may be more prevalent in the HL population compared to the general Cosmos population, warranting further directed study and validation in the future.
Differential Effect of Transferrin Lobe Iron Occupancy on a Murine Model of Inflammation
Authors: Parrow Nermi L. , George Nisha Ajit , Ali Faris , Wattad Nadia , Guerra Amaliris , Ginzburg Yelena , Rivella Stefano , Fleming Robert E.
Published: December 2023

Introduction: Iron status is both affected by and a determinant of the inflammatory response. Several lines of evidence support a role for transferrin as a signaling as well as an iron delivery molecule. We previously demonstrated that mice with transferrin mutations that prevent iron binding to the C-lobe of transferrin (C-blocked) have increased red cell production relative to erythropoietin and increased hepcidin expression relative to iron status compared to mice with transferrin mutations that prevent iron binding to the N-lobe of transferrin (N-blocked). Based on these observations, we hypothesize that two forms of transferrin would differentially modulate the hematopoietic and iron distribution changes that occur with inflammation. We explored this hypothesis by comparing the effects of lipopolysaccharide (LPS) administered either acutely or in repeated doses to wild-type, N-lobe blocked, or C-lobe blocked transferrin mutant mice.

Methods: For a model of acute inflammation, 14 day old wild-type (wt), N-blocked and C-blocked Tf mutant mice were treated with 1mg/kg LPS or carrier i.p. and sacrificed 6 hours later. Repeated LPS dosing, seven daily i.p. injections of 0.3 mg/kg LPS or carrier beginning at seven days of age, served as a model of chronic inflammation.

Results: While wild-type and C-blocked mice had the expected hypoferremia in response to acute LPS administration, there was no effect on serum iron in the N-blocked mice. These mice moreover demonstrated an unanticipated increase in liver iron concentrations with LPS. All strains manifested expected increases in liver hepcidin expression; however, these were attenuated in the N-blocked mice relative to the C-blocked. Moreover, N-blocked mice have higher serum C reactive protein concentrations compared to C-blocked and wt mice following acute LPS administration. The elevated Hamp1 expression was not sustained in the chronic model. Although serum iron returned to baseline in wt and C-blocked mice, it remained elevated in N-blocked mice. Hemoglobin concentrations were decreased in all strains after repeated endotoxin dosing; however, C-blocked mice demonstrated higher neutrophil to lymphocyte ratios than wt or N-blocked mice, and increased circulating RBC count relative to WBCs.

Conclusions: We conclude that the specificity of transferrin lobe iron occupancy is an important modulator of the inflammatory response and speculate that this modulation includes an effect on hematopoietic cell lineage determination.
Normative Data of Beta-2-Microglobulin and Plasma Proteins from an Agrarian Indian Community By a Door-to-Door Survey: Results of Simple (IMAGe-002B) Study
Authors: Vashishth Yash , Yanamandra Uday , Bobdey Saurabh , Sharma Vaibhav , Bhatti V K , Muthukrishnan J , Malhotra Pankaj , Nair Velu
Published: December 2023

Introduction: Most diagnostic laboratories in India follow the reference intervals given in Western literature whose Caucasian reference population is entirely different from the Indian ethnic population (viz., dietary habits, lifestyle, socioeconomic status, ethnicity, and environmental factors).

Objectives: To collate normative data of beta-2-microglobulin (β2M) and plasma proteins from an otherwise healthy population from an agrarian Indian Community. The secondary objectives were to evaluate the correlation of β2M levels with age, gender, and BMI of these individuals.

Methods: A cross-sectional study was conducted in an agrarian village in India with a 24.76Km perimeter and 4588.3 hectares with an 89.2% population coverage for adults (>45y) spending 12096 man-hours. This was a part of SIMPLe (Screening Intervention for Myeloma and Prevention of Lifestyle diseases) study registered vide CTRI/2023/03/051220 after obtaining informed consent. Demographic details, medical history, and blood samples were collected after a thorough medical examination to ascertain the normal health status of the study participants. Hemogram, biochemistry (Liver and renal function tests), β2M, and serum protein electrophoresis (SPEP) were performed in all individuals. Only individuals with normal renal and liver function tests were included in the final analysis. Bivariate analysis (Fit Y by X) was done to study the correlations. Any p value < 0.05 was considered significant. The data was analyzed using JMP ver. 16.0.0.

