bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of Sleep Disordered Breathing in Adult Sickle Cell Clinic Patients and Cardiovascular Correlates
Authors: Whitesell Peter , Mehari Alem , Mellman Thomas , Stokes Daniel , Mirzada Freba , Rock Angela , Taylor James 
Published: December 2023

Sleep disordered breathing (SDB) is strongly correlated with hypertension and cardiovascular disease in the general population, and especially in African Americans. In Sickle Cell Disease (SCD), the adverse effect of nocturnal hypoxemia is anticipated to have additional adverse effects with the sickling of red blood cells and microvascular thrombosis unique to the disease. Prospective data regarding the prevalence and consequences of SDB in this population are lacking.
In an ongoing study, 27 adult subjects (age &gt; 18 years), with homozygous HbSS genotype, presenting to the Howard University Sickle Cell Center for routine follow up have been recruited irrespective of the presence of sleep symptoms. Exclusion criteria include previous diagnosis or treatment of a sleep disorder or requirement for supplemental oxygen. Testing occurs when subjects are in a stable phase of disease, with no hospitalizations or medication changes for 4 weeks. In addition to clinical history and questionnaires, participants are assessed with blood work, 6 minute walk testing, pain and sleep diaries during 1 week actigraphy, transthoracic echocardiography and overnight in lab polysomnography with capnography.
At the time of this interim analysis, the mean age is 42 (range 29-71, +/- std dev 11) and male:female distribution is 17:10. The mean BMI is 20.4 (+/- 4.5). Mean Hgb is 9.1 g/dl (+/- 1.8) and mean LDH is 325 iu/L (+/- 163).
Polysomnography scoring utilized a 3% desaturation criterion for hyponeas as per American Academy of Sleep Medicine Scoring Manual Chapter VIII, 1A. Mean sleep efficiency is 77% ( std dev +/- 4.2%). 48% of subjects demonstrate some degree of sleep disordered breathing as defined by an AHI &gt; 5 events/hour (33% mild, 4% moderate, 11% severe). 70% of subjects demonstrate an RDI &gt; 5 events/hour (40% mild, 19% moderate, 11% severe). Twelve participants (44%) exhibit more than 5 minutes sleep duration at saturations &lt;89% (mean = 187 minutes). Hypercapnia is not suggested as an important component of SDB with the mean ET CO2 = 40.7 mm Hg (range 30-46 mm Hg).
Echocardiographic values (LVPWd, Lad, MV E/A, PVV, and RVSP) do not correlate with any indices of sleep disordered breathing other than minutes &lt;89% saturation correlating with RVSP.
In summary, this interim analysis of sleep in a population of unselected Sickle Cell Clinic patients demonstrates a striking frequency of sleep disordered breathing. This is despite a generally low BMI for these patients which is typically considered one of the most important risk factor for sleep apnea. Ongoing recruitment is planned to confirm these findings. Correlation with clinical outcomes and potential response to therapeutic interventions will be important future research questions.
Development of Organoid-Based Cytotherapeutics for Taste Loss Induced By Anti-Cancer Chemotherapy and Radiotherapy
Authors: Kim Donghoon , Park Sung-Soo , Jeong Yong-Taek , Kim Jin-Woo , Kim Heeje 
Published: December 2023

