bluuebunny/crossref_metadata_2025 huggingface dataset:
Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated–dependent and –independent mechanisms
Authors: Siu Wai Yi , Lau Anita , Arooz Talha , Chow Jeremy P.H. , Ho Horace T.B. , Poon Randy Y.C.
Published: June 2022

Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G1 checkpoint through activation of the p53-p21CIP1/WAF1 pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G1 checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G2 checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.
Overexpression of glucosylceramide synthase and P-glycoprotein in cancer cells selected for resistance to natural product chemotherapy
Authors: Gouazé Valerie , Yu Jing Y. , Bleicher Richard J. , Han Tie-Yan , Liu Yong-Yu , Wang Hongtao , Gottesman Michael M. , Bitterman Arie , Giuliano Armando E. , Cabot Myles C.
Published: June 2022

Resistance to natural product chemotherapy drugs is a major obstacle to successful cancer treatment. This type of resistance is often acquired in response to drug exposure; however, the mechanisms of this adverse reaction are complex and elusive. Here, we have studied acquired resistance to Adriamycin, Vinca alkaloids, and etoposide in MCF-7 breast cancer cells, KB-3-1 epidermoid carcinoma cells, and other cancer cell lines to determine if there is an association between expression of glucosylceramide synthase, the enzyme catalyzing ceramide glycosylation to glucosylceramide, and the multidrug-resistant (MDR) phenotype. This work shows that glucosylceramide levels increase concomitantly with increased drug resistance in the KB-3-1 vinblastine-resistant sublines KB-V.01, KB-V.1, and KB-V1 (listed in order of increasing MDR). The levels of glucosylceramide synthase mRNA, glucosylceramide synthase protein, and P-glycoprotein (P-gp) also increased in parallel. Increased glucosylceramide levels were also present in Adriamycin-resistant KB-3-1 sublines KB-A.05 and KB-A1. In breast cancer, detailed analysis of MCF-7 wild-type and MCF-7-AdrR cells (Adriamycin-resistant) demonstrated enhanced glucosylceramide synthase message and protein, P-gp message and protein, and high levels of glucosylceramide in resistant cells. Similar results were seen in vincristine-resistant leukemia, etoposide-resistant melanoma, and Adriamycin-resistant colon cancer cell lines. Cell-free glucosylceramide synthase activity was higher in lysates obtained from drug-resistant cells. Lastly, glucosylceramide synthase promoter activity was 15-fold higher in MCF-7-AdrR compared with MCF-7 cells. We conclude that selection pressure for resistance to natural product chemotherapy drugs selects for enhanced ceramide metabolism through glucosylceramide synthase in addition to enhanced P-gp expression. A possible connection between glucosylceramide synthase and P-gp in drug resistance biology is suggested.
Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells
Authors: Lee Eric A. , Keutmann Michael K. , Dowling Melissa L. , Harris Eleanor , Chan Gordon , Kao Gary D.
Published: June 2022

Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G1-S and G2. Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.
Small interfering RNA urokinase silencing inhibits invasion and migration of human hepatocellular carcinoma cells
Authors: Salvi Alessandro , Arici Bruna , De Petro Giuseppina , Barlati Sergio
Published: June 2022

The serine protease urokinase-type plasminogen activator (u-PA) is involved in a variety of physiologic and pathological processes; in particular, u-PA mRNA is up-regulated in human hepatocellular carcinoma (HCC) biopsies and its level of expression is inversely correlated with patients' survival. To determine the role of u-PA in the invasiveness properties of HCC, we successfully down-regulated u-PA by RNA interference (RNAi) technology, in an HCC-derived cell line at high level of u-PA expression. RNAi is a multistep process involving generation of small interfering RNAs (siRNA) that cause specific inhibition of the target gene. SKHep1C3 cells were transfected with a U6 promoter plasmid coding for an RNA composed of two identical 19-nucleotide sequence motifs in an inverted orientation, separated by a 9-bp spacer to form a hairpin dsRNA capable of mediating target u-PA inhibition. Stable transfectant cells showed a consistently decreased level of u-PA protein. In biological assays, siRNA u-PA–transfected cells showed a reduction of migration, invasion, and proliferation. In conclusion, u-PA down-regulation by RNAi technology decreases the invasive capability of HCC cells, demonstrating that stable expression of siRNA u-PA could potentially be an experimental approach for HCC gene therapy.
Aryl hydrocarbon receptor activation of an antitumor aminoflavone: Basis of selective toxicity for MCF-7 breast tumor cells
Authors: Loaiza-Pérez Andrea I. , Kenney Susan , Boswell Jamie , Hollingshead Melinda , Alley Michael C. , Hose Curtis , Ciolino Henry P. , Yeh Grace C. , Trepel Jane B. , Vistica David T. , Sausville Edward A.
Published: June 2022

