bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical trials for chimeric antigen receptor T-cell therapy: lessons learned and future directions
Authors: Schroeder Brett A. , Jess Jennifer , Sankaran Hari , Shah Nirali N. 
Published: July 2022

Purpose of review
The purpose of this review is to summarize the status and utilization of chimeric antigen receptor T-cell (CAR-T) therapy based on the most recent clinical trials in patients with leukemia and lymphoma. Additionally, this review will highlight limitations in current strategies, discuss efforts in toxicity mitigation, and outline future directions for investigation.

Recent findings
CD19 targeted CAR-T-cell therapy (CD19-CAR) is highly effective in patients with relapsed/refractory (r/r) B-cell hematologic malignancies. However, multiple challenges have arisen, particularly life-threatening adverse events, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Despite these challenges, recent CD19-CAR trials, including two randomized studies, have demonstrated both impressive initial results along with durable responses. Combined with results emerging from ‘real-world’ experience, the efficacy of CAR-T-cells is high, propelling CAR-T-cells studies targeting alternate B-cell antigens [e.g. CD20, CD22 and CD269 (BCMA)] and other targets for hematologic malignancies, along with solid and CNS tumors.

Summary
Given the benefit for CD19-CAR, determining the appropriate place in utilization for both an individual patient's treatment course and more broadly in the generalized treatment paradigm is critically needed. We discuss the most recent trials exploring this topic and future directions in the field.
Application of the Method of Melanin Bleaching After Immunohistochemical Staining of Melanin-containing Tissues
Authors: Huang Jianping , Wu Xuejing , Feng Changyin , Yang Yinghong 
Published: July 2022

Objective:
The purpose of this research was to investigate the method of melanin bleaching in immunohistochemical staining of melanin-containing tissues.

Materials and Methods:
Forty melanin-containing tissue samples were selected, including 30 with malignant melanoma and 10 with blue naevi. The samples were divided into the following 3 groups: the prestaining bleaching group, nonbleaching group, and poststaining bleaching group. Each group was subjected to HMB45 and MelanA immunohistochemical staining. The detection system used was Roche ventana ultraview universal alkaline phosphatase red kit.

Results:
In the prestaining bleaching group, melanin pigment was mostly removed. However, antigen expression was also affected, which resulted in significantly weaker positive staining and even represented false-negative expression. In the nonbleaching group, positive staining resulted in a red color that could easily be distinguished from the brown granules of melanin pigment. However, some melanin granules covered the tissue, impacting our observation of tissue structure. In the poststaining bleaching group, the results of positive staining were comparable to those in the nonbleaching group. The melanin pigment in these sections was almost completely removed, resulting in clearer staining and easier observation of tissue and cell structure.

Conclusion:
The method of melanin bleaching after immunohistochemical staining of melanin-containing tissue can almost completely bleach the melanin pigment and do not impact the expression of antigen. In our work, poststaining bleaching allowed for clearer immunohistochemical staining results and more obvious observation of tissue structure. This method also has the advantages of requiring simple reagents, utilizing simple operation procedures, and producing practical staining results, which makes it worthy of promotion!
The First Dorsal Metacarpal Artery Perforator Free Flap: The Comet Flap
Authors: Abu-Ghname Amjed , Lazo Daniel , Chade Salomao , Fioravanti Alex , Colicchio Olimpio , Alvarez Daniel , Junior Ernani , Maricevich Marco 
Published: July 2022

Background:
Distal extremity defects pose a particular challenge to the reconstructive surgeon; however, advances in perforator flaps have expanded the potential reconstructive options. In this article, the authors present their experience in reconstructing distal extremity defects using a thin, cutaneous free flap based on the perforator of the first dorsal metacarpal artery: the comet flap.

Methods:
A retrospective review was performed on all patients who presented with a distal extremity defect and underwent reconstruction using a comet flap between 2015 and 2019. Patient demographics, flap anatomy and harvest, and postoperative course were reviewed and analyzed.

