Recent advances in the treatment of renal stones using flexible ureteroscopys.

Upper urinary tract stones are a common urological disease that can be treated by flexible ureteroscopy (FURS) through the natural urinary tract, in addition to extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolithotomy (PCNL). The advantages of FURS are less trauma, faster recovery, and fewer complications, while its disadvantages include poor results of lithotripsy and stone extraction when dealing with larger stones, and prolonged operation time. Over the last two decades, the emergence of new technologies such as FURS combined with negative pressure suction, robot-assisted FURS, and artificially intelligent FURS, coupled with improvements in laser technology (the use of thulium fiber lasers (TFL) and the invention of single-use flexible ureteroscopes (su-fURS) suitable for primary level application, have significantly increased the global adoption of FURS. This surge in usage holds a promising future in clinical application, benefiting a growing number of patients with renal calculi. Accompanied by changes in technical concepts and therapeutic modalities, the scope of indications for FURS is broadening, positioning it as a potential primary choice for urolithiasis treatment in the future. This review outlines the progress in employing flexible ureteroscopy for the treatment of renal calculi in order to generate insights for further research.

Comprehensive Evaluation of the m6A Regulator Prognostic Risk Score in the Prediction of Immunotherapy Response in Clear Cell Renal Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is known for its high drug resistance. The tumor-immune crosstalk mediated by the epigenetic regulation of N6-methyladenosine (m6A) modification has been demonstrated in recent studies. Therefore, m6A modification-mediated immune cell infiltration characteristics may be helpful to guide immunotherapy for ccRCC. Methods: This study comprehensively analyzed m6A modifications using the clinical parameters, single-cell RNA sequencing data, and bulk RNA sequencing data from the TCGA-ccRC cohort and 13 external validation cohorts. A series of bioinformatic approaches were applied to construct an m6A regulator prognostic risk score (MRPRS) to predict survival and immunotherapy response in ccRCC patients. Immunological characteristics, enriched pathways, and mutation were evaluated in high- and low-MRPRS groups. Results: The expressional alteration landscape of m6A regulators was profiled in ccRCC cell clusters and tissue. The 8 regulator genes with minimal lambda were integrated to build an MRPRS, and it was positively correlated with immunotherapeutic response in extent validation cohorts. The clinicopathological features and immune infiltration characteristics could be distinguished by the high- and low-MRPRS. Moreover, the MRPRS-mediated mutation pattern has an enhanced response to immune checkpoint blockade in the ccRCC and pan-cancer cohorts. Conclusions: The proposed MRPRS is a promising biomarker to predict clinical outcomes and therapeutic responses in ccRCC patients.

Urinary Exosomes Diagnosis of Urological Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: Exosomes could be released directly into the urine by the urological tumoral cells, so testing urinary exosomes has great potential for non-invasive diagnosis and monitor of urological tumors. The objective of this study is to systematically review and meta-analysis of urinary exosome for urological tumors diagnosis. MATERIALS AND METHODS: A systematic review of the recent English-language literature was conducted according to the PRISMA statement recommendations (CRD42021250613) using PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases up to April 30, 2021. Risk-of-bias assessment was performed according to the QUADAS 2 tool. The true diagnostic value of urinary exosomes by calculating the number of true positive, false positive, true negative, and false negative, diagnoses by extracting specificity and sensitivity data from the selected literature. RESULTS: Sixteen eligible studies enrolling 3224 patients were identified. The pooled sensitivity and specificity of urinary exosomes as a diagnostic tool in urological tumors were 83% and 88%, respectively. The area under the summary receiver operating characteristic curve was 0.92 (95% CI: 0.89-0.94). Further subgroup analyses showed that our results were stable irrespective of the urinary exosome content type and tumor type. CONCLUSION: Urinary exosomes may serve as novel non-invasive biomarkers for urological cancer detection. Future clinical trial designs must validate and explore their utility in treatment decision-making. SYSTEMATIC REVIEW REGISTRATION: [ https://www.crd.york.ac.uk/prospero/], identifier [CRD42021250613].

Meta-Analysis of the Diagnostic Value of Cell-free DNA for Renal Cancer.