Aminoflavone (4H-1-benzopyran-4-one, 5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl; NSC 686288) demonstrates differential antiproliferative activity in the National Cancer Institute's anticancer drug screen. We demonstrate here that MCF-7 human breast cancer cells are sensitive to aminoflavone both in vitro and when grown in vivo as xenografts in athymic mice. As previous work has indicated that aminoflavone requires metabolic activation by cytochrome P450 1A1 (CYP1A1), we investigated the effect of aminoflavone on CYP1A1 expression and on the aryl hydrocarbon receptor (AhR), a transcriptional regulator of CYP1A1. In aminoflavone-sensitive but not aminoflavone-resistant cells, the drug caused a 100-fold induction of CYP1A1 mRNA and a corresponding increase in ethoxyresorufin-O-deethylase activity. An AhR-deficient variant of the MCF-7 breast carcinoma, AHR100, with diminished CYP1A1 inducibility, exhibits cellular resistance to aminoflavone and is refractory to CYP1A1 mRNA induction by the drug. The increase in CYP1A1 mRNA in the aminoflavone-sensitive MCF-7 breast tumor cell results from transcriptional activation of xenobiotic-responsive element (XRE)–controlled transcription. Aminoflavone treatment causes a translocation of the AhR from the cytoplasm to the nucleus with subsequent formation of AhR-XRE protein DNA complexes. In contrast to the aminoflavone-sensitive MCF-7 cells, the resistant cell lines (MDA-MB-435, PC-3, and AHR100) demonstrated constitutive nuclear localization of AhR. Additionally, aminoflavone failed to induce ethoxyresorufin-O-deethylase activity, CYP1A1 transcription, AhR-XRE complex formation, and apoptosis in aminoflavone-resistant cells. These results suggest that the cytotoxicity of aminoflavone in a sensitive breast tumor cell line is the result of the engagement of AhR-mediated signal transduction.
Lack of neurotoxicity of the vascular targeting agent ZD6126 following repeated i.v. dosing in the rat
Authors: Horner Steve A. , Gould Sarah , Noakes James P. , Rattray Niccola J. , Allen Sandra L. , Zotova Elena , Arezzo Joseph C.
Published: June 2022

The vascular targeting agent ZD6126 is a water-soluble prodrug of N-acetylcolchinol that acts by disrupting the cytoskeleton of tumor endothelial cells. It is currently undergoing clinical evaluation in man. As peripheral neuropathy is a major dose-limiting toxicity associated with tubulin binding agents, the neurotoxic potential of ZD6126 was investigated in male and female Wistar rats. ZD6126 was administered i.v. at up to maximum tolerated doses using subacute (0 to 20 mg/kg/d for 5 days) and chronic (0 to 10 mg/kg/d for 5 days, repeated monthly for 6 months) dosing regimens. A separate study examined a combination of ZD6126 (three cycles of ZD6126 given as in the chronic dosing regimen) and paclitaxel (12 mg/kg/wk for 9 weeks) to assess whether coadministration of ZD6126 altered the time course or magnitude of a paclitaxel-induced neuropathy. Neurotoxic potential was examined using a comprehensive series of tests including a functional observation battery, measurements of muscle strength (forelimb and hind limb grip strength), nociception (tail flick test), locomotor activity, neuropathology, and whole nerve electrophysiology. There was no evidence that ZD6126 induced neurotoxicity in the rat following either subacute or chronic i.v. dosing. In a chronic electrophysiology study, ZD6126 produced a slight slowing of the maturational increase of caudal nerve amplitude, with some evidence of reversibility. However, this was not associated with any changes in caudal nerve conduction velocity, motor nerve conduction velocity or amplitude, functional observation battery behavioral and function parameters (including no effects on tail flick latency), and neuropathology. As expected, paclitaxel administration was associated with a significant decrease in caudal nerve conduction velocity (P = 0.0001). Coadministration of ZD6126 did not increase the neurotoxicity of paclitaxel. These studies suggest that ZD6126 should not induce the peripheral neuropathy associated with other antitubulin chemotherapeutic agents and that ZD6126 may not exacerbate the neurotoxicity of other agents with dose-limiting neuropathies.
A hybrid fibronectin motif protein as an integrin targeting selective tumor vascular thrombogen
Authors: Liu Cheng , Dickinson Craig , Shobe Justin , Doñate Fernando , Ruf Wolfram , Edgington Thomas
Published: June 2022