Results:
A total of 16 patients were included. The mean patient age was 36.5 years. Trauma was the most common cause. The average defect size was 5.4 × 3.2 cm. The average pedicle length of the comet flap ranged from 3.5 to 30 cm, depending on involvement of the radial vessels. All donor sites underwent uncomplicated closure with local rhomboid flaps. One flap was complicated by an acute venous thrombosis that was successfully treated operatively. The flap survival rate was 95 percent. All patients were able to maintain their preoperative range of motion and were satisfied with their final outcome. Follow-up time ranged from 6 to 50 months.

Conclusions:
Local flaps remain an important reconstructive approach for distal extremity defects; however, in complex soft-tissue injuries, free tissue transfers become necessary. The comet flap is a safe, versatile, and reliable flap for reconstructing upper and lower extremity defects that can be performed in a single procedure under regional anesthesia.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
Suspensionplasty for Revision Thumb Carpometacarpal Osteoarthritis Surgery: Comparing Suture Button Suspensionplasty to Ligament Reconstruction and Tendon Interposition
Authors: Guerrero Evan M. , Ferlauto Harrison R. , Grier A. Jordan , Wahl Elizabeth P. , Richard Marc J. , Ruch David S. 
Published: July 2022

Summary:
Several surgical procedures have been described to treat thumb carpometacarpal osteoarthritis, including suture button suspensionplasty and ligament reconstruction and tendon interposition. To date, no single procedure has demonstrated clinical superiority. Suture button suspensionplasty has achieved favorable outcomes at 5 years in primary cases, but has not been validated in revision surgery. In this study, it was evaluated for revision of failed thumb carpometacarpal osteoarthritis surgery, and outcomes were compared to ligament reconstruction and tendon interposition outcomes. A retrospective chart review identified patients who underwent suture button suspensionplasty or ligament reconstruction and tendon interposition after failure of previous thumb carpometacarpal osteoarthritis surgery since 2010. Eighteen patients were included, with nine patients in each group. Eighteen patients had mean final follow-up of 35 months. There were two complications in the ligament reconstruction and tendon interposition group and none in the suture button suspensionplasty group. No patients required additional surgery. The suture button suspensionplasty group had an average visual analogue scale pain score improvement of 2.9, compared to 2.4 in the ligament reconstruction and tendon interposition group. Average final Quick Disabilities of the Arms, Shoulder and Hand questionnaire score was 15.1 in the suture button suspensionplasty group, compared to 22.6 in the ligament reconstruction and tendon interposition group. Mean operative time of 86.3 minutes in the suture button suspensionplasty group was significantly shorter than the 121-minute mean in the ligament reconstruction and tendon interposition group. Suture button suspensionplasty is an effective treatment option for revision of previous thumb carpometacarpal osteoarthritis surgery, with outcomes comparable to revision using ligament reconstruction and tendon interposition, and the added benefit of shorter operative times and early mobilization.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, III.
Island perforator muscle flaps for chronic osteomyelitis of the lower extremities: a retrospective analysis of 21 consecutive cases
Authors: Zhao Xiaozhuo , Shen Yuming 
Published: July 2022

Background:
One of the procedures for treating chronic osteomyelitis is the management of dead space resulting from aggressive debridement of the marrow cavity. To fill the void created by debridement, various muscle flaps have been recommended by many surgeons for their convenience and anti-infective properties. The objective of our study was to evaluate the efficacy of island perforator muscle flaps for the reconstruction of chronic osteomyelitis debridement defects of the lower extremities and provide indications for the selection of the muscle flap.

Methods:
A retrospective review of consecutive patients with chronic osteomyelitis of the lower extremities who underwent reconstruction using the island perforator muscle flap procedure from 2015 through 2018 was conducted. Data were collected on characteristics of the patients, wound site, wound size, surgical procedure, muscle choice, and wound healing.

Results:
For the 21 patients included in the study, all muscle flaps survived. Wounds healed completely within 4 weeks. No infection relapses were identified during the follow-up period of at least 12 months. Simple primary closure, with no additional incision in the donor site, was achieved in five patients. In eight patients, an additional incision was made to harvest a muscle flap, but both the wound and donor site were closed primarily.