Cell-free DNA (cf-DNA) has been reported to represent a suitable material for liquid biopsy in the diagnosis and prognosis of various cancers. We performed a meta-analysis of published data to investigate the diagnostic value of cf-DNA for renal cancer (RCa). Systematic searches were conducted using Pubmed, Embase databases, Web of Science, Medline and Cochrane Library to identify relevant publications until the 31st March 2021. For all patients, we evaluated the true diagnostic value of cf-DNA by calculating the number of true positive, false positive, true negative, and false negative, diagnoses by extracting specificity and sensitivity data from the selected literature. In total, 8 studies, featuring 754 RCa patients, and 355 healthy controls, met our inclusion criteria. The overall diagnostic sensitivity and specificity for cf-DNA was 0.71 (95% confidence interval (CI), 0.55-0.83) and 0.79 (95% CI, 0.66-0.88), respectively. The pooled positive likelihood ratio and pooled negative likelihood ratio were 3.42 (95% CI, 2.04-5.72) and 0.36 (95% CI, 0.23-0.58), respectively. The area under the summary receiver operating characteristic curve was 0.82 (95% CI, 0.79-0.85), and the diagnostic odds ratio was 7.80 (95% CI, 4.40-13.85). Collectively, our data demonstrate that cf-DNA has high specificity and sensitivity for diagnosing RCa. Therefore, cf-DNA is a useful biomarker for the diagnosis of RCa.

Highly Water-Stable Dye@Ln-MOFs for Sensitive and Selective Detection toward Antibiotics in Water.

The host-guest composite, RhB@Tb-dcpcpt, is synthesized by trapping rhodamine B (RhB) into the channels of [Me2NH2][Tb3(dcpcpt)3(HCOO)]·DMF·15H2O (Tb-dcpcpt, DMF = N,N'-dimethylformamide) via an ion-exchange process. The photophysical property of RhB@Tb-dcpcpt exhibits stable columinescence of RhB and Tb3+ ions in the whole excitation range of 300-390 nm, realizing an excitation-wavelength-independent yellow light emission. Powder X-ray diffraction and photoluminescence analysis illustrate the outstanding stabilities of RhB@Tb-dcpcpt on structural and photophysical properties in water medium. Subsequently, a bifunctional sensing process toward antibiotics is designed in terms of luminescent intensity and color. As a result, RhB@Tb-dcpcpt could realize sensitive and selective detection toward nitrofuran antibiotics (nitrofurazone and nitrofurantoin) via  luminescent quenching process and toward quinolone antibiotics (ciprofloxacin and norfloxacin) via luminescent color-changing process. Systematic analysis on the sensing mechanism reveals that photoinduced electron transfer and inner filter effect contribute to the realization of the sensing process.

White-Light-Emitting Decoding Sensing for Eight Frequently-Used Antibiotics Based on a Lanthanide Metal-Organic Framework.

Developing multi-selective luminescence sensing technology to differentiate serial compounds is very important but challenging. White-light-emitting decoding sensing based on lanthanide metal-organic frameworks (Ln-MOFs) is a promising candidate for multi-selective luminescence sensing application. In this work, three isomorphic Ln-MOFs based on H3dcpcpt (3-(3,5-dicarboxylphenyl)-5-(4-carboxylphenl)-1H-1,2,4-triazole) ligand, exhibiting red, blue, and green emission, respectively, have been synthesized by solvothermal reactions. The isostructural mixed Eu/Gd/Tb-dcpcpt is fabricated via the in-situ doping of different Ln3+ ions into the host framework, which can emit white light upon the excitation at 320 nm. It is noteworthy that this white-light-emitting complex could serve as a convenient luminescent platform for distinguishing eight frequently-used antibiotics: five through luminescence-color-changing processes (tetracycline hydrochloride, yellow; nitrofurazone, orange; nitrofurantoin, orange; sulfadiazine, blue; carbamazepine, blue) and three through luminescence quenching processes (metronidazole, dimetridazole, and ornidazole). Moreover, a novel method, 3D decoding map, has been proposed to realize multi-selective luminescence sensing applications. This triple-readout map features unique characteristics on luminescence color and mechanism. The mechanism has been systematically interpreted on the basis of the structural analysis, energy transfer and allocation process, and peak fitting analysis for photoluminescence spectra. This approach presents a promising strategy to explore luminescent platforms capable of effectively sensing serial compounds.