Introduction
Ulcerative mucositis and taste loss are common side effects induced by cancer therapy, including chemotherapy and radiation therapy. These conditions cause significant oral pain and loss of taste, impacting food intake and physical health abnormalities such as malnutrition, as well as depression and mental health deterioration, which can affect prognosis. To address these challenges, an appropriate treatment for oral mucositis is required. While various types of oral mucositis treatments have been developed (e.g., patch, spray, ointment), most show indirect healing effects such as pain control and inflammation relief. Thus, a direct method for treating oral lesions should be developed. This research was supported by the Korean Fund for Regenerative Medi- cine (KFRM) grant funded by the Korea Government (the Ministry of Science and ICT, the Ministry of Health & Welfare) (21C0712L1-11).
Methods
To compensate for the difficulty in supplying human tissue, we conducted preliminary experiments using mice to establish protocols for manufacturing human oral tissue-derived cell therapeutics. we devised an organoid-derived cell sheet transplantation. First, we generated organoids derived from oral mucosa and prepared a cell sheet using a temperature-responsive cell culture dish. The harvested cell sheet was transplanted to the lesion site to enable structural and functional recovery of the oral mucosa and gustatory organs.
Results
We have developed a cell-therapeutic platform based on regenerative medicine technology to recover oral lesions in cancer chemotherapy and radiotherapy patients. Specifically, we developed a method for producing autologous cell therapeutics. The oral mucosa tissue of a patient scheduled for anticancer treatment was collected, and epithelial cells were obtained from the tissue. Using these cells, we generated organoids with differentiated taste bud cells, and isolated cells from the organoids were seeded onto temperature-responsive cell culture dishes and cultured beyond confluence for the formation of a sheet. We performed immunostaining to detect various types of taste cells in the cell sheet. We also confirmed the success of cell sheet transplantation and the subsequent healing effect.
Conclusion
Improving the prognosis and acquiring the will to recover of cancer chemotherapy and radiotherapy patients through repairing taste function and rapid healing of lesions are crucial. We have developed a cell therapy technology that enables the structural and functional recovery of the oral mucosa and gustatory organs, providing a promising solution to treat the side effects of anti-cancer treatment. Our research provides an R&D initiative for the treatment and prevention of intractable diseases by culturing, manufacturing, and transplanting living autologous cells.
Engineering Off-the-Shelf Gamma Delta CAR T Cells for the Treatment of Acute Myeloid Leukemia
Authors: Dwivedi Alka , Fu Lynn , Chien Chris Daniel , Pouzolles Marie , Shah Nirali N. , Taylor Naomi 
Published: December 2023

Chimeric antigen receptor T cell therapy (CART) therapy has shown remarkable success in the treatment of B cell acute lymphoblastic leukemias (B-ALL) and lymphomas. However, CART therapies for acute myeloid leukemia (AML), where 5-year survival rates are significantly lower than for B-ALL, are only in their infancy. CD33-CART have potent activity against AML in preclinical models and a first-in-child/first-in-human phase 1/2 CD33-CART clinical trial for AML is ongoing in the Pediatric Oncology Branch of the National Cancer Institute (NCT03971799). Nonetheless, published outcomes suggest a modest efficacy of approximately 50% (Shahzad et al., Front Immunol 2023), highlighting the critical need to develop new strategies to improve CART accessibility and a more robust anti-AML response. We hypothesized that off-the-shelf gamma delta (γδ) CD33 CART cells could potentially overcome current challenges for the treatment of AML. γδ lineage T cells are unconventional lymphocytes whose functions are not restricted to MHC-mediated antigen presentation; they are primed for immediate responses, including tumor killing. Furthermore, allogeneicγδ T cells have the potential to induce robust anti-tumor cytotoxicity without causing graft versus host disease (GVHD).
Here, we generated γδ CAR T cells from healthy donor elutriated lymphocytes by activation with zoledronic acid and IL-2 for 7-14 days. Within 9 days post stimulation, the vast majority of lymphocytes were Vδ2+ and 30-40% were successfully transduced with a lentiviral CD33 CAR construct harboring the 4-1BB costimulatory domain. Importantly, and unlike conventional alpha beta (ab) T lymphocytes, &gt;98% of these γδ CD33CAR T cells expressed IFNγ under basal conditions. This characteristic likely accounted for the efficient in vitro killing of AML cell lines by untransduced γδ T lymphocytes under conditions of high effector/target (E/T) ratios. While untransduced γδ T cells did not exhibit cytotoxicity following repeat AML stimulations, γδ CD33CAR T lymphocytes exhibited proficient in vitro cytotoxicity, with killing rates that were more rapid than those initiated by ab CD33 CART (Figure 1). These characteristics were associated with a prolonged metabolic activity of γδT cells; γδ CD33 CART expressed high levels of the GLUT1 glucose transporter for &gt;14 days post activation whereas GLUT1 levels on ab CD33 CART returned to resting within 10 days. High GLUT1 levels were linked to efficient killing under conditions of basal glucose levels. Most notably, γδ CD33CAR T lymphocytes achieved high in vivo cytotoxicity, assessed using bioluminescent AML cell line xenografts in humanized NSG mice. Together, these data highlight the feasibility of generating allogeneic γδ CD33CART with a strong anti-AML cytotoxic response.
Investigating the Vasodilatory Effects of Tgpolyhb: A Potential Hemoglobin-Based Oxygen Carrier for Sickle Cell Disease and Thalassemia
Authors: Munoz Carlos J , Lucas Daniela , Muller Cynthia R , Gopal Srila , Cabrales Pedro 
Published: December 2023