Conclusions:
The results showed that the island perforator muscle flap is less invasive, easy to harvest, and effective, which can be a good choice for the management of dead space resulting from debridement for chronic osteomyelitis in the lower extremity.
Ventilator-associated pneumonia and intubation location in adults with traumatic injuries: Systematic review and meta-analysis
Authors: Baumann Laura , Harper Kelsey , Riblet Natalie , Hatton Colman , Atchinson Patricia Ruth , Roginski Matthew 
Published: July 2022

BACKGROUND
Ventilator-associated pneumonia (VAP) is an important cause of morbidity and mortality among critically ill patients, particularly those who present with traumatic injuries. This review aims to determine whether patients with traumatic injuries who are intubated in the prehospital setting are at higher risk of developing VAP compared with those intubated in the hospital.

METHODS
A systematic review of Medline, Scopus, and Cochrane electronic databases was conducted from inception to January 2021. Inclusion criteria were patients with traumatic injuries who were intubated in the prehospital or hospital settings with VAP as an outcome. Using a random-effects model, the risk of VAP across study arms was compared by calculating a summary relative risk with 95% confidence intervals. The results of individual studies were also summarized qualitatively.

RESULTS
The search identified 754 articles of which 6 studies (N = 2,990) met the inclusion criteria. All studies were good quality based on assessment with the Newcastle Ottawa scale. Prehospital intubation demonstrated an increased risk of VAP development in two of the six studies. Among the six studies, the overall quality weighted risk ratio was 1.09 (95% confidence interval, 0.90–1.31).

CONCLUSION
Traumatically injured patients who are intubated in the prehospital setting have a similar risk of developing VAP compared with those that are intubated in the hospital setting.

LEVEL OF EVIDENCE
Systematic review and meta-analysis; Level IV.
Imaging of sleep disorders in pre-Parkinsonian syndromes
Authors: Ota Yoshiaki , Kanel Prabesh , Bohnen Nicolaas 
Published: July 2022

Purpose of review
Neuroimaging has been advanced in the last years and enabled clinicians to evaluate sleep disorders, especially isolated rapid eye movement sleep disorder (iRBD), which can be seen in alpha-synucleinopathies. iRBD is the best prodromal clinical marker for phenoconversion to these neurodegenerative diseases. This review aims to provide an update on advanced neuroimaging biomarkers in iRBD.

Recent findings
Advanced structural MRI techniques, such as diffusion tensor imaging and functional MRI, neuromelanin-sensitive MRI, and scintigraphic neuroimaging such as cholinergic PET, dopamine transporter imaging – single-photon emission computerized tomography, perfusional single-photon emission computerized tomography, and cardiac metaiodobenzylguanidine can provide diagnostic and prognostic imaging biomarkers for iRBD, in isolation and more robustly when combined.

Summary
New advanced neuroimaging can provide imaging biomarkers and aid in the appropriate clinical assessment and future therapeutic trials.
Cryo-EM structure of a eukaryotic zinc transporter at a low pH suggests its Zn2+-releasing mechanism
Authors: Zhang Senfeng , Fu Chunting , Luo Yongbo , Xie Qingrong , Xu Tong , Sun Ziyi , Su Zhaoming , Zhou Xiaoming 
Published: July 2022

AbstractZinc transporter 8 (ZnT8) is mainly expressed in pancreatic islet β cells and is responsible for H+-coupled uptake (antiport) of Zn2+ into the lumen of insulin secretory granules. Structures of human ZnT8 and its prokaryotic homolog YiiP have provided structural basis for constructing a plausible transport cycle for Zn2+. However, the mechanistic role that protons play in the transport process remains unclear. Here we present a lumen-facing cryo-EM structure of ZnT8 from Xenopus tropicalis (xtZnT8) in the presence of Zn2+ at a luminal pH (5.5). Compared to a Zn2+-bound xtZnT8 structure at a cytosolic pH (7.5), the low-pH structure displays an empty transmembrane Zn2+-binding site with a disrupted coordination geometry. Combined with a Zn2+-binding assay our data suggest that protons may disrupt Zn2+ coordination at the transmembrane Zn2+-binding site in the lumen-facing state, thus facilitating Zn2+ release from ZnT8 into the lumen.
Structural analysis of 1-deoxy-D-xylulose 5-phosphate synthase from Pseudomonas aeruginosa and Klebsiella pneumoniae reveals conformational changes upon cofactor binding
Authors: Hamid Rawia , Adam Sebastian , Lacour Antoine , Gomez Leticia Monjas , Hirsch Anna K. H. 
Published: July 2022