Targeted thrombotic eradication of solid tumors is a novel therapeutic strategy. The feasibility, efficacy, selectivity, and safety are dependent on multiple variables of protein design, molecular assembly, vascular target, and exclusive restriction of function to the tumor vasculature. To advance this strategy, we describe a design of an integrin targeting selective tumor vascular thrombogen. We adopted the fibronectin structural motif of tandem repeating modules with four type III repeat modules of fibronectin followed by two structurally homologous modules of the extracellular domain of tissue factor. This hybrid protein of six tandem modules recognizes integrins and selectively docks and initiates the thrombogenic protease cascade locally on the target cell surfaces. The protein is inactive in blood but is functionally active once assembled on integrin-positive cells. When administered i.v. to tumor-bearing mice, it selectively induces extensive local microthrombosis of the tumor microvasculature. The principles are addressed from the perspective of protein structural design for a class of selective tumor vascular thrombogen proteins that, through interaction with tumor angiogenic endothelium, elicit thrombotic occlusion rather than apoptosis or arrest of angiogenesis. This response can produce local tumor infarction followed by intratumoral ischemia-reperfusion injury, inflammation, and a local host tumor eradicative response.
Transcriptional signature of flavopiridol-induced tumor cell death
Authors: Lü Xing , Burgan William E. , Cerra Michael A. , Chuang Eric Y. , Tsai Mong-Hsun , Tofilon Philip J. , Camphausen Kevin
Published: June 2022

Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the antiproliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF359 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics.
A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway
Authors: Zhang Yuesheng , Gordon Gary B.
Published: June 2022

Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in the upstream region of many anticarcinogenic/antioxidant genes and have been shown to mediate the coordinate transcriptional up-regulation of these genes by many chemical agents [i.e., the ARE-mediated inducers]. There is strong evidence that increased expression of ARE-regulated genes inhibits cancer development. The signaling system leading to ARE activation has been partly elucidated, and nuclear factor erythroid 2–related factor 2 (Nrf2) has been identified as the key transcriptional factor that serves to transmit the inducer signal to ARE. It is now known that nuclear factor erythroid 2–related factor 2, which is normally sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, dissociates from Kelch-like ECH-associated protein 1 on exposure to ARE-mediated inducers, translocates to the nucleus, complexes with other nuclear factors, and binds to ARE. Rapid and simple assays have been devised to identify chemical agents that can stimulate this signaling pathway. Moreover, many ARE-mediated inducers have been identified, and several of them have shown promising cancer preventive activity.
Anti-α4 integrin monoclonal antibody inhibits multiple myeloma growth in a murine model
Authors: Olson Dian L. , Burkly Linda C. , Leone Diane R. , Dolinski Brian M. , Lobb Roy R.
Published: June 2022

In a syngeneic murine model of multiple myeloma with many of the characteristics of the human disease, a monoclonal antibody (mAb) to the integrin very late antigen-4 (VLA-4), given after the myeloma has already homed to and begun to establish itself within the bone marrow compartment, produces statistically significant effects on multiple disease variables. These include reductions in circulating levels of IgG2b; percentage of IgG2b-positive myeloma cells circulating in blood; spleen weight; and myeloma cell burden in spleen, bone marrow, and liver. mAb therapy had no effect on nonmalignant hematopoietic cells. An acute 6-day regimen of mAb treatment, initiated very late in disease to avoid mAb elimination in the immunocompetent animals, still significantly reduced spleen and blood myeloma cell burden. The ability of the (VLA-4) mAb to affect multiple variables in this model, even as monotherapy, suggests this pathway plays a central role in disease progression.
Dorsal Finger Fold Recognition by Convolutional Neural Networks for the Detection and Monitoring of Joint Swelling in Patients with Rheumatoid Arthritis
Authors: Hügle Thomas , Caratsch Leo , Caorsi Matteo , Maglione Jules , Dan Diana , Dumusc Alexandre , Blanchard Marc , Kalweit Gabriel , Kalweit Maria
Published: June 2022

