Lesion recognition by XPC, TFIIH and XPA in DNA excision repair.

Nucleotide excision repair removes DNA lesions caused by ultraviolet light, cisplatin-like compounds and bulky adducts1. After initial recognition by XPC in global genome repair or a stalled RNA polymerase in transcription-coupled repair, damaged DNA is transferred to the seven-subunit TFIIH core complex (Core7) for verification and dual incisions by the XPF and XPG nucleases2. Structures capturing lesion recognition by the yeast XPC homologue Rad4 and TFIIH in transcription initiation or DNA repair have been separately reported3-7. How two different lesion recognition pathways converge and how the XPB and XPD helicases of Core7 move the DNA lesion for verification are unclear. Here we report on structures revealing DNA lesion recognition by human XPC and DNA lesion hand-off from XPC to Core7 and XPA. XPA, which binds between XPB and XPD, kinks the DNA duplex and shifts XPC and the DNA lesion by nearly a helical turn relative to Core7. The DNA lesion is thus positioned outside of Core7, as would occur with RNA polymerase. XPB and XPD, which track the lesion-containing strand but translocate DNA in opposite directions, push and pull the lesion-containing strand into XPD for verification.

An engineered IL-2 partial agonist promotes CD8+ T cell stemness.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.

Reversible and irreversible inhibitors of coronavirus Nsp15 endoribonuclease.

The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less-explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is an irreversible inhibitor that might act via covalent modification of Cys residues within Nsp15. Moreover, we demonstrate that three of these inhibitors (hexachlorophene, IPA-3, and CID5675221) block severe acute respiratory syndrome coronavirus 2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors and pinpoints lead compounds for further development against coronavirus disease 2019 and related coronavirus infections.

Soft tissue tumor imaging in adults: whole-body staging in sarcoma, non-malignant entities requiring special algorithms, pitfalls and special imaging aspects. Guidelines 2024 from the European Society of Musculoskeletal Radiology (ESSR).

OBJECTIVES: The revised European Society of Musculoskeletal Radiology (ESSR) consensus guidelines on soft tissue tumor imaging represent an update of 2015 after technical advancements, further insights into specific entities, and revised World Health Organization (2020) and AJCC (2017) classifications. This second of three papers covers algorithms once histology is confirmed: (1) standardized whole-body staging, (2) special algorithms for non-malignant entities, and (3) multiplicity, genetic tumor syndromes, and pitfalls. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements that had undergone interdisciplinary revision were scored online by the level of agreement (0 to 10) during two iterative rounds, that could result in 'group consensus', 'group agreement', or 'lack of agreement'. RESULTS: The three sections contain 24 statements with comments. Group consensus was reached in 95.8% and group agreement in 4.2%. For whole-body staging, pulmonary MDCT should be performed in all high-grade sarcomas. Whole-body MRI is preferred for staging bone metastasis, with [18F]FDG-PET/CT as an alternative modality in PET-avid tumors. Patients with alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma should be screened for brain metastases. Special algorithms are recommended for entities such as rhabdomyosarcoma, extraskeletal Ewing sarcoma, myxoid liposarcoma, and neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors. Satisfaction of search should be avoided in potential multiplicity. CONCLUSION: Standardized whole-body staging includes pulmonary MDCT in all high-grade sarcomas; entity-dependent modifications and specific algorithms are recommended for sarcomas and non-malignant soft tissue tumors. CLINICAL RELEVANCE STATEMENT: These updated ESSR soft tissue tumor imaging guidelines aim to provide support in decision-making, helping to avoid common pitfalls, by providing general and entity-specific algorithms, techniques, and reporting recommendations for whole-body staging in sarcoma and non-malignant soft tissue tumors. KEY POINTS: An early, accurate, diagnosis is crucial for the prognosis of patients with soft tissue tumors. These updated guidelines provide best practice expert consensus for standardized imaging algorithms, techniques, and reporting. Standardization can improve the comparability examinations and provide databases for large data analysis.

Enhancing Patient Adherence to Newly-Prescribed Medicine for Chronic Diseases: A Comprehensive Review and Cost-Effective Approach to Implementing the New Medicine Service in Community Pharmacies in Poland.

New Medicine Service (NMS) components are an important element to improve patient compliance with medical recommendations. NMS provides support to patients prescribed new medicines, helping them to manage long-term conditions. The purpose of this service is to provide patients with advice, guidelines, and educational materials regarding the use of new medicines to increase patient compliance and therapy safety. The NMS has already been introduced in many European countries. This review aims to identify the benefits and potential barriers to implementing the NMS in community pharmacies and to suggest solutions that would increase its effectiveness. Previous studies have primarily shown that the NMS improves patient compliance with therapy, accelerating the expected effects of the therapy. Pharmacist support during implementation of a new drug therapy substantially increases patient safety. As the experience of numerous countries shows, both pharmacists and patients express positive opinions on this service. Therefore, it seems that NMS should be an indispensable part of pharmaceutical patient care in any healthcare system. This article aims to review the implementation of the New Medicine Service (NMS) for community pharmacists in Poland and the provision of a cost-effective approach to improve patient adherence to newly-prescribed medicine for chronic diseases.

