Resilient anatomy and local plasticity of naive and stress haematopoiesis.

The bone marrow adjusts blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses are unknown owing to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent haematopoiesis, erythropoiesis and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of normal and stress haematopoiesis. In the steady state, across the skeleton, single stem cells and multipotent progenitors distribute through the marrow enriched near megakaryocytes. Lineage-committed progenitors are recruited to blood vessels, where they contribute to lineage-specific microanatomical structures composed of progenitors and immature cells, which function as the production sites for each major blood lineage. This overall anatomy is resilient to insults, as it was maintained after haemorrhage, systemic bacterial infection and granulocyte colony-stimulating factor (G-CSF) treatment, and during ageing. Production sites enable haematopoietic plasticity as they differentially and selectively modulate their numbers and output in response to insults. We found that stress responses are variable across the skeleton: the tibia and the sternum respond in opposite ways to G-CSF, and the skull does not increase erythropoiesis after haemorrhage. Our studies enable in situ analyses of haematopoiesis, define the anatomy of normal and stress responses, identify discrete microanatomical production sites that confer plasticity to haematopoiesis, and uncover unprecedented heterogeneity of stress responses across the skeleton.

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

In situ mapping identifies distinct vascular niches for myelopoiesis.

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis-the differentiation of myeloid progenitors into a large variety of innate immune cells-in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells-monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte-dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation.

BAP1 regulation of the key adaptor protein NCoR1 is critical for γ-globin gene repression.

Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the ε-globin and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the ß-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.

Signatures of Topological States in Conjugated Macrocycles.

Single-molecule electrical junctions possess a molecular core connected to source and drain electrodes via anchor groups, which feed and extract electricity from specific atoms within the core. As the distance between electrodes increases, the electrical conductance typically decreases, which is a feature shared by classical Ohmic conductors. Here we analyze the electrical conductance of cycloparaphenylene (CPP) macrocycles and demonstrate that they can exhibit a highly nonclassical increase in their electrical conductance as the distance between electrodes increases. We demonstrate that this is due to the topological nature of the de Broglie wave created by electrons injected into the macrocycle from the source. Although such topological states do not exist in isolated macrocycles, they are created when the molecule is in contact with the source. They are predicted to be a generic feature of conjugated macrocycles and open a new avenue to implementing highly nonclassical transport behavior in molecular junctions.

High-Throughput µPAD with Cascade Signal Amplification through Dual Enzymes for arsM in Paddy Soil.

The arsM gene is a critical biomarker for the potential risk of arsenic exposure in paddy soil. However, on-site screening of arsM is limited by the lack of high-throughput point-of-use (POU) methods. Here, a multiplex CRISPR/Cas12a microfluidic paper-based analytical device (µPAD) was constructed for the high-throughput POU analysis of arsM, with cascade amplification driven by coupling crRNA-enhanced Cas12a and horseradish peroxidase (HRP)-modified probes. First, seven crRNAs were designed to recognize arsM, and their LODs and background signal intensities were evaluated. Next, a step-by-step iterative approach was utilized to develop and optimize coupling systems, which improved the sensitivity 32 times and eliminated background signal interference. Then, ssDNA reporters modified with HRP were introduced to further lower the LOD to 16 fM, and the assay results were visible to the naked eye. A multiplex channel microfluidic paper-based chip was developed for the reaction integration and simultaneous detection of 32 samples and generated a recovery rate between 87.70 and 114.05%, simplifying the pretreatment procedures and achieving high-throughput POU analysis. Finally, arsM in Wanshan paddy soil was screened on site, and the arsM abundance ranged from 1.05 × 106 to 6.49 × 107 copies/g; this result was not affected by the environmental indicators detected in the study. Thus, a coupling crRNA-based cascade amplification method for analyzing arsM was constructed, and a microfluidic device was developed that contains many more channels than previous paper chips, greatly improving the analytical performance in paddy soil samples and providing a promising tool for the on-site screening of arsM at large scales.