AbstractIsoprenoid precursor biosynthesis is an essential part of primary metabolism in all living organisms. While eukaryotes utilize the mevalonate (MEV) pathway for isoprenoid-precursor biosynthesis, the most important bacterial pathogens rely on the methylerythritol-phosphate (MEP) pathway. Therefore, enzymes involved in the MEP pathway are potentially valuable targets for the development of novel antibacterials to tackle the current antimicrobial resistance crisis. Within the MEP pathway, the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) represents a crucial, rate-limiting first step and a branch point in the biosynthesis of the vitamins B1 and B6. Herein, we present two novel, high-resolution DXPS crystal structures of the important ESKAPE pathogens Pseudomonas aeruginosa and Klebsiella pneumoniae in both the co-factor-bound and apo forms. We demonstrate that the absence of the cofactor ThDP leads to a disordered loop close to the active site and may be important for the design of potent DXPS inhibitors, albeit being different in both structures. In addition, we report the complex structure of paDXPS with a fluoropyruvate adduct, shedding more light on the structural basis of DXPS catalysis. Lastly, we have determined a complex structure of paDXPS with a thiamine analogue, opening up a route for structure-based drug design of this essential enzyme of the MEP pathway.
Impact of storage on starch digestibility and texture of a high-amylose wheat bread
Authors: Corrado M. , Zafeiriou P. , Ahn-Jarvis J.H. , Savva G.M. , Edwards C.H. , Hazard B.A. 
Published: July 2022

AbstractStaling is a complex process that determines the shelf-life of baked products like bread. Breads made using high-amylose flour may elicit a lower glycaemic response, with benefits for health, however the impact of storage on novel high-amylose wheat foods structure are not known.We investigated the staling behaviour of high-amylose bread made from a starch branching enzyme II (sbeII) wheat mutant compared to a wild-type (WT) control, by measuring starch digestibility (susceptibility to amylolysis) and bread texture over time in different storage conditions. Breads prepared from sbeII and WT control wheat flours were subjected to fresh, refrigerated and frozen storage, and starch digestibility and crumb texture were measured up to three days. Starch from sbeII flour was characterised by a larger proportion of long chains resulting in increased amylose content, typical of sbeII mutant wheat. Starch in sbeII bread was less susceptible to amylolysis when freshly baked (~17% difference of starch digested at 90 min, C90) and after storage (26%-28% C90 difference, depending on the storage condition), compared to the WT control. Texture of freshly baked sbeII bread was similar to the WT control; storage conditions affected the progression of crumb firming and resilience to touch for both breads, but changes in crumb texture were less pronounced in sbeII bread. Overall, sbeII bread was less prone to staling than conventional WT bread during the first three days of storage, particularly when stored in the fridge or at room temperature.
The integrated stress response induces a common cell-autonomous death receptor 5-dependent apoptosis switch
Authors: Muniozguren Nerea L. , Zappa Francesca , Acosta-Alvear Diego 
Published: July 2022

AbstractThe integrated stress response (ISR) is a fundamental signaling network that reprograms the transcriptome and proteome to leverage the cell’s biosynthetic capacity against different stresses. Signaling plasticity is enabled by distinct ISR sensor kinases that detect specific perturbations. The ISR is dichotomous, with tailored homeostatic outputs and a terminal one engaged upon overwhelming stress. Through a chemical-genetics approach that uncouples natural stress inputs from ISR actuation, we show that the ISR engages an input-agnostic, cell-autonomous apoptosis mechanism that requires unconventional signaling by death receptor 5. Our results indicate that a common ISR mechanism eliminates terminally injured cells.
Locomotor-related propriospinal V3 neurons produce primary afferent depolarization and modulate sensory transmission to motoneurons
Authors: Lin Shihao , Hari Krishnapriya , Lucas-Osma Ana M. , Black Sophie , Khatmi Aysan , Fouad Karim , Gorassini Monica A. , Li Yaqing , Fenrich Keith K. , Bennett David J. 
Published: July 2022

