Corrigendum to "Detailed urban roughness parametrization for anthropogenic heat flux estimation using earth observation data" [Heliyon 9(7) (July 2023) e18361].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e18361.].

Detailed urban roughness parametrization for anthropogenic heat flux estimation using earth observation data.

Anthropogenic Heat (AH) emissions modify the energy balance in urban areas and is crucial for urban microclimate modelling and improved weather forecast modelling. Therefore, the present study conducted on Delhi and its surroundings firstly aims to estimate AH using Earth Observation (EO) data of Landsat 8 then, evaluate the impact of detailed urban roughness parameterization on the estimation of AH and further validate the obtained flux values with ground based observations of Large Aperture Scintillometer (LAS) setup. The study has been conducted over three time periods for October 2017, March 2018 and June 2018 by processing six Landsat tiles. Three methods have been employed on EO data for AH computation i.e. single urban roughness value for entire study area (Method 1), LULC based roughness values adopted from the literature (Method 2) and lastly, detailed pixel-by-pixel varying roughness values calculated from fine scale urban parameterization (Method 3) for each time period, The average AH values are higher for the month of June 2018: 359.91, 368.57 and 359.16 W/m2 as compared to month of March 2018 (322.44, 330.84 and 298.35 W/m2) and October 2017 (318.00, 331.04 and 306.71 W/m2) for method 1, method 2 and method 3 respectively. Net radiation and Sensible Heat Flux shows a good correspondence with in-situ measurements for most of the tiles and method 3 shows better spatial distribution of fluxes as compared to other two methods. However, due to difference in approach for estimation of fluxes (LAS setup computes latent heat flux as residual while EO based approach computes AH as residual), conclusive results could not be drawn with respect to aptness of a single method. Accurate estimation of AH in urban areas can assist further in formulating policies, regulations and action plans related to mitigation and control of heat stress, climate change and improved weather forecasting.

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma.

Treatment resistance is observed in all advanced cancers. Colorectal cancer (CRC) presenting as colorectal adenocarcinoma (COAD) is the second leading cause of cancer deaths worldwide. Multimodality treatment includes surgery, chemotherapy, and targeted therapies with selective utilization of immunotherapy and radiation therapy. Despite the early success of anti-epidermal growth factor receptor (anti-EGFR) therapy, treatment resistance is common and often driven by mutations in APC, KRAS, RAF, and PI3K/mTOR and positive feedback between activated KRAS and WNT effectors. Challenges in the direct targeting of WNT regulators and KRAS have caused alternative actionable targets to gain recent attention. Utilizing an unbiased drug screen, we identified combinatorial targeting of DDR1/BCR-ABL signaling axis with small-molecule inhibitors of EGFR-ERBB2 to be potentially cytotoxic against multicellular spheroids obtained from WNT-activated and KRAS-mutant COAD lines (HCT116, DLD1, and SW480) independent of their KRAS mutation type. Based on the data-driven approach using available patient datasets (The Cancer Genome Atlas (TCGA)), we constructed transcriptomic correlations between gene DDR1, with an expression of genes for EGFR, ERBB2-4, mitogen-activated protein kinase (MAPK) pathway intermediates, BCR, and ABL and genes for cancer stem cell reactivation, cell polarity, and adhesion; we identified a positive association of DDR1 with EGFR, ERBB2, BRAF, SOX9, and VANGL2 in Pan-Cancer. The evaluation of the pathway network using the STRING database and Pathway Commons database revealed DDR1 protein to relay its signaling via adaptor proteins (SHC1, GRB2, and SOS1) and BCR axis to contribute to the KRAS-PI3K-AKT signaling cascade, which was confirmed by Western blotting. We further confirmed the cytotoxic potential of our lead combination involving EGFR/ERBB2 inhibitor (lapatinib) with DDR1/BCR-ABL inhibitor (nilotinib) in radioresistant spheroids of HCT116 (COAD) and, in an additional devastating primary cancer model, glioblastoma (GBM). GBMs overexpress DDR1 and share some common genomic features with COAD like EGFR amplification and WNT activation. Moreover, genetic alterations in genes like NF1 make GBMs have an intrinsically high KRAS activity. We show the combination of nilotinib plus lapatinib to exhibit more potent cytotoxic efficacy than either of the drugs administered alone in tumoroids of patient-derived recurrent GBMs. Collectively, our findings suggest that combinatorial targeting of DDR1/BCR-ABL with EGFR-ERBB2 signaling may offer a therapeutic strategy against stem-like KRAS-driven chemoradioresistant tumors of COAD and GBM, widening the window for its applications in mainstream cancer therapeutics.

