tbuckley/cabot-search huggingface dataset:
Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices
Authors: Ayalew Tefferi, Animesh Pardanani, Naseema Gangat
Journal: American Journal of Hematology (2024)

Abstract The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Determination of optimal timing for AHSCT is facilitated by molecular risk stratification. Non‐transplant treatment options in MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi): momelotinib (FDA approved on September 15, 2023), ruxolitinib (November 16, 2011), fedratinib (August 16, 2019), and pacritinib (February 28, 2022); all four JAKi are effective in reducing spleen size and alleviating symptoms, considered a drug class effect and attributed to their canonical JAK–STAT inhibitory mechanism of action. In addition, momelotinib exhibits erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type‐I (ACVR1). In transplant‐ineligible or deferred patients, the order of treatment preference is based on specific symptoms and individual assessment of risk tolerance. Because of drug‐induced immunosuppression and other toxicities attributed to JAKi, we prefer non‐JAKi drugs as initial treatment for MF‐associated anemia that is not accompanied by treatment‐requiring splenomegaly or constitutional symptoms. Otherwise, it is reasonable to consider momelotinib as the first‐line JAKi treatment of choice, in order to target the triad of quality‐of‐life offenders in MF: anemia, splenomegaly, and constitutional symptoms/cachexia. For second‐line therapy, we favor ruxolitinib, over fedratinib, based on toxicity profile. Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib‐resistance/intolerance, respectively. Splenectomy remains a viable option for drug‐resistant symptomatic splenomegaly and cytopenia.
Partial Heart Transplant in a Neonate With Irreparable Truncal Valve Dysfunction
Authors: Joseph W. Turek, Lillian Kang, Douglas M. Overbey, Michael P. Carboni, Taufiek K. Rajab
Journal: JAMA (2024)

Importance The treatment of neonates with irreparable heart valve dysfunction remains an unsolved problem because there are no heart valve implants that grow. Therefore, neonates with heart valve implants are committed to recurrent implant exchanges until an adult-sized valve can fit. Objective To deliver the first heart valve implant that grows. Design, Setting, and Participants Case report from a pediatric referral center, with follow-up for more than 1 year. Participants were a recipient neonate with persistent truncus arteriosus and irreparable truncal valve dysfunction and a donor neonate with hypoxic-ischemic brain injury. Intervention First-in-human transplant of the part of the heart containing the aortic and pulmonary valves. Main Outcomes and Measures Transplanted valve growth and hemodynamic function. Results Echocardiography demonstrated adaptive growth and excellent hemodynamic function of the partial heart transplant valves. Conclusions and Relevance In this child, partial heart transplant delivered growing heart valve implants with a good outcome at age 1 year. Partial heart transplants may improve the treatment of neonates with irreparable heart valve dysfunction.
Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy
Authors: Larissa Nitschke, Thomas A. Cooper
Journal: Journal of Clinical Investigation (2024)

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated the therapeutic potential for calcium channel modulation to block the synergistic effects and rescue myopathy.
Magnetic Resonance Angiography with Hour‐Scale Duration after Single Low‐Dose Administration of Biocompatible Gadolinium Oxide Nanoprobe
Authors: Jiaojiao Wang, Bing Han, Min Ma, Yujie Zhao, Bingjie Li, Junzi Zhou, Chao Wu, Xuening Zhang, Jinbin Pan, Shao‐Kai Sun
Journal: Advanced Healthcare Materials (2024)