Vitamin A or E and a catechin synergize as vaccine adjuvant to enhance immune responses in mice by induction of early interleukin-15 but not interleukin-1ß responses.

Vitamins A and E and select flavonoids in the family of catechins are well-defined small molecules that, if proven to possess immunomodulatory properties, hold promise as vaccine adjuvants and various therapies. In an effort to determine the in vivo immunomodulatory properties of these molecules, we found that although mucosal and systemic vaccinations with a recombinant HIV-1BaL gp120 with either a catechin, epigallo catechin gallate (EGCG) or pro-vitamin A (retinyl palmitate) alone in a vegetable-oil-in-water emulsion (OWE) suppressed antigen-specific responses, the combination of EGCG and vitamin A or E in OWE (Nutritive Immune-enhancing Delivery System, NIDS) synergistically enhanced adaptive B-cell, and CD4(+) and CD8(+) T-cell responses, following induction of relatively low local and systemic innate tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-17, but relatively high levels of early systemic IL-15 responses. For induction of adaptive interferon-γ and TNF-α responses by CD4(+) and CD8(+) T cells, the adjuvant effect of NIDS was dependent on both IL-15 and its receptor. In addition, the anti-oxidant activity of NIDS correlated positively with higher expression of the superoxide dismutase 1, an enzyme involved in reactive oxygen species elimination but negatively with secretion of IL-1ß. This suggests that the mechanism of action of NIDS is dependent on anti-oxidant activity and IL-15, but independent of IL-1ß and inflammasome formation. These data show that this approach in nutritive vaccine adjuvant design holds promise for the development of potentially safer effective vaccines.

Clear Experimental Demonstration of Hole Gas Accumulation in Ge/Si Core-Shell Nanowires.

Selective doping and band-offset in germanium (Ge)/silicon (Si) core-shell nanowire (NW) structures can realize a type of high electron mobility transistor structure in one-dimensional NWs by separating the carrier transport region from the impurity-doped region. Precise analysis, using Raman spectroscopy of the Ge optical phonon peak, can distinguish three effects: the phonon confinement effect, the stress effect due to the heterostructures, and the Fano effect. The Fano effect is the most important to demonstrate hole gas accumulation in Ge/Si core-shell NWs. Using these techniques, we obtained conclusive evidence of the hole gas accumulation in Ge/Si core-shell NWs. The control of hole gas concentration can be realized by changing the B-doping concentration in the Si shell.

Maintenance of long-term immunological memory by Ig+CD45R+ non-plasma B cells following mucosal immunizations.

To determine whether long-term immunological B cell memory following mucosal vaccinations is maintained by terminally differentiated Ig-CD45R- plasma cells or Ig+CD45R+ B cells, we immunized mice orally with the non-toxic B subunit of cholera toxin (CTB) as a carrier protein haptenated with FITC (CTB-FITC) plus CT adjuvant. We found that the adoptive transfer of Ig+CD45R+ but not the Ig-CD45R- cells, resulted in higher numbers of FITC-specific IgA-secreting cells in the intestine as well as higher anti-FITC serum IgA titers, suggesting that long term B cell immunological memory following oral vaccinations preferentially resided within the Ig+CD45R+ B cell population.

A novel retinoic acid, catechin hydrate and mustard oil-based emulsion for enhanced cytokine and antibody responses against multiple strains of HIV-1 following mucosal and systemic vaccinations.

Non-replicating protein- or DNA-based antigens generally require immune-enhancing adjuvants and delivery systems. It has been particularly difficult to raise antibodies against gp120 of HIV-1, which constitutes an important approach in HIV vaccine design. While almost all effort in adjuvant research has focused on mimicking the pathogens and the danger signals they engender in the host, relatively little effort has been spent on nutritive approaches. In this study, a new nutritive immune-enhancing delivery system (NIDS) composed of vitamin A, a polyphenol-flavonoid, catechin hydrate, and mustard oil was tested for its adjuvant effect in immune responses against the gp120 protein of HIV-1(CN54). Following a combination of two mucosal and two systemic vaccinations of mice, we found significant enhancement of both local and systemic antibodies as well as cytokine responses. These data have important implications for vaccine and adjuvant design against HIV-1 and other pathogens.