ABSTRACTWhen a muscle is stretched it not only responds with a reflex, but the sensory afferent feedback also depolarizes many afferents throughout the spinal cord (termed primary afferent depolarization, PAD), readying the whole limb for further disturbances. This sensory-evoked PAD is thought to be caused by a trisynaptic circuit, where sensory input activates first order excitatory neurons that activate GABAergic neurons that in turn activate GABAA receptors on afferents to cause PAD, though the identity of these first order neurons is unclear. Here we show that these first order neurons are propriospinal V3 neurons, since they receive extensive sensory input and in turn innervate GABAergic neurons that cause PAD, because optogenetic activation or inhibition of V3 neurons in mice mimics or inhibits sensory-evoked PAD, respectively. Furthermore, persistent inward sodium currents (Na PICs) intrinsic to V3 neurons enable them to respond to transient inputs with long-lasting responses, explaining the long time-course of PAD. Also, local optogenetic activation of V3 neurons at one segment causes PAD in other segments, due to the long propriospinal tracts of these neurons, explaining the widespread radiation of PAD across the spinal cord. This in turn facilitates monosynaptic reflex transmission to motoneurons across the spinal cord. Additionally, we find that V3 neurons directly innervate proprioceptive afferents, causing a glutamate receptor mediated PAD (glutamate PAD). Finally, we show that increasing the spinal cord excitability with either GABAA receptor blockers or chronic spinal cord injury causes an increase in the glutamate PAD, perhaps contributing to spasms after SCI. Overall, we show the V3 neuron has a prominent role in modulating sensory transmission, in addition to its previously described role in locomotion.
Generation of a transparent killifish line through multiplex CRISPR/Cas9-mediated gene inactivation
Authors: Krug Johannes , Albertz Carolin , Hopfenmüller Vera L. , Englert Christoph 
Published: July 2022

AbstractBody pigmentation is a major limitation for in vivo imaging and thus for the performance of longitudinal studies in biomedicine. A possibility to circumvent this obstacle is the employment of pigmentation mutants, which are used in fish species like zebrafish and medaka. To address the molecular basis of aging, the short-lived African killifish Nothobranchius furzeri has recently been established as a model organism. Despite its short lifespan, N. furzeri shows typical signs of mammalian aging including telomere shortening, accumulation of senescent cells and loss of regenerative capacity. Here, we report the generation of a transparent N. furzeri line by simultaneous inactivation of three key loci responsible for pigmentation. We demonstrate that this stable line, named klara, can serve as a tool for different in vivo applications including behavioral experiments addressing mate choice and the establishment of a senescence reporter by homology-directed repair-mediated integration of a fluorophore into the cdkn1a (p21) locus.
Complex Traits and Candidate Genes: Estimation of Genetic Variance Components Across Modes of Inheritance
Authors: Feldmann Mitchell J. , Covarrubias-Pazaran Giovanny , Piepho Hans-Peter 
Published: July 2022

AbstractLarge-effect loci—those discovered by genome-wide association studies or linkage mapping—associated with key traits segregate amidst a background of minor, often undetectable genetic effects in both wild and domesticated plants and animals. Accurately attributing mean differences and variance explained to the correct components in the linear mixed model (LMM) analysis is important for both selecting superior progeny and parents in plant and animal breeding, but also for gene therapy and medical genetics in humans. Marker-assisted prediction (MAP) and its successor, genomic prediction (GP), have many advantages for selecting superior individuals and understanding disease risk. However, these two approaches are less often integrated to simultaneously study the modes of inheritance of complex traits. This simulation study demonstrates that the average semivariance can be applied to models incorporating Mendelian, oligogenic, and polygenic terms, simultaneously, and yields accurate estimates of the variance explained for all relevant terms. Our previous research focused on large-effect loci and polygenic variance exclusively, and in this work we want to synthesize and expand the average semivariance framework to a multitude of different genetic architectures and the corresponding mixed models. This framework independently accounts for the effects of large-effect loci and the polygenic genetic background and is universally applicable to genetics studies in humans, plants, animals, and microbes.