tbuckley/cabot-search huggingface dataset:
Lee Silverman voice treatment versus NHS speech and language therapy versus control for dysarthria in people with Parkinson’s disease (PD COMM): pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial
Authors: Catherine M Sackley, Caroline Rick, Marian C Brady, Rebecca Woolley, Christopher Burton, Smitaa Patel, Patricia Masterson-Algar, Avril Nicoll, Christina H Smith, Sue Jowett, Natalie Ives, Gillian Beaton, Sylvia Dickson, Ryan Ottridge, Leslie Sharp, Helen Nankervis, Carl E Clarke
Journal: BMJ (2024)

To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease.
Childhood infections, asthma and allergy trajectories, and chronic rhinosinusitis in middle age: A prospective cohort study across six decades
Authors: Jennifer L. Perret, N. Sabrina Idrose, E. Haydn Walters, Dinh S. Bui, Adrian J. Lowe, Caroline J. Lodge, Anne R. Fernandez, Vivian Yao, Iain Feather, Xiao‐Wen Zeng, Bruce R. Thompson, Bircan Erbas, Michael J. Abramson, Shyamali C. Dharmage
Journal: Allergy (2024)

Abstract Introduction Evidence on the early life risk factors of adult CRS, and the history of asthma and allergies across the life course, is limited. Aim To investigate relationships between respiratory infective/allergic conditions in childhood, and asthma and allergies across the life course and CRS in middle age. Methods Data were from the population‐based Tasmanian Longitudinal Health Study (TAHS) cohort, first studied in 1968 when aged 6–7 years ( n = 8583) and serially followed into middle age ( n = 3609). Using a well‐accepted epidemiological definition, participants were assigned a CRS‐severity subtype at age 53: no sinusitis/CRS (reference); past doctor diagnosis only; current symptoms without doctor diagnosis; and doctor‐diagnosed CRS with current symptoms. Relationships with infective/allergic respiratory illnesses at age 7, and previously published asthma‐allergy trajectories from 7 to 53 years, were examined using multinominal regression. Results In middle age, 5.8% reported current CRS symptoms with 2.5% doctor‐diagnosed. Childhood conditions associated with symptomatic doctor‐diagnosed CRS included frequent head colds (multinomial odds ratio [mOR] = 2.04 (95% confidence interval [95% CI]: 1.24, 3.37)), frequent tonsillitis (mOR = 1.61 [95% CI: 1.00, 2.59]) and current childhood asthma (mOR = 2.23 [95% CI: 1.25, 3.98]). Life course trajectories that featured late‐onset or persistent asthma and allergies were associated with all CRS subtypes in middle age; early‐onset persistent asthma and allergies (mOR = 6.74, 95% CI: 2.76, 16.4); late‐onset asthma allergies (mOR = 15.9, 95% CI: 8.06, 31.4), and late‐onset hayfever (mOR = 3.02, 95% CI: 1.51, 6.06) were associated with symptomatic doctor‐diagnosed CRS. Conclusion Current asthma, frequent head colds and tonsillitis at age 7 could signal a susceptible child who is at higher risk for CRS in mid‐adult life and who might benefit from closer monitoring and/or proactive management. Concurrent asthma and allergies were strongly associated and are potential treatable traits of adult CRS.
Increased Oxygen Stimulation Promotes Chemoresistance and Phenotype Shifting through PLCB1 in Gliomas
Authors: Kang Ma, Shi Wang, Yingjie Ma, Lan Zeng, Kai Xu, Ning Mu, Ying Lai, Yaning Shi, Chuanyan Yang, Beike Chen, Yulian Quan, Lan Li, Yongling Lu, Yang Yang, Yan Liu, Rong Hu, Xiaoming Wang, Yujie Chen, Xiuwu Bian, Hua Feng, Fei Li, Tunan Chen
Journal: Drug Resistance Updates (2024)
One-month daily and three-month weekly rifapentine plus isoniazid are comparable in completion rate and safety for latent tuberculosis infection in non-HIV Population: A randomized controlled trial
Authors: Hung-Ling Huang, Meng-Rui Lee, Chih-Hsin Lee, Meng-Hsuan Cheng, Po-Liang Lu, Chau-Chyun Sheu, Jann-Yuan Wang, Inn-Wen Chong, Jinn-Moon Yang
Journal: Clinical Microbiology and Infection (2024)