Radiation Induced Metabolic Alterations Associate With Tumor Aggressiveness and Poor Outcome in Glioblastoma.

Glioblastoma (GBM) is uniformly fatal with a 1-year median survival, despite best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified tumor-promoting effects of prior RT on patient-derived intracranial GBM xenografts and characterized metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24 hrs following 20 Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p < 0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (i.e., modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed a significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, Tricarboxylic acid cycle (TCA) intermediates, and rise in energy carriers (ATP, GTP). GSH and ASC showed highest Variable Importance on Projection prediction (VIPpred) (1.65) in Orthogonal Partial least square Discriminant Analysis (OPLS-DA); Ascorbate catabolism was identified by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occurring 2 months vs. 24 hrs following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, and elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications.

Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain-infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment.

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice.

Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1-KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro, and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth.

Tyrosine phosphorylation regulates ERß ubiquitination, protein turnover, and inhibition of breast cancer.

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERß exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERß, but not ERα, that dictates ERß transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERß activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERß, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERß-specific agonists such as S-equol enhance ERß phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERß activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERß tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERß signaling is an attractive target for anticancer treatment.

Bortezomib inhibits STAT5-dependent degradation of LEF-1, inducing granulocytic differentiation in congenital neutropenia CD34(+) cells.

The transcription factor lymphoid enhancer-binding factor 1 (LEF-1), which plays a definitive role in granulocyte colony-stimulating factor (G-CSF) receptor-triggered granulopoiesis, is downregulated in granulocytic progenitors of severe congenital neutropenia (CN) patients. However, the exact mechanism of LEF-1 downregulation is unclear. CN patients are responsive to therapeutically high doses of G-CSF and are at increased risk of developing acute myeloid leukemia. The normal expression of LEF-1 in monocytes and lymphocytes, whose differentiation is unaffected in CN, suggests the presence of a granulopoiesis-specific mechanism downstream of G-CSF receptor signaling that leads to LEF-1 downregulation. Signal transducer and activator of transcription 5 (STAT5) is activated by G-CSF and is hyperactivated in acute myeloid leukemia. Here, we investigated the effects of activated STAT5 on LEF-1 expression and functions in hematopoietic progenitor cells. We demonstrated that constitutively active STAT5a (caSTAT5a) inhibited LEF-1-dependent autoregulation of the LEF-1 gene promoter by binding to the LEF-1 protein, recruiting Nemo-like kinase and the E3 ubiquitin-ligase NARF to LEF-1, leading to LEF-1 ubiquitination and a reduction in LEF-1 protein levels. The proteasome inhibitor bortezomib reversed the defective G-CSF-triggered granulocytic differentiation of CD34(+) cells from CN patients in vitro, an effect that was accompanied by restoration of LEF-1 protein levels and LEF-1 messenger RNA autoregulation. Taken together, our data define a novel mechanism of LEF-1 downregulation in CN patients via enhanced ubiquitination and degradation of LEF-1 protein by hyperactivated STAT5.

Efficacy of certain yogic and naturopathic procedures in premature ejaculation: A pilot study.