Results: A total of 850 individuals were included in this community-based door-to-door survey. The mean age of the study population was 57.6±10.5y, with a slight female predominance (56.3%). The distribution of β2M and various plasma proteins is mentioned in Table 1. The β2M significantly differed between males and females (χ 2-8.58; dF-1; p-0.0034). On bivariate analysis, β2M was significantly associated with age (correlation coefficient: 0.31; p<0.0001), and BMI (correlation coefficient -0.07; p-0.023).

Conclusion: The data obtained from our studies would act as the first step in collating normative data for β2M and plasma proteins from Indian community.
Ultra-Low-Dose of Decitabine with Venetoclax As Induction and Consolidation Therapy for Elderly or Frail Newly Diagnosed Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome Patients
Authors: Zheng Weiyan , Fu Shan , Luo Xuepin , Zhu Yuanyuan , Huang He
Published: December 2023

Background: Venetoclax with hypomethylating agents is a new standard of care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine which has shown promising results in high-risk AML in phase 2 trials. We hypothesized that venetoclax with 10-day decitabine may be effective in ND and secondly AML/MDS, particularly for high-risk subgroups.

Methods: We retrospectively analyzed 45 patients with ND AML, secondary AML (sAML), or high-risk MDS who was older than 60 years or unfit for intensive chemotherapy due to frail / due to the COVID-19 pandemic. Patients were required adequate end-organ function. Patients received decitabine (6mg/m2 IV for 10-days) with oral venetoclax (400mg daily for 3 weeks (D10+VEN)) for induction, followed by the same chemo-free regimen for consolidation if patients responsed to induction therapy. The primary efficacy endpoint was overall response rate (ORR). The second endpoint was overall survival (OS) and progress free survival (PFS).

Findings: Between January, 2020 and July , 2023, 45 patients were treated with this regimen, 31 (68.9%) had ND AML, 8 patients (17.8%) had untreated sAML, 6 patients (13.3%) had untreated high-risk MDS. The median age was 65 years (IQR, 59-69) and 26(57.8%) patients had ECOG performance status of 3 or higher. The ORR among all patients was 82.2% and in disease subgroups were: ND AML, 87.1% (27/31) (95% CI 79, 94); untreated sAML, 75% (6/8); untreated high-risk MDS, 66.7%(4/6). According 2022 ELN risk classification by genetics, the ORR in favorable risk patients was 87.5%(7/8), intermediate risk patients was 100%(12/12), adverse risk patients was 72%(18/25). The most common treatment-emergent adverse events included infections with grade 3/4 neutropenia (n=36, 80%) and febrile neutropenia (n=7, 15.6%). There were 2 grade 5 adverse events including one infections with Enterobacter cloacae Bacteremias combined with heart failure because of the shortage of Blood product transfusion during the COVID-19 pandemic, and one case of intracranial hemorrhage related to prolonged grade 3/4 thrombocytopenia. The one year OS of all patients was 71.9%(23/32), and in favorable risk patients was 83.3% (5/6), intermediate risk patients was 72.7%(8/11), adverse risk patients was 73.3%(11/15). The two-year OS of all patients was 58.3%(7/12).