Background: Hemoglobin-based oxygen carriers (HBOC) hold promise in improving oxygen delivery to organs and tissues, potentially reducing the need for transfusions and associated complications, thus presenting an alternative approach to managing anemia.
Methods: We created a polymerized human hemoglobin called TgPolyHb, using transglutaminase, which has demonstrated effective oxygen transport and blood flow maintenance in animal studies. Our hypothesis suggests that TgPolyHb will not induce vasoconstriction or hypertension, side effects observed in previous generations of HBOC, such as HBOC-201. In the present study, we assessed the potential of TgPolyHb to reduce the side effects previously seen with HBOC-201, comparing it to stroma-free acellular hemoglobin (hHb - negative control) in Golden Syrian Hamsters. The animals were instrumented with a metallic frame with a small cover slip placed over the dorsal skin fold to observe and quantify microcirculatory health following a toapload infusion (arterial injection of 10% of their blood volume).
Results: The innovative HBOC, TgPolyHb, exhibited vasodilation effects in comparison to HBOC-201 and hHb, both exhibited a 10% reduction in diameter compared to baseline. Furthermore, TgPolyHb demonstrated a 10% increase in functional capillaries compared to HBOC-201 and hHb. Functional capillary density is an important marker of tissue health.
Conclusions: Our study provides preliminary data that could lead future investigations of HBOC such as TgPolyHb in decreasing transfusion burden in severe anemias.
Implementation of 4T Score Documentation on PF4 Testing in Patients with Suspected Heparin-Induced Thrombocytopenia
Authors: Ruiz Maria Andreina , Gopalani Radhan , Justiz Jessica , Clarke Heidi , Dittmar Erika 
Published: December 2023

Purpose: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. Diagnosis requires clinical evaluation and laboratory testing. The 4T score is a pretest clinical scoring tool used to determine the probability of HIT. A non-profit health system implemented mandatory documentation of 4T score calculation prior to ordering PF4 tests for suspected HIT patients. The purpose of this performance improvement project is to evaluate the implementation of 4T score documentation on PF4 testing and argatroban utilization.
Methods: This was a retrospective, multi-site chart review of patients conducted to assess the impact of mandatory 4T score documentation prior to a PF4 order. The study included adult patients who were admitted to one of the practice sites between January 2020 and November 2022 with a suspicion of HIT and a PF4 order. The primary outcomes included the number of PF4 tests ordered and the percentage of positive PF4 results. Secondary outcomes included number of SRA orders and percentage of positive SRA results, turnaround time for SRA, and the utilization of argatroban. Data collection included baseline demographics, documentation of 4T score, PF4 results, SRA results, documentation of heparin allergy, initial anticoagulant prescribed, platelet trend, ordering provider, and duration of argatroban therapy in patients with a positive PF4 result. The analysis involved using χ2 test and Fisher's exact test for the primary outcomes.
Results: Mandatory 4T score documentation significantly reduced PF4 orders by 68% over a two-year period (p&lt;0.0001). It also improved the percentage of positive PF4 results from 12% to 24% (p=0.60) and positive SRA results from 19% to 44% (p=0.35). Notably, after documentation of the mandatory 4T score tool, only 21% of the patients had a PF4 order placed. A total of 42 patients with a positive PF4 test were included to assess argatroban utilization. The turnaround time for SRA in these patients was 3.6 days while duration of argatroban therapy was 6.8 days.
Conclusion: Implementation of mandatory 4T score documentation significantly reduced PF4 orders and improved HIT diagnostic testing in a non-profit health system. Challenges remain with SRA turnaround time and corresponding duration of argatroban therapy. The results of this project have demonstrated that standardized documentation is essential for optimizing HIT diagnosis and management protocols. Future efforts will focus on optimizing confirmatory HIT testing and non-heparin anticoagulation therapy.
CD70 CAR NK Cells in the Treatment of Multiple Myeloma
Authors: Lin Paul , Reyes Silva Francia C. , Lin Pei , Gilbert April L. , Acharya Sunil , Nunez Cortes Ana K. , Banerjee Pinaki , Fang Dexing , Melo Garcia Luciana , Daher, MD May , Basar Rafet , Patel Krina K. , Lee Hans C. , Orlowski Robert Z. , Rafei Hind , Marin David , Champlin Richard E. , Shpall Elizabeth J. , Rezvani Katayoun 
Published: December 2023