CONTEXT: Premature ejaculation (PE) is the most common sexual disorder of young males. Even though there are number of treatment options available for PE, patient's satisfaction and drug side effects remain to be a problem. Non-pharmacological treatment options like Yoga and Naturopathy have been implicated in sexual fulfillment, pleasure and efficacy of some of these approaches has been established in previous studies. AIM: To assess the efficacy of certain yogic and naturopathic procedures in the management of PE. MATERIALS AND METHODS: A total of 12 patients with PE satisfying the DSM IV TR diagnostic criteria were selected and allotted into two groups, Yoga group and Naturopathic group by following the randomization method. In the Yoga group, various asanas, mudra, bandha and pranayama were practiced 1 hour daily for 21 days. In the Naturopathy group, lower abdomen massage and steam bath, hip bath and lingasnana, mud pack on lower abdomen, and acupressure were done 1 hour daily for 21 days. Criteria of assessment were based on the scoring of Premature Ejaculation Severity Index (PESI). Statistical analysis was done by using paired and unpaired "t" tests. RESULTS: In the Yoga group (n = 6), 7.3% relief was observed (P < 0.01) and in the Naturopathy group (n = 6), 2.4% of relief was observed (P > 0.05) on the total score of PESI. There was no significant difference (P > 0.05) found in between the two groups. CONCLUSION: Both Yoga and Naturopathic procedures didn't provide relief (<25%) on total score of PESI.

Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis.

We found that hematopoietic cell-specific Lyn substrate 1 (HCLS1 or HS1) is highly expressed in human myeloid cells and that stimulation with granulocyte colony-stimulating factor (G-CSF) leads to HCLS1 phosphorylation. HCLS1 binds the transcription factor lymphoid-enhancer binding factor 1 (LEF-1), transporting LEF-1 into the nucleus upon G-CSF stimulation and inducing LEF-1 autoregulation. In patients with severe congenital neutropenia, inherited mutations in the gene encoding HCLS1-associated protein X-1 (HAX1) lead to profound defects in G-CSF-triggered phosphorylation of HCLS1 and subsequently to reduced autoregulation and expression of LEF-1. Consistent with these results, HCLS1-deficient mice are neutropenic. In bone marrow biopsies of the majority of tested patients with acute myeloid leukemia, HCLS1 protein expression is substantially elevated, associated with high levels of G-CSF synthesis and, in some individuals, a four-residue insertion in a proline-rich region of HCLS1 protein known to accelerate intracellular signaling. These data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo.

Anti-anxiety and anti-depressant activities of Sarasvata choorna in experimental animals.

The present study was undertaken to evaluate the anxiolytic and anti-depressant activity of Sarasvata choorna. The anxiolytic activity was evaluated in elevated plus maze (EPM) and the anti-depressant activity was evaluated in forced swimming test (FST). The efficacy of Sarasvata choorna was compared with the standard anti-anxiety (diazepam 2 mg/kg) and anti-depressant (imipramine - 5 mg/kg) drugs. It was observed that Sarasvata choorna at the dose of 390 mg/kg is as effective as standard drugs used in anti-anxiety and anti-depressant activities in mice by increasing time spent in open arm and entries to open arm in EPM model and increasing immobility time in FST model respectively. Hence it can be concluded that Sarasvata choorna may be used as a potent therapeutic agent in treating anxiety and depressive disorders.

NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD(+)-sirtuin-1-dependent pathway.

We identified nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B cell colony enhancing factor (PBEF), as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Intracellular NAMPT and NAD(+) amounts in myeloid cells, as well as plasma NAMPT and NAD(+) levels, were increased by G-CSF treatment of both healthy volunteers and individuals with congenital neutropenia. NAMPT administered both extracellularly and intracellularly induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells and of the promyelocytic leukemia cell line HL-60. Treatment of healthy individuals with high doses of vitamin B3 (nicotinamide), a substrate of NAMPT, induced neutrophilic granulocyte differentiation. The molecular events triggered by NAMPT include NAD(+)-dependent sirtuin-1 activation, subsequent induction of CCAAT/enhancer binding protein-alpha and CCAAT/enhancer binding protein-beta, and, ultimately, upregulation of G-CSF synthesis and G-CSF receptor expression. G-CSF, in turn, further increases NAMPT levels. These results reveal a decisive role of the NAD(+) metabolic pathway in G-CSF-triggered myelopoiesis.