Conclusion: Ultra-low-dose of ten-day decitabine with venetoclax as induction and consolidation chemo-free therapy in elderly or frail newly diagnosed acute myeloid leukemia and high risk myelodysplastic syndrome result in high overall response rate and high 1-year overall survivial.
Venetoclax–based low intensity therapy in molecular failure of NPM1-mutated AML
Authors: Jimenez-Chillon Carlos , Othman Jad , Taussig David , Jimenez-Vicente Carlos , Martinez-Roca Alexandra , Tiong Ing Soo , Jain Manish , Aries James , Cakmak Seda , Knapper Steven , Kristensen Daniel Tuyet , Murthy Vidhya , Galani Joy Zacharoula , Kallmeyer Charlotte , Ngu Loretta , Veale David , Bolam Simon , Orfali Nina , Parker Anne , Manson Cara , Parker Jane , Erblich Thomas , Richardson Deborah , Mokretar Katya , Potter Nicola , Overgaard Ulrik Malthe , Roug Anne Stidsholt , Wei Andrew H. , Esteve Jordi , Jädersten Martin , Russell Nigel , Dillon Richard
Published: December 2023

Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax–based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.
Quantitative proteomics analysis based on data-independent acquisition reveals the effect of Shenling Baizhu powder (SLP) on protein expression in MAFLD rat liver tissue
Authors: Song Sufei , Zheng Jixian , Zhao Dongmei , Zheng Anni , Zhu Ye , Xu Qiuling , Liu Tao
Published: December 2023

Background

Metabolic associated fatty liver disease (MAFLD) has become the most common chronic liver disease worldwide, and it is also a high-risk factor for the development of other metabolic diseases. Shenling Baizhu powder (SLP) is a traditional Chinese herbal formula with good clinical efficacy against MAFLD. However, its molecular mechanism for the treatment of MAFLD is still not fully understood. This study used quantitative proteomics analysis to reveal the SLP action mechanism in the treatment of MAFLD by discovering the effect of SLP on protein expression in the liver tissue of MAFLD rats.

Materials and methods

Q-Orbitrap LC–MS/MS was used to identify the incoming blood compounds of SLP. The 18 SD male rats were randomly divided into 3 groups (n = 6): control group, HFD group and SLP group. The HFD group and SLP group were established as MAFLD rat models by feeding them a high-fat diet for 4 weeks. Afterwards, the SLP group was treated with SLP (10.89 g/kg/d) for 3 weeks. Biochemical parameters and liver pathological status were measured. Rat liver tissue was analyzed using DIA-based quantitative proteomics and the DEPs were validated by western blotting analysis.

Results

A total of 18 active compounds of SLP were identified and isolated to enter the bloodstream. Comparison of DEPs between control group vs. HFD group and HFD group vs. SLP group revealed that SLP restored the expression of 113 DEPs. SLP catalyzes oxidoreductase activity and binding activity on mitochondria and endoplasmic reticulum to promote lipid oxidative catabolism, maintain oxoacid metabolic homeostasis in vivo and mitigate oxidative stress-induced hepatocyte injury. And 52 signaling pathways including PPAR signaling, arachidonic acid metabolism and glycine, serine and threonine metabolism were enriched by KEGG. PPI topology analysis showed that Cyp4a2, Agxt2, Fabp1, Pck1, Acsm3, Aldh1a1, Got1 and Hmgcs2 were the core DEPs. The western blotting analysis verified that SLP was able to reverse the increase in Fabp1 and Hmgcs2 and the decrease in Pck1 induced by HFD, and the results were consistent proteomic data.

Conclusion

SLP ameliorates hepatic steatosis to exert therapeutic effects on MAFLD by inhibiting the expression of lipid synthesis genes and inhibiting lipid peroxidation in mitochondria. This study provides a new idea and basis for the study of SLP in the treatment of MAFLD and provides an experimental basis for the clinical application of SLP.
Association between fatty acid metabolism gene mutations and Mycobacterium tuberculosis transmission revealed by whole genome sequencing
Authors: Li Yameng , Kong Xianglong , Li Yifan , Tao Ningning , Wang Tingting , Li Yingying , Hou Yawei , Zhu Xuehan , Han Qilin , Zhang Yuzhen , An Qiqi , Liu Yao , Li Huaichen
Published: December 2023

Background

Fatty acid metabolism greatly promotes the virulence and pathogenicity of Mycobacterium tuberculosis (M.tb). However, the regulatory mechanism of fatty acid metabolism in M.tb remains to be elucidated, and limited evidence about the effects of gene mutations in fatty acid metabolism on the transmission of M.tb was reported.