Abstract Long‐term contrast‐enhanced angiography offers significant advantages in theranostics for diverse vascular diseases, particularly in terms of real‐time dynamic monitoring during acute vascular events; However, achieving vascular imaging with a duration of hours through a single administration of low‐dose contrast agent remains challenging. Herein, a hyaluronic acid‐templated gadolinium oxide (HA@Gd 2 O 3 ) nanoprobe‐enhanced magnetic resonance angiography (MRA) is proposed to address this bottleneck issue for the first time. The HA@Gd 2 O 3 nanoprobe synthesized from a facile one‐pot biomineralization method owns ultrasmall size, good biocompatibility, optimal circulation half‐life (≈149 min), and a relatively high T 1 relaxivity ( r 1 ) under both clinical 3 T (8.215 mM −1 s −1 ) and preclinical 9.4 T (4.023 mM −1 s −1 ) equipment. The HA@Gd 2 O 3 nanoprobe‐enhanced MRA highlights major vessels readily with significantly improved contrast, extended imaging duration for at least 2 h, and ultrahigh resolution of 0.15 mm under 9.4 T, while only requiring half clinical dosage of Gd. This technique can enable rapid diagnosis and real‐time dynamic monitoring of vascular changes in a model of acute superior mesenteric vein thrombosis with only a single injection of nanoprobe. The HA@Gd 2 O 3 nanoprobe‐enhanced MRA provides a sophisticated approach for long‐term (hour scale) vascular imaging with ultrahigh resolution and high contrast through single administration of low‐dose contrast agent.
Risk factors and clinical impact of thrombosis during induction chemotherapy for pediatric acute lymphoblastic leukemia: A report from <scp>CYP‐C</scp>
Authors: Marie‐Claude Pelland‐Marcotte, Ketan Kulkarni, Thai Hoa Tran, David Stammers, Sumit Gupta, Lillian Sung, Uma H. Athale
Journal: American Journal of Hematology (2024)

Abstract Thromboembolism (TE) is associated with reduced survival in pediatric acute lymphoblastic leukemia (ALL). It has been hypothesized that TE might signal leukemic aggressiveness. The objective was to determine risk factors for TE during ALL induction (TE ind ) therapy and whether TE ind is associated with treatment refractoriness. This retrospective cohort study using the population‐based Cancer in Young People Canada (CYP‐C) registry included children &lt;15 years of age diagnosed with ALL (2000–2019) and treated at one of 12 Canadian pediatric centers outside of Ontario. Univariate and multivariable logistic regression models were used to determine risk factors for TE ind and whether TE ind predicted induction failure and ALL treatment intensification. The impact of TE ind on overall and event‐free survival was estimated using Cox proportional hazard regression models. The study included 2589 children, of which 45 (1.7%) developed a TE ind . Age (&lt;1 year and ≥10 years vs. 1–&lt;10 years), T‐cell phenotype, high‐risk ALL, and central nervous system involvement were all associated with TE ind in univariate analysis. Age and T‐cell phenotype remained independent predictors of TE ind in multivariable analysis. Induction failure occurred in 53 patients (2.1%). TE ind was not associated with induction failure (OR: not estimable) or treatment intensification (adjusted OR [95% CI]: 0.66 [0.26–1.69]). TE ind was independently associated with overall survival (adjusted HR [95% CI]: 2.54 [1.20–5.03]) but not event‐free survival (adjusted HR [95% CI] 1.86 [0.98–3.51]). In this population‐based study of children treated with contemporary chemotherapy protocols, TE ind was associated with age and T‐cell phenotype and mortality but did not predict induction failure.
Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model
Authors: Lily A. Cisco, Matthew T. Sipple, Katherine M. Edwards, Charles A. Thornton, John D. Lueck
Journal: Journal of Clinical Investigation (2024)

Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling in mice. Mice with forced skipping of exon 29 in the CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl– bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl– bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.
Individualized rabbit anti‐thymocyte globulin dosing in adult haploidentical hematopoietic cell transplantation with high‐risk hematologic malignancy: Exposure–response analysis and population pharmacokinetics simulations
Authors: Masahiro Teramoto, Takuto Takahashi, Kana Matsumoto, Mutaz Jaber, Katsuji Kaida, Hiroya Tamaki, Kazuhiro Ikegame, Satoshi Yoshihara
Journal: American Journal of Hematology (2024)

Abstract Hematopoietic cell transplantation (HCT) for hematologic malignancies with non‐remission disease and/or prior post‐transplant relapse have poor relapse‐free survival. We previously demonstrated the efficacy of haploidentical reduced‐intensity HCT regimen with glucocorticoid‐based graft‐versus‐host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure–response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17–70) and majority had a non‐remission disease prior to HCT (88%). rATG concentration on day 0 of HCT ( C day_0 ) was the strongest predictor of Grade 2–4 aGVHD through day +100. Patients with C day_0 ≥ 20 μg/mL had an approximately 3‐fold lower risk of Grade 2–4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3–4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2‐fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced‐intensity haploidentical HCT regimen with exposure‐optimized rATG may provide a promising option to patients undergoing high‐risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.
For her seventy-third birthday, my mother
Authors: Woods Nash
Journal: JAMA (2024)