Mucosal HIV transmission and vaccination strategies through oral compared with vaginal and rectal routes.

IMPORTANCE OF THE FIELD: There are currently over thirty million people infected with HIV and there are no vaccines available to prevent HIV infections or disease. The genitourinary, rectal and oral mucosa are the mucosal HIV transmission routes. An effective vaccine that can induce both systemic and local mucosal immunity is generally accepted as a major means of protection against mucosal HIV transmission and AIDS. WHAT THE READER WILL GAIN: Structure and cells that comprise the oral, vaginal and rectal mucosa pertaining to HIV transmission and vaccination strategies through each mucosal route to prevent mucosal and systemic infection will be discussed. AREAS COVERED IN THIS REVIEW: Covering publications from 1980s through 2010, mucosal transmission of HIV and current and previous approaches to vaccinations are discussed. TAKE HOME MESSAGE: Although oral transmission of HIV is far less common than vaginal and rectal transmissions, infections through this route do occur through oral sex as well as vertically from mother to child. Mucosal vaccination strategies against oral and other mucosal HIV transmissions are under intensive research but the lack of consensus on immune correlates of protection and lack of safe and effective mucosal adjuvants and delivery systems hamper progress towards a licensed vaccine.

Deletion of Pten expands lung epithelial progenitor pools and confers resistance to airway injury.

RATIONALE: Pten is a tumor-suppressor gene involved in stem cell homeostasis and tumorigenesis. In mouse, Pten expression is ubiquitous and begins as early as 7 days of gestation. Pten(-/-) mouse embryos die early during gestation indicating a critical role for Pten in embryonic development. OBJECTIVES: To test the role of Pten in lung development and injury. METHODS: We conditionally deleted Pten throughout the lung epithelium by crossing Pten(flox/flox) with Nkx2.1-cre driver mice. The resulting Pten(Nkx2.1-cre) mutants were analyzed for lung defects and response to injury. MEASUREMENTS AND MAIN RESULTS: Pten(Nkx2.1-cre) embryonic lungs showed airway epithelial hyperplasia with no branching abnormalities. In adult mice, Pten(Nkx2.1-cre) lungs exhibit increased progenitor cell pools composed of basal cells in the trachea, CGRP/CC10 double-positive neuroendocrine cells in the bronchi, and CC10/SPC double-positive cells at the bronchioalveolar duct junctions. Pten deletion affected differentiation of various lung epithelial cell lineages, with a decreased number of terminally differentiated cells. Over time, Pten(Nxk2.1-cre) epithelial cells residing in the bronchioalveolar duct junctions underwent proliferation and formed uniform masses, supporting the concept that the cells residing in this distal niche may also be the source of procarcinogenic stem cells. Finally, increased progenitor cells in all the lung compartments conferred an overall selective advantage to naphthalene injury compared with wild-type control mice. CONCLUSIONS: Pten has a pivotal role in lung stem cell homeostasis, cell differentiation, and consequently resistance to lung injury.

The biology of feather follicles.

The feather is a complex epidermal organ with hierarchical branches and represents a multi-layered topological transformation of keratinocyte sheets. Feathers are made in feather follicles. The basics of feather morphogenesis were previously described (Lucas and Stettenheim, 1972). Here we review new molecular and cellular data. After feather buds form (Jiang et al., this issue), they invaginate into the dermis to form feather follicles. Above the dermal papilla is the proliferating epidermal collar. Distal to it is the ramogenic zone where the epidermal cylinder starts to differentiate into barb ridges or rachidial ridge. These neoptile feathers tend to be downy and radially symmetrical. They are replaced by teleoptile feathers which tend to be bilateral symmetrical and more diverse in shapes. We have recently developed a "transgenic feather" protocol that allows molecular analyses: BMPs enhance the size of the rachis, Noggin increases branching, while anti- SHH causes webbed branches. Different feather types formed during evolution (Wu et al., this issue). Pigment patterns along the body axis or intra-feather add more colorful distinctions. These patterns help facilitate the analysis of melanocyte behavior. Feather follicles have to be connected with muscles and nerve fibers, so they can be integrated into the physiology of the whole organism. Feathers, similarly to hairs, have the extraordinary ability to go through molting cycles and regenerate. Some work has been done and feather follicles might serve as a model for stem cell research. Feather phenotypes can be modulated by sex hormones and can help elucidate mechanisms of sex hormone-dependent growth control. Thus, the developmental biology of feather follicles provides a multi-dimension research paradigm that links molecular activities and cellular behaviors to functional morphology at the organismal level.