Results

Overall, a total of 3193 M.tb isolates were included in the study, of which 1596 (50%) were genomic clustered isolates. Most of the tuberculosis isolates belonged to lineage2(n = 2744,85.93%), followed by lineage4(n = 439,13.75%) and lineage3(n = 10,0.31%).Regression results showed that the mutations of gca (136,605, 317G > C, Arg106Pro; OR, 22.144; 95% CI, 2.591-189.272), ogt(1,477,346, 286G > C ,Gly96Arg; OR, 3.893; 95%CI, 1.432–10.583), and rpsA (1,834,776, 1235 C > T, Ala412Val; OR, 3.674; 95% CI, 1.217–11.091) were significantly associated with clustering; mutations in gca and rpsA were also significantly associated with clustering of lineage2. Mutation in arsA(3,001,498, 885 C > G, Thr295Thr; OR, 6.278; 95% CI, 2.508–15.711) was significantly associated with cross-regional clusters. We also found that 20 mutation sites were positively correlated with cluster size, while 11 fatty acid mutation sites were negatively correlated with cluster size.

Conclusion

Our research results suggested that mutations in genes related to fatty acid metabolism were related to the transmission of M.tb. This research could help in the future control of the transmission of M.tb.
An attacin antimicrobial peptide, Hill_BB_C10074, from Hermetia illucens with anti-Pseudomonas aeruginosa activity
Authors: Fahmy Leila , Ali Youssif M. , Seilly David , McCoy Reece , Owens Róisín M. , Pipan Miha , Christie Graham , Grant Andrew J
Published: December 2023

Background

There is a global need to develop new therapies to treat infectious diseases and tackle the rise in antimicrobial resistance. To date, the larvae of the Black Solider Fly, Hermetia illucens, have the largest repertoire of antimicrobial peptides derived from insects. Antimicrobial peptides are of particular interest in the exploration of alternative antimicrobials due to their potent action and reduced propensity to induce resistance compared with more traditional antibiotics.

Results

The predicted attacin from H. illucens, Hill_BB_C10074, was first identified in the transcriptome of H. illucens populations that had been fed a plant-oil based diet. In this study, recombinant Hill_BB_C10074 (500 µg/mL), was found to possess potent antimicrobial activity against the serious Gram-negative pathogen, Pseudomonas aeruginosa. Sequence and structural homology modelling predicted that Hill_BB_C10074 formed a homotrimeric complex that may form pores in the Gram-negative bacterial outer membrane. In vitro experiments defined the antimicrobial action of Hill_BB_C10074 against P. aeruginosa and transmission electron microscopy and electrochemical impedance spectroscopy confirmed the outer membrane disruptive power of Hill_BB_C10074 which was greater than the clinically relevant antibiotic, polymyxin B.

Conclusions

Combining predictive tools with in vitro approaches, we have characterised Hill_BB_C10074 as an important insect antimicrobial peptide and promising candidate for the future development of clinical antimicrobials.
Humoral and T cell responses to SARS-CoV-2 reveal insights into immunity during the early pandemic period in Pakistan
Authors: Masood Kiran Iqbal , Qaiser Shama , Abidi Syed Hani , Khan Erum , Mahmood Syed Faisal , Hussain Areeba , Ghous Zara , Imtiaz Khekahsan , Ali Natasha , Hasan Muhammad , Memon Haris Ali , Yameen Maliha , Ali Shiza , Baloch Sadaf , Lakhani Gulzar , Alves Paula M. , Iqbal Najeeha Talat , Ahmed Kumail , Iqbal Junaid , Bhutta Zulfiqar A. , Hussain Rabia , Rottenberg Martin , Simas J. Pedro , Veldhoen Marc , Ghias Kulsoom , Hasan Zahra
Published: December 2023

Background

Protection against SARS-CoV-2 is mediated by humoral and T cell responses. Pakistan faced relatively low morbidity and mortality from COVID-19 through the pandemic. To examine the role of prior immunity in the population, we studied IgG antibody response levels, virus neutralizing activity and T cell reactivity to Spike protein in a healthy control group (HG) as compared with COVID-19 cases and individuals from the pre-pandemic period (PP).