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Polymyxin B-targeted liposomal photosensitizer cures MDR A. baumannii burn infections and accelerates wound healing via M1/M2 macrophage polarization
Authors: Zixin Cui, Yiyang Li, Yannan Qin, Jianzhou Li, Lei Shi, Meijuan Wan, Min Hu, Yunru Chen, Yanhong Ji, Yuzhu Hou, Feng Ye, Chengcheng Liu
Journal: Journal of Controlled Release (2024)
Comparison of fludarabine‐based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry‐based study
Authors: Naoki Kurita, Nobuhiko Imahashi, Shigeru Chiba, Masatsugu Tanaka, Hikaru Kobayashi, Naoyuki Uchida, Takuro Kuriyama, Naoyuki Anzai, Yuichiro Nawa, Nobuaki Nakano, Takahide Ara, Makoto Onizuka, Yuna Katsuoka, Satoshi Koi, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Junya Kanda
Journal: American Journal of Hematology (2024)

Abstract Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine‐based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry‐based study aimed to analyze the impact of five fludarabine‐containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100–140 mg/m 2 ) and low‐dose total body irradiation (TBI; FM140T); melphalan (80–99 mg/m 2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3‐year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively ( p &lt; .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2–2.2); FB4M, 2.1 (95% CI, 1.6–2.8); FB4T, 2.7 (95% CI, 2.0–3.7); and FB2T, 2.2 (95% CI, 1.6–3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non‐relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan‐based conditioning, FM140T may be the preferred regimen.
Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation
Authors: Samuel Young, Christian Schiffer, Alice Wagner, Jannika Patz, Anton Potapenko, Leonie Herrmann, Verena Nordhoff, Tim Pock, Claudia Krallmann, Birgit Stallmeyer, Albrecht Röpke, Michelina Kierzek, Cristina Biagioni, Tao Wang, Lars Haalck, Dirk Deuster, Jan N. Hansen, Dagmar Wachten, Benjamin Risse, Hermann M. Behre, Stefan Schlatt, Sabine Kliesch, Frank Tüttelmann, Christoph Brenker, Timo Strünker
Journal: Journal of Clinical Investigation (2024)

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.
Metal‐Phenolic Nanocapsules with Photothermal Antibacterial and Ros Scavenging Ability for Diabetic Wound Healing
Authors: Xudong Qin, Rui Tian, Bo Wang, Haixia Yang, Junyang Chen, Xin Wang, Jianliang Zhou, Qing Chen, Jian Tian, Ying‐Wei Yang
Journal: Advanced Healthcare Materials (2024)

The presence of bacteria in diabetic wounds not only leads to the formation of biofilms but also triggers oxidative stress and inflammatory responses, which hinder the wound-healing process. Therefore, it is imperative to formulate a comprehensive strategy that can proficiently eliminate bacteria and enhance the wound microenvironment. Herein, this work develops multifunctional metal-phenolic nanozymes (TA-Fe/Cu nanocapsules), wherein the one-pot coordination of tannic acid (TA)and Fe
Association of individual comorbidities with outcomes in allogeneic hematopoietic cell transplantation from unrelated adult donors versus unrelated cord blood: A study on behalf of the Donor/Source and Transplant Complications Working Groups of the Japanese Society for Transplantation and Cellular Therapy
Authors: Takaaki Konuma, Kaito Harada, Akihito Shinohara, Naoyuki Uchida, Naoki Shingai, Ayumu Ito, Yukiyasu Ozawa, Masatsugu Tanaka, Masashi Sawa, Makoto Onizuka, Yuta Katayama, Nobuhiro Hiramoto, Nobuaki Nakano, Takafumi Kimura, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Hideki Nakasone, Junya Kanda
Journal: American Journal of Hematology (2024)