Highly Light-Harvesting MOF-on-MOF Heterostructure: Cascading Functionality to Flexible Photogating of Organic Photoelectrochemical Transistor and Bienzyme Cascade Detection.

Recently, organic photoelectrochemical transistor (OPECT) bioanalysis has become a prominent technique for the high-performance detection of biomolecules. However, as a sensitive index of the OPECT, the dynamic regulation transconductance (gm) is still severely deficient. Herein, this work reports a new photosensitive metal-organic framework (MOF-on-MOF) heterostructure for the effective modulation of maximum gm and natural bienzyme interfacing toward choline detection. Specifically, the bidentate ligand MOF (b-MOF) was assembled onto the UiO-66 MOF (u-MOF) by a modular assembly method, which could facilitate the charge separation and generate enhanced photocurrents and offer a biophilic environment for the immobilization of choline oxidase (ChOx) and horseradish peroxidase (HRP) through hydrogen-bonded bridges. The transconductance of the OPECT could be flexibly altered by increased light intensity to maximal value at zero gate bias, and sensitive choline detection was achieved with a detection limit of 0.2 µM. This work reveals the potential of MOF-on-MOF heterostructures for futuristic optobioelectronics.

2D-on-2D Al-Doped NiCo LDH Nanosheet Arrays for Fabricating High-Energy-Density, Wide Voltage Window, and Ultralong-Lifespan Supercapacitors.

Battery-type electrode materials with high capacity, wide potential windows, and good cyclic stability are crucial to breaking through energy storage limitations and achieving high energy density. Herein, a novel 2D-on-2D Al-doped NiCo layered double hydroxide (NiCoAlx LDH) nanosheet arrays with high-mass-loading are grown on a carbon cloth (CC) substrate via a two-step hydro/solvothermal deposition strategy, and the effect of Al doping is employed to modify the deposition behavior, hierarchical morphology, phase stability, and multi-metallic synergistic effect. The optimized NiCoAl0.1 LDH electrode exhibits capacities of 5.43, 6.52, and 7.25 C cm-2 (9.87, 10.88, and 11.15 F cm-2) under 0-0.55, 0-0.60, and 0-0.65 V potential windows, respectively, illustrating clearly the importance of the wide potential window. The differentiated deposition strategy reduces the leaching level of Al3+ cations in alkaline solutions, ensuring excellent cyclic performance (108% capacity retention after 40 000 cycles). The as-assembled NiCoAl0.1 LDH//activated carbon cloth (ACC) hybrid supercapacitor delivers 3.11 C cm-2 at 0-2.0 V, a large energy density of 0.84 mWh cm-2 at a power density of 10.00 mW cm-2, and excellent cyclic stability with ≈135% capacity retention after 150 000 cycles.

Conductance Quantization in 2D Semi-Metallic Transition Metal Dichalcogenides.

Conductance quantization of 2D materials is significant for understanding the charge transport at the atomic scale, which provides a platform to manipulate the quantum states, showing promising applications for nanoelectronics and memristors. However, the conventional methods for investigating conductance quantization are only applicable to materials consisting of one element, such as metal and graphene. The experimental observation of conductance quantization in transition metal dichalcogenides (TMDCs) with complex compositions and structures remains a challenge. To address this issue, an approach is proposed to characterize the charge transport across a single atom in TMDCs by integrating in situ synthesized 1T'-WTe2 electrodes with scanning tunneling microscope break junction (STM-BJ) technique. The quantized conductance of 1T'-WTe2 is measured for the first time, and the quantum states can be modulated by stretching speed and solvent. Combined with theoretical calculations, the evolution of quantized and corresponding configurations during the break junction process is demonstrated. This work provides a facile and reliable avenue to characterize and modulate conductance quantization of 2D materials, intensively expanding the research scope of quantum effects in diverse materials.