Despite the high response rates of chimeric antigen receptor (CAR) - T cells targeting the B-cell maturation antigen (BCMA) for multiple myeloma (MM), patients eventually still relapse. At this time there is no clear subsequent therapy. Furthermore, CAR T-cell therapy is associated with significant toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.
CD70 is a normally transiently expressed on activated T-cells, B-cells, or dendritic cells, but have been found to be upregulated on many hematologic and solid cancer cells such as acute myeloid leukemia, triple negative breast cancer, and renal cell carcinoma. However, CD70 as a potential target for treatment of multiple myeloma, including patients who have progressed on BCMA targeted therapies, has not been fully investigated.
We assessed bone marrow aspirates from MM patients by flow cytometry and demonstrated that CD70 was expressed on the majority of myeloma cells, and on average, relapsed myeloma patients had higher expression of CD70. In addition, using immunohistological staining, we found that CD70 was expressed on 10 of 10 patients who had progressed on BCMA targeted therapies (seven who had progressed on belantamab mafodotin, an antibody drug conjugate, three who had progressed on idecabtagene vicleucel, a BCMA CAR-T), suggesting that CD70 could be a viable target in patients who have failed BCMA targeted therapy.
As natural killer (NK) cells are a promising off-the-shelf treatment with minimal toxicity as compared to CAR-T cells, we generated CD70-targeting CAR NK cells for the treatment of MM. We found in the chromium cytotoxicity assay that CD70 CAR NK cells had higher killing as compared to non-transduced (NT) NK cells at multiple effector-to-target ratios against MM1s, a myeloma cell line confirmed to express CD70. There was no difference in killing when co-cultured with H929, a myeloma cell line lacking CD70 expression, demonstrating the specificity of the CD70 CAR NK cell. The enhanced killing was also confirmed in an incucyte assay in which the CD70 CAR NK cells cleared tumor faster than NT NK, even in MM1s in which BCMA was knocked out using CRISPR (simulating BCMA antigen loss). When tested in a myeloma mouse model, the CD70 CAR NK exhibited greater tumor control as shown in Figure 1, when compared to NT NK, which lead to increased survival of the mice. Similar results were seen in a mouse model using BCMA KO myeloma cells.
In summary, we were able to demonstrate that CD70 can be a feasible target for the treatment of multiple myeloma, including in patients who have failed BCMA targeted therapy. Based on these results, we have initiated a Phase I/II clinical trial (NCT05092451) that is currently recruiting.
Successful Treatment Outcomes of Hematopoietic Stem Cell Transplantation with Reduced-Toxicity Conditioning Regimen Incorporating Treosulfan in Pediatric Patients with XIAP Deficiency
Authors: Suh Jin Kyung , Im Ho Joon , Kang Sung Han , Kim Hyery , Choi Eun Seok , Koh Kyung-Nam 
Published: December 2023

Background
X-linked inhibitor of apoptosis (XIAP) defciency is an inherited primary immunodefciency characterized by chronic infammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and infammatory bowel disease (IBD). Although hematopoietic stem celltransplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory.
Methods
We have performed HSCT with treosulfan based RTC regimen for pediatric patients with non-malignant disorders since January 2016, and reviewed the medical records of patients with XIAP deficiency who underwent treosulfan based HSCT to investigate outcomes of HSCT for patients with XIAP deficiency.
Results
Since January 2016, 4 patients with XIAP deficiency had undergone HSCT using RTC regimen consisted of fludarabine (150-180 mg/m 2), treosulfan (42 g/m 2), rabbit ATG (5-7.5 mg/kg), and thiotepa (10 mg/kg). All patients were male and received HSCT (2 from URD and 2 from HFD) at median 13.7 years old (range, 12.8-15.3), median 2 years (range, 0.5-3.9) after diagnosis of XIAP. They all achieved engraftment and complete donor chimerism at the time of last evaluation. One patient who received HFD HSCT developed acute GI GVHD grade 3 and VOD within 1 month from HSCT, which was recovered after treatment with systemic steroid and defibrotide. Except the patient, there was no fatal acute regimen related toxicity ≥ CTCAE grade 3. Two patients developed chronic GVHD: one had limited disease which was resolved after systemic steroid therapy and the other had extensive disease. During the median 43 months (range, 33.1-63.0) follow-up, all survived without disease recurrence.
Conclusions
HSCT with treosulfan based RTC regimen is promising treatment option for pediatric patients with XIAP deficiency, with successful engraftment and low treatment-related toxicity. However, further studies including a larger multicenter trial and measures to refine the regimen are mandate to verify efficacy and safety of this regimen.
Renal Failure in Patients with Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant in LATAM - on Behalf of Gelamm
Authors: Martinez-Cordero Humberto , Fuentes Lacouture Maria Cynthia , Von Glasenapp Seisha Alana , Peña Camila , Riva Eloisa 
Published: December 2023