Abstract We retrospectively evaluated the effect of 17 individual comorbidities, defined by the hematopoietic cell transplantation (HCT)‐specific comorbidity index, on non‐relapse mortality (NRM) and overall survival (OS) in 9531 patients aged between 16 and 70 years who underwent their first allogeneic HCT from 8/8 and 7/8 allele‐matched unrelated donors (8/8 and 7/8 MUDs) or single‐unit unrelated cord blood (UCB) between 2011 and 2020 using data from a Japanese registry database. In the multivariate analysis, infection (adjusted hazard ratio [HR], 1.62, 95% confidence interval [CI], 1.33–1.99 for 8/8 and 7/8 MUDs; adjusted HR, 1.33, 95%CI, 1.12–1.58 for UCB) and moderate/severe hepatic comorbidity (adjusted HR, 1.57, 95%CI, 1.04–2.38 for 8/8 and 7/8 MUDs; adjusted HR, 1.53, 95%CI, 1.09–2.15 for UCB) had a significant impact on NRM in both donor groups. Cardiac comorbidity (adjusted HR, 1.40, 95%CI, 1.08–1.80), mild hepatic comorbidity (adjusted HR, 1.22, 95%CI, 1.01–1.48), rheumatologic comorbidity (adjusted HR, 1.67, 95%CI, 1.11–2.51), renal comorbidity (adjusted HR, 2.44, 95%CI, 1.46–4.09), and severe pulmonary comorbidity (adjusted HR, 1.40, 95%CI, 1.11–1.77) were significantly associated with an increased risk of NRM but only in UCB recipients. Renal comorbidity had the strongest impact on poor OS in both donor groups (adjusted HR, 1.73, 95%CI, 1.10–2.72 for 8/8 and 7/8 MUDs; adjusted HR, 2.24, 95%CI, 1.54–3.24 for UCB). Therefore, unrelated donor selection should be taken into consideration along with the presence of specific comorbidities, such as cardiac, rheumatologic, renal, mild hepatic, and severe pulmonary comorbidities.
Induced protein degradation for therapeutics: past, present, and future
Authors: Hojong Yoon, Justine C. Rutter, Yen-Der Li, Benjamin L. Ebert
Journal: Journal of Clinical Investigation (2024)

The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered "undruggable." Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger protein degradation have been developed and are currently under clinical evaluation. These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.
Correction:<i>Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK-pot’ collaboration</i>
Journal: Annals of the Rheumatic Diseases (2024)

CorrectionCorrection: Effectiveness of TNF-inhibitors, abatacept, IL6inhibitors
FORGEdb: a tool for identifying candidate functional variants and uncovering target genes and mechanisms for complex diseases
Authors: Charles E Breeze, Eric Haugen, María Gutierrez-Arcelus, Xiaozheng Yao, Andrew Teschendorff, Stephan Beck, Ian Dunham, John Stamatoyannopoulos, Nora Franceschini, Mitchell J Machiela, Sonja I Berndt
Journal: Genome biology (2024)

The majority of disease-associated variants identified through genome-wide association studies are located outside of protein-coding regions. Prioritizing candidate regulatory variants and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb ( https://forgedb.cancer.gov/ ; https://forge2.altiusinstitute.org/files/forgedb.html ; and https://doi.org/10.5281/zenodo.10067458 ), a standalone and web-based tool that integrates multiple datasets, delivering information on associated regulatory elements, transcription factor binding sites, and target genes for over 37 million variants. FORGEdb scores provide researchers with a quantitative assessment of the relative importance of each variant for targeted functional experiments.
Author Correction: Homology-mediated inter-chromosomal interactions in hexaploid wheat lead to specific subgenome territories following polyploidization and introgression
Authors: Jizeng Jia, Yilin Xie, Jingfei Cheng, Chuizheng Kong, Meiyue Wang, Lifeng Gao, Fei Zhao, Jingyu Guo, Kai Wang, Guangwei Li, Dangqun Cui, Tiezhu Hu, Guangyao Zhao, Daowen Wang, Zhengang Ru, Yijing Zhang
Journal: Genome biology (2024)
“I feel like I’m living the authenticity of my being”: gender identity developmental trajectories of trans youth in Portugal
Authors: Marta Conceição, Jaime Moura, Pedro Alexandre Costa
Journal: International Journal of Transgender Health (2024)

Research into the identity development of trans people has been emerging, but there is still a need for further study. While significant processes for identity construction take place during late adolescence and early adulthood, it is important to understand which milestones are associated with the trajectories of gender identity (GI) development.