ObjectivesThe weekly rifapentine plus isoniazid for 3 months (3HP) improves completion rate of latent tuberculosis infection treatment, but flu-like symptoms are common. The novel 1HP regimen, involving daily rifapentine plus isoniazid for 28 days, has demonstrated low toxicity in HIV-infected populations. We aimed to investigate whether 1HP has a lower incidence rate of systemic drug reaction (SDR) compared with 3HP during treatment in non-HIV populations.MethodsThis randomized, multicentre trial compared the completion rate and risks of SDRs of 1HP and 3HP in aged ≥13 years non-HIV subjects with latent tuberculosis infection between September 2019 and September 2023 (ClinicalTrials.gov: NCT04094012). We also investigated associations between SDRs and plasma levels of drugs and their metabolites.ResultsA total of 251 and 239 individuals were randomly assigned to 1HP and 3HP groups, respectively, with completion rates of 82.9% (208/251) and 84.5% (202/239), respectively. Among them, 12.7% (32/251) and 10.9% (26/239) of 1HP and 3HP groups experienced SDRs, respectively (p 0.522), predominantly urticaria in 1HP group (59.4% [19/32]) and flu-like syndrome in 3HP group (80.8% [21/26]). Among participants experiencing SDRs, 43.8% (14/32) and 34.6% (9/26) in 1HP and 3HP groups, respectively, completed treatment (p 0.470). Cutaneous reactions were more common in 1HP than 3HP group (32.7% [82/251] vs. 13.0% [31/239], p < 0.001). In 1HP group, urticaria was associated with a higher plasma desacetyl-rifapentine level (ug/mL) at both 2 (median [interquartile range]: 36.06 [17.46–50.79] vs. 22.94 [14.67–31.65], p 0.018) and 6 hours (26.13 [15.80–53.06] vs. 29.83 [18.13–34.01], p 0.047) after dosing.DiscussionIn non-HIV population, the incidence rate of SDR under 1HP is not lower than 3HP. Notably, urticaria, rather than flu-like syndrome, was the predominant SDR associated 1HP. The findings of this study underscore the feasibility of 1HP regimen in non-HIV populations with a high-completion rate exceeding 80%.
Epithelial Na+ Channel Activation after Bile Duct Ligation with Mineralocorticoid Receptor Blockade
Authors: Xue-Ping Wang, Stephanie M. Mutchler, Rolando Carrisoza-Gaytan, Andrew J. Nickerson, Catherine J. Baty, Mohammad Al-Bataineh, Amber Vandevender, Tetsuji Morimoto, Priyanka Srinivasan, Roderick J. Tan, Michael J. Jurczak, Lisa M. Satlin, Ossama B. Kashlan
Journal: Journal of the American Society of Nephrology (2024)