Digital biomarkers such as wearables are of increasing interest in monitoring rheumatic diseases, but they usually lack disease specificity. In this study, we apply convolutional neural networks (CNN) to real-world hand photographs in order to automatically detect, extract, and analyse dorsal finger fold lines as a correlate of proximal interphalangeal (PIP) joint swelling in patients with rheumatoid arthritis (RA). Hand photographs of RA patients were taken by a smartphone camera in a standardized manner. Overall, 190 PIP joints were categorized as either swollen or not swollen based on clinical judgement and ultrasound. Images were automatically preprocessed by cropping PIP joints and extracting dorsal finger folds. Subsequently, metrical analysis of dorsal finger folds was performed, and a CNN was trained to classify the dorsal finger lines into swollen versus non-swollen joints. Representative horizontal finger folds were also quantified in a subset of patients before and after resolution of PIP swelling and in patients with disease flares. In swollen joints, the number of automatically extracted deep skinfold imprints was significantly reduced compared to non-swollen joints (1.3, SD 0.8 vs. 3.3, SD 0.49, p < 0.01). The joint diameter/deep skinfold length ratio was significantly higher in swollen (4.1, SD 1.4) versus non-swollen joints (2.1, SD 0.6, p < 0.01). The CNN model successfully differentiated swollen from non-swollen joints based on finger fold patterns with a validation accuracy of 0.84, a sensitivity of 88%, and a specificity of 75%. A heatmap of the original images obtained by an extraction algorithm confirmed finger folds as the region of interest for correct classification. After significant response to disease-modifying antirheumatic drug ± corticosteroid therapy, longitudinal metrical analysis of eight representative deep finger folds showed a decrease in the mean diameter/finger fold length (finger fold index, FFI) from 3.03 (SD 0.68) to 2.08 (SD 0.57). Conversely, the FFI increased in patients with disease flares. In conclusion, automated preprocessing and the application of CNN algorithms in combination with longitudinal metrical analysis of dorsal finger fold patterns extracted from real-world hand photos might serve as a digital biomarker in RA.
Sequential Geriatric Assessment in Older Patients with Colorectal Cancer during Chemotherapy: Subgroup Analysis of a Prospective, Multicenter Study EpiReal 75
Authors: Li Moying , Schulte Nadine , Elting Frederik , Winkler Eva C. , Hetjens Svetlana , Berger Anne Katrin , Zschäbitz Stefanie , Hofmann Jan , Hofmann Jasmin , Hilbertz Lieselotte , Kuhn Merlin , Khakzar Carolin , Jesenofsky Ralf , Betge Johannes , Zhan Tianzuo , Belle Sebastian , Ebert Matthias Philip , Härtel Nicolai
Published: June 2022

Introduction: Colorectal cancer (CRC) is a disease of older patients, but evidence-based guidelines for chemotherapy in older patients are scarce. Geriatric assessment (GA) evaluates a patient’s functional status (FS) and helps in decision-making when choosing chemotherapy for older patients. However, the change of FS during chemotherapy is rarely studied as GA is mostly performed once instead of sequentially. Methods: We performed a subgroup analysis of a prospective, multicenter study EpiReal 75. Patients aged ≥75 years with gastrointestinal malignancy prior to initiation of chemotherapy or receiving palliative chemotherapy were screened. We defined geriatric core assessments including the Eastern Cooperative Oncology Group score, Barthel’s activities of daily living (ADL) scale, Lawton’s instrumental activities of daily living (IADL) scale, and G-8 questionnaire, which were performed at baseline and repeated every 3 months. Quality of life (QoL) assessed by QLQ-C30 questionnaire was also re-evaluated every 3 months. We defined any deterioration in any of the geriatric parameters as unstable in the corresponding function. Results: 28 patients with CRC were enrolled between April 2014 and December 2018. 20 patients were evaluable for statistical analysis with a mean age of 78.5 years (range, 75–88). Most patients received chemotherapy in palliative setting. During 3 months of chemotherapy, 25% of patients became more dependent as measured by ADL or IADL. During a median follow-up of 15 months, patients with unstable ADL or IADL had a significantly shorter overall survival (OS) than those with stable ADL or IADL (plogrank = 0.0055 and 0.0253, respectively), without a significant difference in progression-free survival (PFS). Also, unstable IADL correlated with a deterioration in aspects of QoL such as role functioning and emotional functioning (p = 0.0189 and 0.0239, respectively). 20% of patients experienced treatment-related grade 3 adverse events (AEs), no grade 4–5 AEs occurred. Conclusion: Sequential GA revealed changes in FS in older patients with CRC receiving chemotherapy. A deterioration of FS during chemotherapy did not influence PFS but had a negative impact on OS and QoL. It is therefore important to maintain FS in older patients with cancer, and regular performance of geriatric core assessments should be encouraged in the clinical practice.
Midgestation Leptin Infusion Induces Characteristics of Clinical Preeclampsia in Mice, Which Is Ablated by Endothelial Mineralocorticoid Receptor Deletion
Authors: Faulkner Jessica L. , Wright Derrian , Antonova Galina , Jaffe Iris Z. , Kennard Simone , Belin de Chantemèle Eric J.
Published: June 2022

Background:

Patients with preeclampsia demonstrate increases in placental leptin production in midgestation, and an associated increase in late gestation plasma leptin levels. The consequences of mid-late gestation increases in leptin production in pregnancy is unknown. Our previous work indicates that leptin infusion induces endothelial dysfunction in nonpregnant female mice via leptin-mediated aldosterone production and endothelial mineralocorticoid receptor (ECMR) activation, which is ablated by ECMR deletion. Therefore, we hypothesized that leptin infusion in mid-gestation of pregnancy induces endothelial dysfunction and hypertension, hallmarks of clinical preeclampsia, which are prevented by ECMR deletion.