Single-Molecule Cross-Plane Conductance of Polycyclic Aromatic Hydrocarbon Derivatives.

In the cross-plane single-molecule junctions, the correlation between molecular aromaticity and conductance remained puzzling. Cross-plane break junction (XPBJ) provides new insight into understanding the role of aromaticity and conjugation to molecules on charge transport through the planar molecules. In this work, we investigated the modulation of cross-plane charge transport in pyrene derivatives by hydrogenation and substituents based on the XPBJ method that differs from those used in-plane transport. We measured the electrical conductance of the hydrogenated derivatives of the pyrenes and found that hydrogenation reduces conductance, and the fully hydrogenated molecule has the lowest conductance. Conductance of pyrene derivatives increased after substitution by both electron-donating and electron-withdrawing groups. By calculating, the trend in decreased conductance of hydrogenated pyrene was found to be consistent with the change in aromaticity. Electron-withdrawing substituents reduce the aromaticity of the molecule and narrow the HOMO-LUMO gap, while electron-donating groups increase the aromaticity but also narrow the gap. Our work reveals the potential of fine-tuning the structure of the pyrene molecule to control the cross-plane charge transport through the single-molecule junctions.

Regioselective Deacetylation of Peracetylated Deoxy-C-glycopyranosides by Boron Trichloride (BCl3).

A general approach for regioselective deacetylation at sugar 3-OH of peracetylated 6-deoxy-C-glucopyranosides mediated by BCl3 was developed. The approach could be extended to other sugar-derived 6-deoxy-C-glycopyranosides, such as those derived from mannose, galactose, and rhamnose, with deacetylation occurring at varied sugar hydroxyl groups, and further extended to 4-deoxy-C-glucopyranosides with deacetylation occurring at sugar 3-OH. The approach would enable access to synthetically challenging carbohydrate derivatives. A possible mechanism of the regioselectivity was proposed.

Associations of Ambient Particulate Matter with Maternal Thyroid Autoimmunity and Thyroid Function in Early Pregnancy.

This prospective birth cohort study evaluated the association of exposure to PM2.5 (diameter ≤2.5 µm), PM1-2.5 (1-2.5 µm), and PM1 (≤1 µm) with maternal thyroid autoimmunity and function during early pregnancy. A total of 15,664 pregnant women were included at 6 to 13+6 gestation weeks in China from 2018 to 2020. Single-pollutant models using generalized linear models (GLMs) showed that each 10 µg/m3 increase in PM2.5 and PM1-2.5 was related with 6% (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01, 1.12) and 15% (OR = 1.15, 95% CI: 1.08, 1.22) increases in the risk of thyroid autoimmunity, respectively. The odds of thyroid autoimmunity significantly increased with each interquartile range increase in PM2.5 and PM1-2.5 exposure (P for trend <0.001). PM1 exposure was not significantly associated with thyroid autoimmunity. GLM with natural cubic splines demonstrated that increases in PM2.5 and PM1-2.5 exposure were associated with lower maternal FT4 levels, while a negative association between PM1 and FT4 levels was found when exposure exceeded 32.13 µg/m3. Only PM2.5 exposure was positively associated with thyrotropin (TSH) levels. Our findings suggest that high PM exposure is associated with maternal thyroid disruption during the early pregnancy.

Theoretical investigation of Cu5/silicates deposited on rutile TiO2 as a photocatalyst.

Titanium dioxide (TiO2) is an exceptional compound with unique optical properties, which have been intensively used for applications in photocatalysis. Recent studies show that Cu5 atomic quantum clusters (AQCs) could facilitate visible light absorption and enhance the photocatalytic properties of rutile TiO2 by creating mid-gap states. In this work, to move the theory of these catalysts closer to the experiment, we investigate the electronic structures of Cu5 adsorbed on a perfect and reduced rutile TiO2 surface in the absence and presence of silicate SiO32- ions, which are introduced for the purification of Cu5 AQCs. Encouragingly, our DFT simulations predict that the presence of SiO32- does not reduce the gap states of the Cu5@TiO2 composite and could even enhance them by shifting more states into the band gap. Our results also demonstrate that the polarons created by oxygen vacancies (Ov) and Cu5 coexist within the band gap of TiO2. Indeed an Ov behaves like a negative gate on the electronic states located on the AQCs, thereby shifting states out of the valence band into the band gap, which could lead to enhanced photocatalytic performance.