Key Points Bile acids activate the epithelial Na + channel (ENaC), which may lead to subsequent fluid retention in liver disease. Bile duct ligation with spironolactone increased ENaC-dependent Na + and fluid retention without hormone-linked increased ENaC abundance. Counteracting bile acid ENaC activation may be effective for treating fluid retention in liver disease. Background Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system. However, evidence of fluid retention in patients without renin-angiotensin-aldosterone system activation suggests the involvement of additional mechanisms. In vitro , bile acids activate the epithelial Na + channel (ENaC) found in the aldosterone-sensitive distal nephron. If this occurs in vivo , ENaC may become activated in liver disease even with antagonism of aldosterone signaling. Methods To test this, we performed bile duct ligation to induce liver disease and increase circulating bile acids in mice given spironolactone to antagonize aldosterone signaling. We analyzed effects on blood, urine, and body composition. We also determined the effects of taurocholic acid, a primary conjugated bile acid elevated in liver disease, on ion fluxes in microperfused rabbit collecting ducts. Results Bile duct ligation increased benzamil-sensitive natriuresis compared with sham, indicating ENaC activation. These effects were not explained by effects on ENaC expression, cleavage, or localization. Bile duct–ligated mice also gained significantly more fluid than sham-operated animals. Blocking ENaC reversed fluid gains in bile duct–ligated mice but had no effect in shams. In dissected collecting ducts from rabbits, which express ENaC, taurocholic acid stimulated net Na + absorption. Conclusions Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease.
The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells
Authors: Tatsuya Terasaki, Yuichiro Semba, Kensuke Sasaki, Hiroshi Imanaga, Kiyoko Setoguchi, Takuji Yamauchi, Shigeki Hirabayashi, Fumihiko Nakao, Koshi Akahane, Takeshi Inukai, Takaomi Sanda, Koichi Akashi, Takahiro Maeda
Journal: Leukemia (2024)
Parallel Evolution in Mosquito Vectors—A Duplicated Esterase Locus is Associated With Resistance to Pirimiphos-methyl in <i>Anopheles gambiae</i>
Authors: Sanjay C Nagi, Eric R Lucas, Alexander Egyir-Yawson, John Essandoh, Samuel Dadzie, Joseph Chabi, Luc S Djogbénou, Adandé A Medjigbodo, Constant V Edi, Guillaume K Ketoh, Benjamin G Koudou, Faisal Ashraf, Chris S Clarkson, Alistair Miles, David Weetman, Martin J Donnelly
Journal: Molecular Biology and Evolution (2024)

The primary control methods for the African malaria mosquito, Anopheles gambiae, are based on insecticidal interventions. Emerging resistance to these compounds is therefore of major concern to malaria control programs. The organophosphate (OP), pirimiphos-methyl, is a relatively new chemical in the vector control armory but is now widely used in indoor-residual spray campaigns. While generally effective, phenotypic resistance has developed in some areas in malaria vectors. Here, we used a population genomic approach to identify novel mechanisms of resistance to pirimiphos-methyl in A. gambiae s.l mosquitoes. In multiple populations, we found large and repeated signals of selection at a locus containing a cluster of detoxification enzymes, some of whose orthologs are known to confer resistance to OPs in Culex pipiens. Close examination revealed a pair of alpha-esterases, Coeae1f and Coeae2f, and a complex and diverse pattern of haplotypes under selection in A. gambiae, A. coluzzii and A. arabiensis. As in C. pipiens, copy number variants have arisen at this locus. We used diplotype clustering to examine whether these signals arise from parallel evolution or adaptive introgression. Using whole-genome sequenced phenotyped samples, we found that in West Africa, a copy number variant in A. gambiae is associated with resistance to pirimiphos-methyl. Overall, we demonstrate a striking example of contemporary parallel evolution which has important implications for malaria control programs.
The Effectiveness of Dialectical Behavior Therapy Compared to Schema Therapy for Borderline Personality Disorder: A Randomized Clinical Trial
Authors: Nele Assmann, Anja Schaich, Arnoud Arntz, Till Wagner, Philipp Herzog, Daniel Alvarez-Fischer, Valerija Sipos, Kamila Jauch-Chara, Jan Philipp Klein, Michael Hüppe, Ulrich Schweiger, Eva Fassbinder
Journal: Psychotherapy and Psychosomatics (2024)

In the treatment of borderline personality disorder (BPD), there is empirical support for both dialectical behavior therapy (DBT) and schema therapy (ST); these treatments have never been compared directly. This study examines whether either of them is more effective than the other in treating patients with BPD.
Following the Evolutionary Paths of Dscam1 Proteins toward Highly Specific Homophilic Interactions
Authors: Gil Wiseglass, Rotem Rubinstein
Journal: Molecular Biology and Evolution (2024)