Methods:

Leptin was infused via miniosmotic pump (0.9 mg/kg per day) into timed-pregnant ECMR-intact (WT) and littermate-mice with ECMR deletion (KO) on gestation day (GD)11-18.

Results:

Leptin infusion decreased fetal weight and placental efficiency in WT mice compared with WT+vehicle. Radiotelemetry recording demonstrated that blood pressure increased in leptin-infused WT mice during infusion. Leptin infusion reduced endothelial-dependent relaxation responses to acetylcholine (ACh) in both resistance (second-order mesenteric) and conduit (aorta) vessels in WT pregnant mice. Leptin infusion increased placental ET-1 (endothelin-1) production evidenced by increased PPET-1 (preproendothelin-1) and ECE-1 (endothelin-converting enzyme-1) expressions in WT mice. Adrenal aldosterone synthase (
CYP11B2
) and angiotensin II type 1 receptor b (
AT1Rb
) expression increased with leptin infusion in pregnant WT mice. KO pregnant mice demonstrated protection from leptin-induced reductions in pup weight, placental efficiency, increased BP, and endothelial dysfunction.

Conclusions:

Collectively, these data indicate that leptin infusion in midgestation induces endothelial dysfunction, hypertension, and fetal growth restriction in pregnant mice, which is ablated by ECMR deletion.
Cercidospora navarroi, a new species of lichenicolous fungus from the Central Himalayan region of India
Authors: JOSHI YOGESH , BANSAL POOJA , YADAV ARJUN LAL
Published: June 2022

Cercidospora navarroi colonizing the thallus and the apothecial discs of Rinodina intermedia is described as new to science from India and is compared with C. exiguella, C. rinodinae, and C. cf. rinodinae which also colonize the lichen genus Rinodina.
The genus Lambiella Hertel (lichenised fungi) in Tasmania: new combinations, new species and a revised key
Authors: KANTVILAS GINTARAS
Published: June 2022

Two new species of Lambiella Hertel from Tasmania are described and illustrated: L. parvipsephota Kantvilas, which is similar to the widespread L. psephota (Tuck.) Hertel but differs by lacking norstictic acid in the thallus and sedifolia-grey pigment in the apothecia, and by having smaller apothecia and ascospores, 8−13 × 5−7.5 µm; and L. plumbea Kantvilas, characterised by a grey thallus lacking lichen substances, minute apothecia 0.075−0.13 mm wide, and small ascospores 4−8.5 × 3−5 µm. Both are currently known only from Tasmania. A further 11 species of Rimularia are transferred to Lambiella: Lambiella albotessellata (Kantvilas) Kantvilas, Lambiella applanata (Kantvilas & Coppins) Kantvilas, Lambiella aspicilioides (Kantvilas) Kantvilas, Lambiella asteriphila (Kantvilas) Kantvilas, Lambiella campestris (Kantvilas & Elix) Kantvilas, Lambiella circumgrisea (Kantvilas) Kantvilas, Lambiella coppinsiana (Kantvilas) Kantvilas, Lambiella exigua (Hertel & Rambold) Kantvilas, Lambiella globulispora (Sipman & Aptroot) Kantvilas, Lambiella ramboldiana (Kantvilas & Elix) Kantvilas and Lambiella umbratilis (Kantvilas & Coppins) Kantvilas. The complexities of assigning many, chiefly Southern Hemisphere taxa to new generic concepts derived essentially from molecular data are discussed briefly. Lambiella is considered to be the genus of best fit for a suite of lichens that share many salient features, particularly with respect to apothecial anatomy and their Trapelia-type asci. An identification key to the 14 species of Lambiella in Tasmania is provided.
Type specimens of birds in the Natural History Museum, University of Oslo, Norway
Authors: JOHANNESSEN LARS ERIK , LIFJELD JAN T.
Published: June 2022

A list of all known bird type specimens in the collection of the Natural History Museum, University of Oslo, Norway is presented. The specimens originate from northern Australia, eastern Indonesia or Tristan da Cunha, and have either been collected and described by personnel associated with the museum or sent from other museums in exchange for other specimens. The catalogue is not intended as a taxonomic revision of the treated taxa, and consequently no taxonomic revisions are made, but the type status of some specimens formerly considered to be types is refuted. The collection holds name-bearing types of 11 taxa, comprising one holotype and 26 syntypes; two paratypes from the same type series as the holotype; and one paralectotype of a twelfth taxon. The catalogue also includes two specimens of one taxon here refuted as being type specimens.
Western and Central Tropical Pacific Rainfall Response to Climate Change: Sensitivity to Projected Sea Surface Temperature Patterns
Authors: Dutheil C. , Lengaigne M. , Vialard J. , Jullien S. , Menkes C.
Published: June 2022