SAXS unveils porous anodes for potassium-ion batteries: dynamic evolution of pore structures in Fe@Fe2O3/PCNFs composite nanofibers.

The porous structure of composite nanofibers plays a key role in improving their electrochemical performance. However, the dynamic evolution of pore structures and their action during ion intercalation/extraction processes for negative electrodes are not clear. Herein, porous carbon composite nanofibers (Fe@Fe2O3/PCNFs) were prepared as negative electrode materials for potassium-ion batteries. Electrochemical test findings revealed that the composites had good electrochemical characteristics, and the porous structure endowed composite electrodes with pseudo-capacitive behaviors. After 1500 discharge/charge cycles at a current density of 1000 mA g-1, the specific capacity of the potassium-ion batteries was 144.8 mAh g-1. We innovatively used synchrotron small-angle X-ray scattering (SAXS) technique to systematically investigate the kinetic process of potassium formation in composites and showed that the kinetic process of potassium reaction in composites can be divided into four stages, and the pores with smaller average diameter distribution are more sensitive to changes in the reaction process. This work paves a new way to study the deposition kinetics of potassium in porous materials, which facilitates the design of porous structures and realizes the development of alkali metal ion-anode materials with high energies.

Clinical analysis and identification of pediatric patients with colonic ulceration.

BACKGROUND: A wide variety of diseases mimic inflammatory bowel disease (IBD). This study aimed to reduce the misdiagnosis among children with colonic ulcers. METHODS: Eighty-six pediatric patients with colonic ulcers detected by colonoscopy were enrolled in the retrospective study. Children were divided into different groups according to the final diagnosis. The clinical characteristics, laboratory examinations, endoscopic findings, and histopathological results were compared. RESULTS: IBD (n = 37) was just responsible for 43% of patients with colonic ulceration. Other diagnosis included autoimmune diseases (n = 9), infectious enteritis (n = 13), gastrointestinal allergy (n = 8), and other diseases (n = 19). Comparing IBD and non-IBD groups, children with IBD had a higher frequency of symptoms like weight loss/failure to thrive (P < 0.001), perianal lesions (P = 0.001), and oral ulcers (P = 0.022), and higher expression levels of platelet (P = 0.006), neutrophil-to-lymphocyte ratio (NLR) (P = 0.001), erythrocyte sedimentation rate (P < 0.001), C-reactive protein (P < 0.001), Immunoglobulin G (P = 0.012), Interleukin-1ß (P = 0.003), Interleukin-6 (P = 0.024) and TNF-α (P = 0.026), and a wider ulcer distribution in the lower gastrointestinal tract (LGIT) (P < 0.001). Expression levels of hemoglobin (P < 0.001) and albumin (P = 0.001) were lower in IBD patients. Multivariate analysis showed hemoglobin, NLR, Score of ulceration in LGIT, and pseudopolyps contributing to the diagnosis of pediatric IBD with colonic ulcers. CONCLUSIONS: We displayed potential indicators to help diagnose pediatric IBD differentiating from other disorders with colonic ulcers more prudently.

Langerhans cell histiocytosis in children with refractory diarrhoea and hypoalbuminaemia as the initial presentation: two case reports and a literature review.

Langerhans cell histiocytosis (LCH) involving the gastrointestinal tract is a rare condition for which clinical experience is limited. We describe the cases of two patients who initially presented with chronic diarrhoea, hypoproteinaemia, and intermittent fever. These findings suggest that in cases of refractory diarrhoea accompanied by recurrent hypoalbuminaemia, especially with abdominal rash, LCH should be considered. Gastrointestinal endoscopy, biopsy, and imaging studies are essential for obtaining a definitive diagnosis. This approach might be helpful for the early recognition of gastrointestinal tract involvement in LCH.