Many adhesion proteins, evolutionarily related through gene duplication, exhibit distinct and precise interaction preferences and affinities crucial for cell patterning. Yet, the evolutionary paths by which these proteins acquire new specificities and prevent cross-interactions within their family members remain unknown. To bridge this gap, this study focuses on Drosophila Down syndrome cell adhesion molecule-1 (Dscam1) proteins, which are cell adhesion proteins that have undergone extensive gene duplication. Dscam1 evolved under strong selective pressure to achieve strict homophilic recognition, essential for neuronal self-avoidance and patterning. Through a combination of phylogenetic analyses, ancestral sequence reconstruction, and cell aggregation assays, we studied the evolutionary trajectory of Dscam1 exon 4 across various insect lineages. We demonstrated that recent Dscam1 duplications in the mosquito lineage bind with strict homophilic specificities without any cross-interactions. We found that ancestral and intermediate Dscam1 isoforms maintained their homophilic binding capabilities, with some intermediate isoforms also engaging in promiscuous interactions with other paralogs. Our results highlight the robust selective pressure for homophilic specificity integral to the Dscam1 function within the process of neuronal self-avoidance. Importantly, our study suggests that the path to achieving such selective specificity does not introduce disruptive mutations that prevent self-binding but includes evolutionary intermediates that demonstrate promiscuous heterophilic interactions. Overall, these results offer insights into evolutionary strategies that underlie adhesion protein interaction specificities.
Intraperitoneal drug delivery systems for peritoneal carcinomatosis: Bridging the gap between research and clinical implementation
Authors: M. Teresa Perelló-Trias, Antonio Jose Serrano-Muñoz, Ana Rodríguez-Fernández, Juan José Segura-Sampedro, Joana Maria Ramis, Marta Monjo
Journal: Journal of Controlled Release (2024)

Several abdominal-located cancers develop metastasis within the peritoneum, what is called peritoneal carcinomatosis (PC), constituting a clinical challenge in their therapeutical management, often leading to poor prognoses. Current multidisciplinary strategies, including cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC), demonstrate efficacy but have limitations. In response, alternative strategies are explored in the drug delivery field for intraperitoneal chemotherapy. Controlled drug delivery offers a promising avenue, maintaining localized drug concentrations for optimal PC management. Drug delivery systems (DDS), including hydrogels, implants, nanoparticles, and hybrid systems, show potential for sustained and region-specific drug release. The present review aims to offer an overview of the advances and current designs of DDS for PC chemotherapy administration, focusing on their composition, main characteristics, and principal experimental outcomes, highlighting the importance of biomaterial rationale design and in vitro/vivo models for their testing. Moreover, since clinical data for human subjects are scarce, we offer a critical discussion of the gap between bench and bedside in DDS translation, emphasizing the need for further research.
Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKC<b>γ</b>/STAT3 axis
Authors: Shaojian Lin, Liangbo Wang, Changxi Han, Yuting Dai, Changsheng Li, Yanting Liu, Bo Zhang, Ning Huang, Anke Zhang, Tao Zhang, Yu Wang, Jing Xie, Hao Tang, Yijun Cheng, Hong Yao, Meiqing Lou, Li Xue, Zhe Bao Wu
Journal: Neuro-Oncology (2024)

Abstract Background Managing nonfunctioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline’s (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. Methods We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. Results Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066. Conclusions HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.
Considerations for the care of transgender patients in orthopaedics and sports medicine: a narrative review
Authors: Madison Hayes-Lattin, Laura M Krivicich, Jack T Bragg, Ashley Rogerson, Matthew J Salzler
Journal: British Journal of Sports Medicine (2024)

Orthopaedic and sports medicine clinicians can improve outcomes for transgender patients by understanding the physiological effects of gender-affirming hormone therapy (GAHT). This narrative review investigated the role of GAHT on bone mineral density, fracture risk, thromboembolic risk, cardiovascular health and ligament/tendon injury in this population. A search from the PubMed database using relevant terms was performed. Studies were included if they were levels 1–3 evidence. Due to the paucity of studies on ligament and tendon injury risk in transgender patients, levels 1–3 evidence on the effects of sex hormones in cisgender patients as well as basic science studies were included for these two topics. This review found that transgender patients on GAHT have an elevated fracture risk, but GAHT has beneficial effects on bone mineral density in transgender women. Transgender women on GAHT also have an increased risk of venous thromboembolism, stroke and myocardial infarction compared with cisgender women. Despite these elevated risks, studies have found it is safe to continue GAHT perioperatively for both transgender women and men undergoing low-risk operations. Orthopaedic and sports medicine clinicians should understand these unique health considerations for equitable patient care.
Dysregulation of immune checkpoint molecules as a characteristic of autoimmune congenital heart block
Authors: Ana-Luisa Stefanski, Hector Rincon-Arevalo, Iris Dressler-Steinbach, Nadja Nomovi, Alma Mackert, Arman Aue, Jacob Ritter, Annika Wiedemann, Franziska Szelinski, Eva Schrezenmeier, Anja A Kühl, Andreia C Lino, Wolfgang Henrich, Thomas Dörner
Journal: Annals of the Rheumatic Diseases (2024)
Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration
Authors: Hao Li, Tianyuan Zhao, Zhiguo Yuan, Tianze Gao, Yongkang Yang, Runmeng Li, Qinyu Tian, Peifu Tang, Quanyi Guo, Licheng Zhang
Journal: Bioactive Materials (2024)