Background
Renal failure (RF) is a well-known complication in patients with multiple myeloma (MM). It is reported that RF occurs in 20% to 50% of patients at the time of diagnosis. Approximately 10% will require hemodialysis. It is important to consider that RF determines a worse short-term prognosis and decreased survival in these patients, especially for those requiring dialysis.
Methods
An international, multicenter, retrospective observational cohort study was conducted. Data were collected from the GELAMM retrospective Registry. We analyzed demographical and clinical characteristics, and overall survival (OS) of newly diagnosed MM patients without RF, patients with RF not requiring hemodialysis (HD), and patients with RF requiring HD. The logistic regression model was used to identify risk factors for worse outcomes.
Results
We included 1104 NDMM patients ≤ 65 years old from GELAMM registry: 854 patients without renal failure, 161 patients (15%) with RF not requiring HD, and 89 patients (8%) requiring HD. There were no differences in terms of demographic and clinical characteristics. With a median follow-up time of 29 months, the median OS was not reached (NR) in patients without RF and in patients with RF without HD requirement, however, it was 43 months (27 - 58 months) in patients with renal failure requiring HD (p=&lt;0.001). The HR for mortality in patients with RF without HD was 1.75 (1.27 -2.41) and for RF and HD 3.49 (2.47 - 4.93) (p&lt; 0.001). The one-year mortality among the three groups was 7% for patients without RF, 12% in patients with RF not requiring dialysis, and 30% in patients with RF requiring dialysis. The multivariate analysis showed that having proceeded with ASCT as a favorable prognostic factor HR 0.238 (0.129-0.521) p&lt; 0.001 and high-risk cytogenetics as an unfavorable prognostic factor HR 2.936 (1.242-6.922) p=0.014.
Discussion
Renal failure confers a worse prognosis in Latin American patients with newly diagnosed multiple myeloma, especially for those who require dialysis, and increases one-year mortality more than 4 times. The use of ASCT decreases the risk of worse time-dependent outcomes, and high-risk cytogenetics increases the risk of death.
Avatrombopag Is Effective in First-Line Treatment of Severe Aplastic Anemia: Early Outcomes of a Prospective Study
Authors: Zhao Xin , Li Jianping , Fan Huihui , Jing Liping , Zhang Li , Zhou Kang , Yang Wenrui , Li Yuan , Yang Yang , Ye Lei , Peng Guangxin , Xiong Youzhen , Shi Jun , Zhang Fengkui 
Published: December 2023

Acquired severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease and its pathogenesis involves T cell-mediated autoimmunity. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for patients not eligible for hematopoietic stem cell transplant, and the response rate is 60-70%. Complete hematological response (CR) predicts better survival of patients received IST treatment, but only a few patients achieve CR within 6 months (5% at 3 months and 12-17% at 6 months). Thrombopoietin receptor agonist (TPO-RA) eltrombopag improves the overall response (OR) rate and CR rate of SAA patients when combined with IST, but its hepatotoxicity is still worrying.
Avatrombopag is another small-molecule TPO-RA without hepatic toxicity. We previously found that SAA patients received avatrombopag and IST as first-line treatment showed both higher CR rate and OR rate at 3 and 6 months. To validate our findings, a prospective, single-arm study of avatrombopag and IST for newly diagnosed SAA was carried out (NCT05720234).
There were 25 patients enrolled in the study by June 31, 2023, including 21 SAA patients and 4 very severe aplastic anemia patients. Patients were diagnosed as AA within 6 months and received ATG, cyclosporine and avatrombopag as first-line treatment. Avatrombopag was administered at the first day of ATG initiation at dose of 60mg per day for patients weight ≥ 50kg and 40mg per day for patients weight &lt; 50kg. ATG was given for 5 consecutive days. Cyclosporine was given orally at dose of 3.5-5mg/kg.d.
There were 15 males and 10 males, at a median age of 37 years old. Eighteen patients achieved the end-point of 3 months and 10 patients achieved end-point of 6 months. There were 15 patients achieved hematologic response at 3 months (83.3%), including 5 complete responders (27.8%) and 10 partial responders. The overall response rate at 6 months was 80%, and CR rate was 60%. One patient evolved to hemolytic paroxysmal nocturnal hemoglobinuria at 3 months, with normal count of platelet and white blood cell.
In conclusion, the addition of avatrombopag to IST as first-line treatment showed earlier hematologic response and higher complete response rate for patients with SAA.