Rainfall projections from the Coupled Model Intercomparison Project (CMIP) models are strongly tied to projected sea surface temperature (SST) spatial patterns through the “warmer-gets-wetter” mechanism. While these models consistently project an enhanced equatorial warming, they, however, indicate much more uncertain changes in zonal SST gradients. That translates into large uncertainties on rainfall projections. Here, we force an atmospheric model with synthetic SSTs whose zonal SST gradient changes span the range of CMIP5 uncertainties in the presence and in the absence of the robust equatorially enhanced warming. Our results confirm that projected rainfall changes are dominated by the effect of circulation changes, which are tied to SST through the “warmer-gets-wetter” mechanism. We show that SPCZ rainfall changes are entirely driven by the uncertain zonal SST gradient changes. The western equatorial Pacific rainfall increase is largely controlled by the robust enhanced equatorial warming for modest zonal SST gradient changes. However, for larger values, the effect of the zonal SST gradient change on rainfall projections becomes dominant due to nonlinear interactions with the enhanced equatorial warming. Overall, our study demonstrates that uncertainties in the zonal SST gradient changes strongly contribute to uncertainties in rainfall projections over both the South Pacific convergence zone and western equatorial Pacific. It is thus critical to reduce these uncertainties to produce more robust precipitation estimates.
Land–Atmosphere Interactions during GRAINEX: Planetary Boundary Layer Evolution in the Presence of Irrigation
Authors: Rappin E. D. , Mahmood R. , Nair U. S. , Pielke Sr. R. A.
Published: June 2022

This paper analyzed observations from the Great Plains Irrigation Experiment (GRAINEX) to better understand land–atmosphere (L–A) interactions and PBL evolution. This study is focused on a day when the largest forcing on the boundary layer originated from the land surface/land use. To examine these impacts, we also applied the Weather Research and Forecasting (WRF) Model. Results from the observations show that compared to nonirrigated areas, air temperature, wind speed, and PBL height (PBLH) were lower while dewpoint temperature and latent heat flux were higher over irrigated areas. Findings suggest that entrainment layer drying and differences in energy partitioning over irrigated and nonirrigated areas played an important role in PBL evolution. In the final hours of the day, the PBL collapsed faster over nonirrigated areas compared to irrigated. The WRF Model simulations agree with these observations. They also show that the extent of irrigation [expressed as irrigation fraction (IF)] in an area impacts L–A response. Under ∼60% IF, the latent heat flux and mixing ratio reach their highest value while temperature and PBLH are at their lowest, and sensible heat flux is near its lowest value. Results are reversed for ∼2% IF. It is concluded that irrigation notably impacts L–A interactions and PBL evolution.
An Accurate Wind Retrieval Method Based on Observing Hydrogen Balloons with Multi-Theodolite Measurements
Authors: Zhou Jie , Gao Hang , Wang Xuesong , Li Jianbing
Published: June 2022

The hydrogen balloon is widely used for wind sensing by tracking it with optical theodolites. The traditional theodolite observation (single- and double-theodolite) methods assume that the balloon is a perfect tracer of the background wind and it rises with a constant speed during the whole observation period, but these assumptions may not hold well in complex wind circumstances. In this paper, an accurate wind field retrieval method based on multi-theodolite measurement is proposed. The extended Kalman filter algorithm is used to filter the angle data observed by the theodolites in order to accurately estimate the trajectory of the balloon, and the motion equation is used to correct the velocity difference between the background wind and the balloon. As a result, not only the horizontal velocity but also the vertical velocity can be accurately retrieved by this method. Numerical simulation and field experiments show that the multi-theodolite observation method excels the traditional single-theodolite method, and the velocity errors can be reduced by even more than 40% in comparison with the single-theodolite method for complex wind cases.

Significanace Statement

In the meteorological community, hydrogen balloon tracking is a widely used wind retrieval method, but the accuracy is limited, especially under complex wind conditions. In this paper, a new method based on tracking the hydrogen balloon with multi-theodolite is proposed, which uses the extended Kalman filter and the motion equation to get an accurate estimation of the balloon’s velocity and fix the inertia effect of balloon, respectively. Simulation and field experiment show that the new method can reduce the velocity error by more than 40% compared with the traditional method.
Extracellular protein kinase A and G are potential biomarkers of some inflammation-associated disorders
Authors: Wu Yan , Ye Jun , Zhao Chunhui , Pang Ji , Li Yueying , Lin Xinyue
Published: June 2022

Introduction

Protein kinase A (PKA) and protein kinase G (PKG) are the main downstream effectors of second messengers cAMP and cGMP, which play important roles in physiological and pathological processes. Recently, there are two findings: one is PKA catalytic subunits α (PKACα) and PKG II can be secreted, the other is that the two secretory protein kinases are associated with the progression of tumors. Previous data also demonstrate that the two kinases, as signal cascades, involved in inflammation-associated disorders. However, it remains unclear whether the secreted PKACα or PKG II could serve as diagnostic biomarkers for inflammation-associated disorders.