Methods

HG and COVID-19 participants were recruited between October 2020 and May 2021. Pre-pandemic sera was collected before 2018. IgG antibodies against Spike and its Receptor Binding Domain (RBD) were determined by ELISA. Virus neutralization activity was determined using a PCR-based micro-neutralization assay. T cell – IFN-γ activation was assessed by ELISpot.

Results

Overall, the magnitude of anti-Spike IgG antibody levels as well as seropositivity was greatest in COVID-19 cases (90%) as compared with HG (39.8%) and PP (12.2%). During the study period, Pakistan experienced three COVID-19 waves. We observed that IgG seropositivity to Spike in HG increased from 10.3 to 83.5% during the study, whilst seropositivity to RBD increased from 7.5 to 33.3%. IgG antibodies to Spike and RBD were correlated positively in all three study groups. Virus neutralizing activity was identified in sera of COVID-19, HG and PP. Spike reactive T cells were present in COVID-19, HG and PP groups. Individuals with reactive T cells included those with and without IgG antibodies to Spike.

Conclusions

Antibody and T cell responses to Spike protein in individuals from the pre-pandemic period suggest prior immunity against SARS-CoV-2, most likely from cross-reactive responses. The rising seroprevalence observed in healthy individuals through the pandemic without known COVID-19 may be due to the activation of adaptive immunity from cross-reactive memory B and T cells. This may explain the more favourable COVID-19 outcomes observed in this population.
Latencies to the first interictal epileptiform discharges recorded by the electroencephalography in different epileptic patients
Authors: Liu Chenyu , Qi Yi , Wang Liang , Zhang Ce , Kang Li , Shang Suhang , Dang Jingxia
Published: December 2023

Purpose

Interictal epileptiform discharges (IEDs) captured in electroencephalography (EEG) have a high diagnostic value for epileptic patients. Extending the recording time may increase the possibility of obtaining IEDs. The purpose of our research was to determine how long it took for various epileptic individuals to receive their first IEDs.

Methods

We retrospectively analyzed patients who were diagnosed with epilepsy and had no anti-seizure medications (ASMs) between September 2018 and March 2019 in the neurology department of the First Affiliated Hospital of Xi'an Jiaotong University. Each individual underwent a 24-h long-term video electroencephalographic monitoring (VEM) procedure. Clinical information including age, gender, age of seizure onset, frequency of seizures, the interval between last seizure and VEM, and results of neuroimaging were gathered. We also calculated the times from the start of the VEM to the first definite IEDs.

Results

A total of 241 patients were examined, including 191 with focal-onset epilepsy and 50 with generalized epilepsy. In individuals with focal-onset epilepsy, the median latency to the first IED was 63.0 min (IQR 19.0–299.0 min), as compared to 30.0 min (IQR 12.5–62.0 min) in patients with generalized epilepsy (p < 0.001). The latency to the first IED is significantly related to the age of seizure onset (HR = 0.988, p = 0.049), the interval between last seizure and VEM (HR = 0.998, p = 0.013). But it is not correlated with seizure frequency, gender and age.

Conclusions

IEDs were discovered during 24-h EEG monitoring in 222/241(92.1%) of the epilepsy patients that were included. Compared to focal-onset epilepsy, generalized epilepsy demonstrated a much shorter latency to IED. Patients with late-onset epilepsy or those without recent episodes may require longer EEG monitoring periods.