History Page: Leaders in MSK Radiology: Stanislas de Sèze, 1903-2000.

This history page is dedicated to the memory and achievements of the French rheumatologist Stanislas de Sèze whose name is connected to the so-called de Sèze view, used to evaluate the sacroiliac joints, the lumbar and lower thoracic spine, pelvis, and hip joints on a single anteroposterior radiograph.

Imaging of musculoskeletal tuberculosis.

Tuberculosis (TB) represents a major public health problem worldwide. Any tissue may be infected. Involvement of the musculoskeletal (MSK) system account for 1-3% of all tuberculous infections. MSK TB may manifest as tuberculous spondylitis, arthritis, osteomyelitis, and soft tissue infections. Although TB spondylitis may present with distinctive imaging features compared to pyogenic infections of the spine, the imaging semiology of extra-spinal TB infections is mostly nonspecific and may mimic other lesions. TB infections should therefore always be considered in the differential diagnosis, particularly in immunocompromised patients. The aim of this article is to review the imaging features of spinal and extra-spinal MSK TB. Magnetic resonance imaging is considered the modality of choice to make the diagnosis and to evaluate the extent of the disease.

Innate lymphoid cell characterization in the rat and their correlation to gut commensal microbes.

Innate lymphoid cells (ILCs) are important for tissue immune homeostasis, and are thoroughly characterized in mice and humans. Here, we have performed in-depth characterization of rat ILCs. Rat ILCs were identified based on differential expression of transcription factors and lack of lineage markers. ILC3s represented the major ILC population of the small intestine, while ILC2s were infrequent but most prominent in liver and adipose tissue. Two major subsets of group 1 ILCs were defined. Lineage- T-bet+ Eomes+ cells were identified as conventional NK cells, while lineage- T-bet+ Eomes- cells were identified as the probable rat counterpart of ILC1s based on their selective expression of the ILC marker CD200R. Rat ILC1s were particularly abundant in liver and intestinal tissues, and were functionally similar to NK cells. Single-cell transcriptomics of spleen and liver cells confirmed the main division of NK cells and ILC1-like cells, and demonstrated Granzyme A as an additional ILC1 marker. We further report differential distributions of NK cells and ILCs along the small and large intestines, and the association of certain bacterial taxa to frequencies of ILCs. In conclusion, we provide a framework for future studies of ILCs in diverse rat experimental models, and novel data on the potential interplay between commensals and intestinal ILCs.

Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2023-overview, and primary local imaging: how and where?

OBJECTIVES: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. RESULTS: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. CONCLUSION: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. CLINICAL RELEVANCE: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. KEY POINTS: • Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. • MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. • In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.

Effects of Platinum Nanoparticles on Rice Seedlings (Oryza sativa L.): Size-dependent Accumulation, Transformation, and Ionomic Influence.

Platinum nanoparticles (PtNPs) are increasing in the environment largely due to their wide use and application in automobile and medical industries. The mechanism of uptake behavior of different-sized PtNPs and their association with PtNPs-induced phytotoxicity to plants remains unclear. The present study investigated PtNP uptake mechanisms and phytotoxicity simultaneously to further understand the accumulation and transformation dynamics. The uptake mechanisms were investigated by comparing the uptake and toxicological effects of three different-sized PtNPs (25, 50, and 70 nm) on rice seedlings across an experimental concentration gradient (0.25, 0.5, and 1 mg/L) during germination. The quantitative and qualitative results indicated that 70 nm-sized PtNPs were more efficiently transferred in rice roots. The increase in the PtNP concentration restricted the particle uptake. Particle aggregation was common in plant cells and tended to dissolve on root surfaces. Notably, the dissolution of small particles was simultaneous with the growth of larger particles after PtNPs entered the rice tissues. Ionomic results revealed that PtNP accumulation induced element homeostasis in the shoot ionome. We observed a significant positive correlation between the PtNP concentration and Fe and B accumulation in rice shoots. Compared to particle size, the exposure concentration of PtNPs had a stronger effect on the shoot ionomic response. Our study provides better understanding of the correlation of ionomic change and NP quantitative accumulation induced by PtNPs in rice seedlings.

A state-of-the-art review on cadmium uptake, toxicity, and tolerance in rice: From physiological response to remediation process.

Cadmium (Cd), a major contaminant of concern, has been extensively reviewed and debated for its anthropogenic global shifts. Cadmium levels in rice grains raise wide food safety concerns. The aim of this review is therefore to capture the dynamics of Cd in paddy soil, translocation pathways of Cd from soil to consumption rice, and assess its bio-accessibility in human consumption. In crop plants, Cd reduces absorption of nutrients and water, triggers oxidative stress, and inhibits plant metabolism. Understanding the mechanisms and behaviour of Cd in paddy soil and rice allows to explain, predict and intervene in Cd transferability from soil to grains and human exposure. Factors affecting Cd movement in soil, and further to rice grain, are elucidated. Recently, physiological and molecular understanding of Cd transport in rice plants have been advanced. Morphological-biochemical characteristics and Cd transporters of plants in such a movement were also highlighted. Ecologically viable remediation approaches, including low input cost agronomic methods, phytoremediation and microbial bioremediation methods, are emerging.

Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair.

Transcription factor IIH (TFIIH) is essential for both transcription and nucleotide excision repair (NER). DNA lesions are initially detected by NER factors XPC and XPE or stalled RNA polymerases, but only bulky lesions are preferentially repaired by NER. To elucidate substrate specificity in NER, we have prepared homogeneous human ten-subunit TFIIH and its seven-subunit core (Core7) without the CAK module and show that bulky lesions in DNA inhibit the ATPase and helicase activities of both XPB and XPD in Core7 to promote NER, whereas non-genuine NER substrates have no such effect. Moreover, the NER factor XPA activates unwinding of normal DNA by Core7, but inhibits the Core7 helicase activity in the presence of bulky lesions. Finally, the CAK module inhibits DNA binding by TFIIH and thereby enhances XPC-dependent specific recruitment of TFIIH. Our results support a tripartite lesion verification mechanism involving XPC, TFIIH, and XPA for efficient NER.

John P. Caffey, 1895-1978.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of Dr. John Caffey, whose name is associated with infantile cortical hyperostosis, also known as Caffey's disease.

History Page: Leaders in MSK Radiology Maxime Ménard, 1872-1926.

This history page in the series "Leaders in Musculoskeletal Radiology" is dedicated to the memory and achievements of French radiologist Maxime Ménard, whose name is associated with the Shenton-Ménard line that Ménard described independently with the British radiologist Edward Shenton. This landmark line describes the relationship of the proximal femur to the acetabulum in hip dysplasia and fractures of the femoral neck.

Imaging of the Craniocervical Junction: A Pictorial Review.

The craniocervical junction (CCJ) is a complex anatomical structure comprising the occiput, the atlas, and the axis. The CCJ plays an important role in maintaining stability, providing protection, and supporting neurovascular structures. The CCJ can be affected by a wide range of congenital variants and traumatic, degenerative, inflammatory, and tumoral pathologies. This pictorial review the normal anatomy of the CCJ and presents the most common anatomical variants and pathologic conditions affecting the CCJ.

Kazimierz S. Kozlowski, 1928.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of the Polish radiologist Kazimierz Kozlowski, whose name is associated with the Kozlowski type of spondylometaphyseal dysplasia.

Lunotriquetral Coalition.

Lunotriquetral (LT) coalition is the most common carpal coalition. Four morphological types of LT coalition have been described. LT coalition is usually asymptomatic, but rarely a fibrocartilaginous type may cause ulnar wrist pain. We report a case of bilateral asymptomatic LT coalition that was seen incidentally on conventional radiography taken after a wrist injury. Conventional radiography is the first imaging technique to detect and classify this type of LT coalition. Magnetic resonance imaging is a useful tool to investigate possible associated pathology of the carpal joints, particularly if surgical treatment of a symptomatic patient is anticipated.

Tardigrade and Manifold Sign: Two New Signs in Dupuytren's Disease.

Dupuytren's disease (DD) is a chronic benign fibroproliferative disorder of the palmar and digital fasciae. It is characterized by formation of nodules and fibrous cords that may eventually lead to contractures with permanent flexion of the finger joints. Correction of the flexion contractures in advanced disease is still performed by open limited fasciectomy; ultrasonography (US)-guided minimally invasive treatment is preferred for early disease.We provide an overview of the detailed anatomy of the palmar aponeurosis and the structures that may be involved in DD. Although magnetic resonance imaging is used as the gold standard, these small anatomical structures are often better visible on US. We describe two new morphological signs due to thickening of these small structures in patients with DD: the tardigrade sign and the manifold sign. Familiarity with detailed imaging anatomy and these new imaging signs of DD will help confirm a correct and early diagnosis and distinguish this disease from various other entities.

History Page: Leaders in MSK Radiology Augusto Pellegrini, 1877-1958.

This history page in the series "Leaders in MSK Radiology" is dedicated to the memory and achievements of the Italian surgeon Augusto Pellegrini, whose name is partially associated with the medical eponym Pellegrini-Stieda disease.

Complications of the Rigid Spine.

We present a short overview of the most common causes and imaging findings of a rigid spine including long-standing spondylarthritis, diffuse idiopathic skeletal hyperostosis, and the less common ossification of the posterior longitudinal ligament. The article also focuses on the pathogenesis and imaging findings of acute complications of the rigid spine due to fractures. These fractures may occur even after minor trauma and are difficult to detect on initial radiographs, resulting in a delayed diagnosis. They are often unstable with a high risk of severe neurologic complications, leading to high morbidity and mortality both in the initial phase and in the months following the fracture. Because the negative predictive value of conventional radiography is low, every patient with a rigid spine with newly appearing pain should be referred for subsequent cross-sectional imaging.