Methods

The serum from suffered coronary disease, diabetes, rheumatoid arthritis, and schizophrenia were collected. The serum PKACα and PKG II were detected by ELISA. All the patients were consent informed.

Results

Our results showed that the serum PKACα and PKG II had obvious changes in coronary disease, rheumatoid arthritis, schizophrenia patients. However, the trends was opposite, especially in rheumatoid arthritis.

Conclusions

Serum PKACα and PKG II could serve as potentially diagnostic biomarkers for some inflammation-associated disorders, such as coronary disease, rheumatoid arthritis, and schizophrenia.
Gene network analysis reveals candidate genes related with the hair follicle development in sheep
Authors: He Junmin , Zhao Bingru , Huang Xixia , Fu Xuefeng , Liu Guifen , Tian Yuezhen , Wu Cuiling , Mao Jingyi , Liu Jing , Gun Shuangbao , Tian Kechuan
Published: June 2022

Background

Merino sheep are the most famous fine wool sheep in the world. They have high wool production and excellent wool quality and have attracted worldwide attention. The fleece of the Merino sheep is composed predominantly of wool fibers grown from secondary wool follicles. Therefore, it is necessary to study the development of hair follicles to understand the mechanism of wool production. The hair follicle is a complex biological system involved in a dynamic process governed by gene regulation. The hair follicle development process is very complex and poorly understood. The purpose of our research is to identify candidate genes related to hair follicle development, provide a theoretical molecular breeding basis for the cultivation of fine wool sheep, and provide a reference for the problems of hair loss and alopecia areata that affect human beings.

Results

We analyzed mRNAs data in skin tissues of 18 Merino sheep at four embryonic days (E65, E85, E105 and E135) and two postnatal days (P7 and P30). G1 to G6 represent hair follicles developmental at six stages (i.e. E65 to P30). We identified 7879 differentially expressed genes (DEGs) and 12623 novel DEGs, revealed different expression patterns of these DEGs at six stages of hair follicle development, and demonstrated their complex interactions. DEGs with stage-specific expression were significantly enriched in epidermal differentiation and development, hair follicle development and hair follicle morphogenesis and were enriched in many pathways related to hair follicle development. The key genes (LAMA5, WNT10A, KRT25, SOSTDC1, ZDHHC21, FZD1, BMP7, LRP4, TGFβ2, TMEM79, SOX10, ITGB4, KRT14, ITGA6, and GLI2) affecting hair follicle morphogenesis were identified by network analysis.

Conclusion

This study provides a new reference for the molecular basis of hair follicle development and lays a foundation for further improving sheep hair follicle breeding. Candidate genes related to hair follicular development were found, which provided a theoretical basis for molecular breeding for the culture of fine wool sheep. These results are a valuable resource for biological investigations of fleece evolution in animals.
Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial)
Authors: Barnes David J. , Dutton Peter , Bruland Øyvind , Gelderblom Hans , Faleti Ade , Bühnemann Claudia , van Maldegem Annemiek , Johnson Hannah , Poulton Lisa , Love Sharon , Tiemeier Gesa , van Beelen Els , Herbschleb Karin , Haddon Caroline , Billingham Lucinda , Bradley Kevin , Ferrari Stefano , Palmerini Emanuela , Picci Piero , Dirksen Uta , Strauss Sandra J. , Hogendoorn Pancras C. W. , Buddingh Emmeline , Blay Jean-Yves , Cleton-Jansen Anne Marie , Hassan Andrew Bassim
Published: June 2022

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.
The impact of social determinants of health on early childhood development: a qualitative context analysis in Iran
Authors: Atashbahar Omolbanin , Sari Ali Akbari , Takian Amirhossein , Olyaeemanesh Alireza , Mohamadi Efat , Barakati Sayyed Hamed
Published: June 2022

Background

Social determinants have a significant impact on children’s development and their abilities and capacities, especially in early childhood. They can bring about inequity in living conditions of children and, as a result, lead to differences in various dimensions of development including the social, psychological, cognitive and emotional aspects. We aimed to identify and analyze the social determinants of Early Childhood Development (ECD) in Iran and provide policy implications to improve this social context.

Methods

In a qualitative study, data were collected through semi-structured interviews with 40 experts from October 2017 to June 2018. Based on Leichter’s (1979) framework and using the deductive approach, two independent researchers conducted the data analysis. We used MAXQDA.11 software for data management.