The Prenatal Ultrasound Diagnosis and Perinatal Outcome of Polydactyly: A Retrospective Cohort Study, 2016-2023.

OBJECTIVE: To determine the significance of polydactyly identified on prenatal ultrasonography and provide a detailed analysis of characteristics and perinatal outcomes of fetal polydactyly. METHODS: This is a retrospective cohort study of pregnancies with a postnatal diagnosis of fetal polydactyly between January 2016 and December 2023. The population was divided into 2 groups at postnatal diagnosis: the isolated polydactyly group and the nonisolated polydactyly group. Clinical data, prenatal ultrasonography, related genetic results, and postnatal outcomes were obtained. RESULTS: Our study cohort comprised 328 fetuses with polydactyly. The overall detection rate of polydactyly by prenatal ultrasound was 19.2%, and the first detection rate in the first-, second-, and third-trimester were 0.9%, 14.6%, and 3.7%, respectively. Preaxial polydactyly (PPD) of hand was the most common type and the most common type of foot polydactyly was postaxial polydactyly (PAP) both in the isolated group and in the nonisolated group; the central polydactyly is rare. Syndactyly was the most common abnormality complicated with polydactyly. Between the nonpolydactyly group, the isolatedpolydactyly group and the nonisolated polydactyly group, there was a significant difference in perinatal outcome (P < .001). CONCLUSION: The second trimester is the best gestational age for prenatal ultrasound detection of polydactyly. Polydactyly of hand was more likely PPD, while polydactyly of foot was more likely PAP. When polydactyly is detected by routine prenatal ultrasound, detailed ultrasound examination and prenatal counseling should be performed to determine the possibility of an underlying genetic syndrome.

Intra-abdominal umbilical venous diameter and abdominal circumference discordance at 15-20 weeks' gestation: simple markers in transverse abdominal plane to predict adverse pregnancy outcomes in monochorionic diamniotic twins.

PURPOSE: This study aimed to investigate the association between simple markers in fetal abdominal plane, intra-abdominal umbilical venous diameter (DIUV) and abdominal circumference (AC) discordance at 15-20 weeks' gestation, and adverse pregnancy outcomes in monochorionic diamniotic (MCDA) twins. METHODS: We performed a retrospective analysis of MCDA twins with two live fetuses examined at 15-20 weeks from Jun 2020 to Dec 2021 at Beijing Obstetrics and Gynecology Hospital. Measurement of fetal AC and DIUV was performed according to standard protocols. Twin pregnancies with major fetal structural anomalies, chromosomal abnormalities, miscarriage, and twin reversed arterial perfusion sequence were excluded. DIUV and AC discordance in MCDA twins with an adverse pregnancy outcome was compared with a normal pregnancy outcome. Furthermore, the performance of DIUV and AC discordance in predicting adverse pregnancy outcomes in MCDA twins was assessed. RESULTS: A total of 105 women with MCDA twin pregnancies were enrolled, contributing 179 visits. Adverse pregnancy outcomes occurred in 33.3% (35/105) of cases in our study. The intra-observer and inter-observer intraclass correlation coefficient (ICC) of both AC and DIUV were very good or excellent. There was no statistical difference in AC and DIUV discordance (%) between 15-16, 17-18, and 19-20 weeks (χ2 = 3.928, P = 0.140; χ2 = 2.840, P = 0.242). Both AC and DIUV discordance were greater in twins with adverse pregnancy outcomes than that in twins with normal pregnancy outcome at each pregnancy periods. Both AC discordance (OR 1.2, 95% CI 1.1-1.3) and DIUV discordance (OR 1.2, 95% CI 1.1-1.2) were associated with adverse pregnancy outcomes. The AUC for predicting adverse pregnancy outcomes by AC discordance was 0.75 (95% CI 0.68-0.83), with a sensitivity of 58.7% (95% CI 51.9-64.5) and a specificity of 86.2% (95% CI 81.7-88.4). The AUC for predicting adverse pregnancy outcomes by DIUV was 0.78 (95% CI 0.70-0.86), with sensitivity and specificity of 65.1% (95% CI 58.1-70.3) and 86.2% (95% CI 81.7-88.4), respectively. CONCLUSIONS: The AC discordance and DIUV discordance could predict adverse pregnancy outcomes in MCDA twins. When these simple markers occurred, intensive surveillance was recommended.