Despite numerous studies on chondrogenesis, the repair of cartilage-particularly the reconstruction of cartilage lacunae through an all-in-one advanced drug delivery system remains limited. In this study, we developed a cartilage lacuna-like hydrogel microsphere system endowed with integrated biological signals, enabling sequential immunomodulation and endogenous articular cartilage regeneration. We first integrated the chondrogenic growth factor transforming growth factor-β3 (TGF-β3) into mesoporous silica nanoparticles (MSNs). Then, TGF-β3@MSNs and insulin-like growth factor 1 (IGF-1) were encapsulated within microspheres made of polydopamine (pDA). In the final step, growth factor-loaded MSN@pDA and a chitosan (CS) hydrogel containing platelet-derived growth factor-BB (PDGF-BB) were blended to produce growth factors loaded composite microspheres (GFs@μS) using microfluidic technology. The presence of pDA reduced the initial acute inflammatory response, and the early, robust release of PDGF-BB aided in attracting endogenous stem cells. Over the subsequent weeks, the continuous release of IGF-1 and TGF-β3 amplified chondrogenesis and matrix formation. μS were incorporated into an acellular cartilage extracellular matrix (ACECM) and combined with a polydopamine-modified polycaprolactone (PCL) structure to produce a tissue-engineered scaffold that mimicked the structure of the cartilage lacunae evenly distributed in the cartilage matrix, resulting in enhanced cartilage repair and patellar cartilage protection. This research provides a strategic pathway for optimizing growth factor delivery and ensuring prolonged microenvironmental remodeling, leading to efficient articular cartilage regeneration.
Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition
Authors: Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M. Totiger, Maurizio Affer, Abimbola Eunice Lawal, Skye Montoya, Francesco Tamiro, Olivia Tonini, Alexandra Chirino, Andrew Adams, Anya K. Sondhi, Stephen Noudali, Alyssa Mauri Cornista, Miah Nicholls, Jumana Afaghani, Paola Robayo, Daniel Bilbao, Stephen D. Nimer, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor
Journal: Leukemia (2024)

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1
When I use a word . . . Love drugs
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

Love potions, also called love-drinks and love philtres, are among the oldest forms of fictional drugs. The terms date from the 13th century (love-drinks) and the 16th and 17th centuries (love potions and love philtres respectively). Fictions that have featured love potions include: all versions of the legend of Tristan and Isolde, whatever the variant spellings of their names; the Prologue to the Wife of Bath's Tale in Chaucer's <i>Canterbury Tales</i>; Sir Philip Sidney's <i>Arcadia</i>; Donizetti's opera buffa <i>L'elisir d'amore</i> and W S Gilbert's burlesque based on it; other works by Gilbert, who was fond of the idea; and Shakespeare's <i>Midsummer Night's Dream</i>. The contents of love potions, in these and contemporary works, are generally unknown and in the case of <i>L'elisir d'amore</i> the love potion consisted of red wine, disqualifying it as a love potion. Some of the so-called love potions turned out to be poisons of one sort or another. Modern love drugs encompass drugs for erectile impotence and drugs with psychotropic actions. But would a drug that enhanced the chances of romance be ethical? There are, for example, doubts about the sincerity and durability of the expected outcome. There are also potential problems with medicinal regulation of love-inducing drugs. And similar concerns would apply to anti-love drugs.