Sculpting skin appendages out of epidermal layers via temporally and spatially regulated apoptotic events.

Complex skin appendages are built from the epidermal cells through various cell events. Here we used TUNEL and caspase-3 immuno-localization to examine apoptosis in feather morphogenesis. We deduced three modes. In Mode 1A, apoptosis occurs within the localized growth zone (LoGZ) to regulate growth (feather buds). In Mode 1B, morphogen secreting cells are present adjacent to LoGZ and apoptosis may work to remove such signaling centers (barb ridges). In Mode 2, keratinocytes apoptosed before terminal differentiation and left spaces between branches (marginal plate). In Mode 3A, keratinocytes cornified and flaked off to free skin appendages (feather sheath, pulp epithelium). In Mode 3B, keratinized apoptosed epithelial cells became permanent structures (rachis, ramus, barbules). Thus, different apoptotic modes can have different impacts on morphogenesis. We further tested effects of imbalanced Shh on apoptosis. Shh suppression reduced marginal plate apoptosis and caused abnormal differentiation of barbule plates. Shh over-expression enhanced proliferation in barb ridges. Expression of Patched in the barbule plate epithelia implies a paracrine mechanism. The current work complements our recent work on LoGZ to show how adding and removing cell masses in temporally and spatially specific ways are coordinated to sculpt skin appendages from epidermal layers.

Molecular biology of feather morphogenesis: a testable model for evo-devo research.

Darwin's theory describes the principles that are responsible for evolutionary change of organisms and their attributes. The actual mechanisms, however, need to be studied for each species and each organ separately. Here we have investigated the mechanisms underlying these principles in the avian feather. Feathers comprise one of the most complex and diverse epidermal organs as demonstrated by their shape, size, patterned arrangement and pigmentation. Variations can occur at several steps along each level of organization, leading to highly diverse forms and functions. Feathers develop gradually during ontogeny through a series of steps that may correspond to the evolutionary steps that were taken during the phylogeny from a reptilian ancestor to birds. These developmental steps include 1) the formation of feather tract fields on the skin surfaces; 2) periodic patterning of the individual feather primordia within the feather tract fields; 3) feather bud morphogenesis establishing anterio-posterior (along the cranio-caudal axis) and proximo-distal axes; 4) branching morphogenesis to create the rachis, barbs and barbules within a feather bud; and 5) gradual modulations of these basic morphological parameters within a single feather or across a feather tract. Thus, possibilities for variation in form and function of feathers occur at every developmental step. In this paper, principles guiding feather tract formation, distributions of individual feathers within the tracts and variations in feather forms are discussed at a cellular and molecular level.

The morphogenesis of feathers.

Feathers are highly ordered, hierarchical branched structures that confer birds with the ability of flight. Discoveries of fossilized dinosaurs in China bearing 'feather-like' structures have prompted interest in the origin and evolution of feathers. However, there is uncertainty about whether the irregularly branched integumentary fibres on dinosaurs such as Sinornithosaurus are truly feathers, and whether an integumentary appendage with a major central shaft and notched edges is a non-avian feather or a proto-feather. Here, we use a developmental approach to analyse molecular mechanisms in feather-branching morphogenesis. We have used the replication-competent avian sarcoma retrovirus to deliver exogenous genes to regenerating flight feather follicles of chickens. We show that the antagonistic balance between noggin and bone morphogenetic protein 4 (BMP4) has a critical role in feather branching, with BMP4 promoting rachis formation and barb fusion, and noggin enhancing rachis and barb branching. Furthermore, we show that sonic hedgehog (Shh) is essential for inducing apoptosis of the marginal plate epithelia, which results in spaces between barbs. Our analyses identify the molecular pathways underlying the topological transformation of feathers from cylindrical epithelia to the hierarchical branched structures, and provide insights on the possible developmental mechanisms in the evolution of feather forms.