Investigation of the genetic and clinical features of laterality disorders in prenatal diagnosis: discovery of a novel compound heterozygous mutation in the DNAH11 gene.

BACKGROUND: Left-right laterality disorders are a heterogeneous group of disorders caused by an altered position or orientation of the thoracic and intra-abdominal organs and vasculature across the left-right axis. They mainly include situs inversus and heterotaxy. Those disorders are complicated by cardiovascular abnormalities significantly more frequently than situs solitus. METHODS: In this study, 16 patients with a fetal diagnosis of laterality disorder with congenital heart defects (CHD) were evaluated with a single nucleotide polymorphism array (SNP-arry) combined with whole-exome sequencing (WES). RESULTS: Although the diagnostic rate of copy number variations was 0 and the diagnostic rate of WES was 6.3% (1/16), the likely pathogenic gene DNAH11 and the candidate gene OFD1 were ultimately identified. In addition, novel compound heterozygous mutations in the DNAH11 gene and novel hemizygous variants in the OFD1 gene were found. Among the combined CHD, a single atrium/single ventricle had the highest incidence (50%, 8/16), followed by atrioventricular septal defects (37.5%, 6/16). Notably, two rare cases of common pulmonary vein atresia (CPVA) were also found on autopsy. CONCLUSION: This study identified the types of CHD with a high incidence in patients with laterality disorders. It is clear that WES is an effective tool for diagnosing laterality disorders and can play an important role in future research.

Clinicopathological risk factors associated with tumor relapse of upper tract urothelial carcinoma after radical nephroureterectomy: A single institution 20-year experience.

Upper tract urothelial carcinoma (UTUC) is a relatively rare yet aggressive malignancy. While radical nephroureterectomy (RNU) remains the cornerstone treatment, UTUC has high local and metastatic relapse rates, leading to a dismal prognosis. To identify the clinicopathological factors associated with an increased risk of local and metastatic relapse in UTUC, we conducted a retrospective analysis of 133 consecutive UTUC patients who underwent RNU from 1998 to 2018. Patients lost to follow-up or with a history of bladder cancer were excluded from the study. The remaining 87 patients were categorized into two subgroups: those with tumor recurrence/relapse (40 cases) and those without recurrence/relapse (47 cases). Clinical and pathological characteristics were compared across the two groups. Multiple factors are associated with UTUC recurrence/relapse including larger tumor size, histology divergent differentiations/subtypes, high tumor grade, advanced pathologic T stage, positive margin, lymphovascular invasion (LVI), positive lymph node status, and preoperative hydronephrosis. Multivariate Cox regression analysis revealed that squamous differentiation predicted recurrence/relapse (p = 0.012), independent of tumor stage. Moreover, compared to the conventional histology type, UTUC with squamous differentiation had a significantly higher relapse rate (p = 0.0001) and poorer survival (p = 0.0039). This observation was further validated in invasive high-grade UTUC cases. Our findings suggest that many pathological factors contribute to UTUC recurrence/relapse, particularly, squamous differentiation may serve as an independent risk predictor for relapse and a potent prognosticator for adverse cancer-specific survival in UTUC patients. Recognizing and thoroughly assessing the pathological factors is essential for better oncologic management of UTUC.