Results

We identified challenges related to ECD context in the form of 8 themes and 22 subthemes in 4 analytical categories relevant to the social determinants of ECD including: Structural factors (economic factors: 6 subthemes, political factors: 2 subthemes), Socio-cultural factors (the socio-cultural setting of society: 6 subthemes, the socio-cultural setting of family: 4 subthemes), Environmental or International factors (the role of international organizations: 1 subtheme, political sanctions: 1 subtheme), and Situational factors (genetic factors: 1 subtheme, the phenomenon of air pollution: 1 subtheme). We could identify 24 policy recommendations to improve the existing ECD context from the interviews and literature.

Conclusion

With regard to the challenges related to the social determinants of ECD, such as increasing social harms, decreasing social capital, lack of public awareness, increasing socio-economic inequities, economic instability, which can lead to the abuse and neglect of children or unfair differences in their growth and development, the following policy-making options are proposed: focusing on equity from early years in policies and programs, creating integration between policies and programs from different sectors, prioritizing children in the welfare umbrella, empowering families, raising community awareness, and expanding services and support for families, specially the deprived families subject to special subsidies.
Characterization of a prognostic model for lung squamous cell carcinoma based on eight stemness index-related genes
Authors: Jiang Wenfa , Xie Ning , Xu Chenyang
Published: June 2022

Background

Cancer stem cells (CSCs) are implicated in cancer progression, chemoresistance, and poor prognosis; thus, they may be promising therapeutic targets. In this study, we aimed to investigate the prognostic application of differentially expressed CSC-related genes in lung squamous cell carcinoma (LUSC).

Methods

The mRNA stemness index (mRNAsi)-related differentially expressed genes (DEGs) in tumors were identified and further categorized by LASSO Cox regression analysis and 1,000-fold cross-validation, followed by the construction of a prognostic score model for risk stratification. The fractions of tumor-infiltrating immune cells and immune checkpoint genes were analyzed in different risk groups.

Results

We found 404 mRNAsi-related DEGs in LUSC, 77 of which were significantly associated with overall survival. An eight-gene prognostic signature (PPP1R27, TLX2, ANKLE1, TIGD3, AMH, KCNK3, FLRT3, and PPBP) was identified and used to construct a risk score model. The TCGA set was dichotomized into two risk groups that differed significantly (p = 0.00057) in terms of overall survival time (1, 3, 5-year AUC = 0.830, 0.749, and 0.749, respectively). The model performed well in two independent GEO datasets (p = 0.029, 0.033; 1-year AUC = 0747, 0.783; 3-year AUC = 0.746, 0.737; 5-year AUC = 0.706, 0.723). Low-risk patients had markedly increased numbers of CD8+ T cells and M1 macrophages and downregulated immune checkpoint genes compared to the corresponding values in high-risk patients (p < 0.05).

Conclusion

A stemness-related prognostic model based on eight prognostic genes in LUSC was developed and validated. The results of this study would have prognostic and therapeutic implications.
Factors associated with low back pain in patients with lumbar spinal stenosis: a cross-sectional study
Authors: Ogon Izaya , Teramoto Atsushi , Takashima Hiroyuki , Terashima Yoshinori , Yoshimoto Mitsunori , Emori Makoto , Iba Kousuke , Takebayashi Tsuneo , Yamashita Toshihiko
Published: June 2022

Background

Low back pain (LBP) is a major symptom of symptomatic lumbar spinal stenosis (SLSS). It is important to assess LBP in patients with SLSS to develop better treatment. This study aimed to analyse the factors associated with LBP in patients with SLSS.

Methods

This cross-sectional study included consecutive patients with SLSS aged between 51 and 79 years who had symptoms in one or both the legs, with and without LBP. The participants were classified into two groups: the high group (LBP visual analogue scale [VAS] score ≥ 30 mm) and the low group (LBP VAS score < 30 mm). We performed multiple logistic regression analysis with the high and low groups as dependent variables, and a receiver operating characteristic (ROC) analysis.

Results

A total of 80 patients with LSS were included (35 men and 45 women; mean age 64.5 years), with 47 and 30 patients in the high and low groups, respectively. Multivariate logistic regression analysis revealed that the sagittal vertical axis (SVA; + 10 mm; odds ratio, 1.331; 95% confidence interval, 1.051 − 1.660) and pelvic incidence-lumbar lordosis (PI-LL; + 1°; odds ratio, 1.065; 95% confidence interval, 1.019–1.168) were significantly associated with LBP. A receiver operating characteristic analysis revealed cut-off values of 47.0 mm of SVA and 30.5° of PI-LL, respectively.

Conclusion

Our results indicated that SVA and PI-LL were significant predictors for LBP in SLSS. It is suggested that these parameters should be taken into consideration when assessing LBP in patients with SLSS.