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ENSO is considered as a strong atmospheric teleconnection that has pronounced global and regional circulation effects. It modifies global monsoon system, especially, Asian and African monsoons. Previous studies suggest that both the frequency and magnitude of ENSO events have increased over the last few decades resulting in a need to study climatic impacts of ENSO magnitude both at global and regional scales. Hence, to better understand the impact of ENSO amplitude over the tropical and extratropical regions focussing on the Asian and African domains, ENSO sensitivity experiments are conducted using ICTPAGCM (‘SPEEDY’). It is anticipated that the tropical Pacific SST forcing will be enough to produce ENSO-induced teleconnection patterns; therefore, the model is forced using NINO3.4 regressed SST anomalies over the tropical Pacific only. SPEEDY reproduces the impact of ENSO over the Pacific, North and South America and African regions very well. However, it underestimates ENSO teleconnection patterns and associated changes over South Asia, particularly in the Indian region, which suggests that the tropical Pacific SST forcing is not sufficient to represent ENSO-induced teleconnection patterns over South Asia. Therefore, SST forcing over the tropical Indian Ocean together with air–sea coupling is also required for better representation of ENSO-induced changes in these regions. Moreover, results obtained by this pacemaker experiment show that ENSO impacts are relatively stronger over the Inter-Tropical Convergence Zone (ITCZ) compared to extratropics and high latitude regions. The positive phase of ENSO causes weakening in rainfall activity over African tropical rain belt, parts of South and Southeast Asia, whereas, the La Niña phase produces more rain over these regions during the summer season. Model results further reveal that ENSO magnitude has a stronger impact over African Sahel and South Asia, especially over the Indian region because of its significant impact over the tropical Atlantic and the Indian Ocean through Walker circulation. ENSO-induced negative (positive) NAO-like response and associated changes over Southern Europe and North Africa get significantly strong following increased intensity of El Niño (La Niña) in the northern (southern) hemisphere in the boreal winter (summer) season. We further find that ENSO magnitude significantly impacts Hadley and Walker circulations. The positive phase of ENSO (El Niño) overall strengthens Hadley cell and a reverse is true for the La Niña phase. ENSO-induced strengthening and weakening of Hadley cell induces significant impact over South Asian and African ITCZ convective regions through modification of ITCZ/monsoon circulation system.

Type-1 diabetes (T1D) is an autoimmune disorder characterized by impaired insulin release by islet β cells. It has been shown that proinflammatory cytokines released during the disease can exacerbate the condition, while anti-inflammatory cytokines offer protection. This study analyzed the clinical role of interleukin (IL)-6, -8, -10, and vitamin D levels in T1D patients compared to healthy controls. The levels of IL-6, IL-8, IL-10, and vitamin D in the participants’ serum samples were analyzed using ELISA. The findings showed that T1D patients had significantly increased levels ( p  < 0.0001) of fasting blood glucose, HbA1c, systolic blood pressure, low-density lipoprotein, triglycerides, cholesterol, and very low-density lipoprotein and decreased levels of high-density lipoprotein and vitamin D ( p  < 0.0001) compared to healthy controls. Moreover, the levels of IL-6, IL-8, and IL-10 were also significantly greater ( p  < 0.0001) in T1D patients. The study also determined the significance of these cytokines among T1D patients and healthy controls using ROC curves. Furthermore, we found that smokers had significantly higher levels of IL-6 ( p  = 0.01) and IL-8 ( p  = 0.003) than non-smokers. These results showed that elevated levels of IL-6, IL-8, and IL-10, decreased vitamin D levels, and smoking among T1D participants could contribute to the worsening of T1D disease and could serve as predictive indicators.

Despite recent improvement in adjuvant therapies, triple-negative, and ER + subtypes of breast cancer (BC) with metastatic potentials remain the leading cause of BC-related deaths. We investigated the role of phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Kα), a key upstream factor of PI3K/AKT, and the therapeutic effect of PIP5Kα inhibitor on subtypes of BC. The clinical importance of PIP5K1α and its association with survivals were analyzed using three BC cohorts from Nottingham ( n  = 913), KM plotter ( n  = 112) and TCGA ( n  = 817). Targeted overexpression or knockdown of PIP5K1α were introduced into BC cell lines. The effects of PIP5K1α and its inhibitor on growth and invasion of BC were confirmed by using in vitro assays including proliferation, migration, apoptosis and luciferase reporter assays and in vivo xenograft mouse models. All statistical tests were two-sided. PIP5K1α was associated with poor patient outcome in triple-negative BC (for PIP5K1α protein, p  = 0.011 and for mRNA expression, p  = 0.028, log-rank test). 29% of triple-negative BC had PIP5K1A gene amplification. Elevated level of PIP5K1α increased expression of pSer-473 AKT ( p  < 0.001) and invasiveness of triple-negative MDA-MB-231 cells ( p  < 0.001). Conversely, inhibition of PIP5K1α using its inhibitor ISA-2011B, or via knockdown suppressed growth and invasiveness of MDA-MB-231 xenografts (mean vehicle-treated controls = 2160 mm 3 , and mean ISA-2011B-treated = 600 mm 3 , p  < 0.001). ISA-2011B-treatment reduced expression of pSer-473 AKT ( p  < 0.001) and its downstream effectors including cyclin D1, VEGF and its receptors, VEGFR1 and VEGFR2 ( p  < 0.001) in xenograft tumors. In ER + cancer cells, PIP5K1α acted on pSer-473 AKT, and was in complexes with VEGFR2, serving as co-factor of ER-alpha to regulate activities of target genes including cyclin D1 and CDK1. Our study suggests that our developed PIP5K1α inhibitor has a great potential on refining targeted therapeutics for treatment of triple-negative and ER + BC with abnormal PI3K/AKT pathways.

Pathological conditions including cancers lead to accumulation of a morphological mixture of highly immunosuppressive cells termed as myeloid-derived suppressor cells (MDSC). The lack of conclusive markers to identify human MDSC, due to their heterogeneous nature and close phenotypical and functional proximity with other cell subsets, made it challenging to identify these cells. Nevertheless, expansion of MDSC has been reported in periphery and tumor microenvironment of various cancers. The majority of studies on breast cancers were performed on murine models and hence limited literature is available on the relation of MDSC accumulation with clinical settings in breast cancer patients. The aim of this study was to investigate levels and phenotypes of myeloid cells in peripheral blood ( n  = 23) and tumor microenvironment of primary breast cancer patients ( n  = 7), compared with blood from healthy donors ( n  = 21) and paired non-tumor normal breast tissues from the same patients ( n  = 7). Using multicolor flow cytometric assays, we found that breast cancer patients had significantly higher levels of tumor-infiltrating myeloid cells, which comprised of granulocytes ( P  = 0.022) and immature cells that lack the expression of markers for fully differentiated monocytes or granulocytes ( P  = 0.016). Importantly, this expansion was not reflected in the peripheral blood. The immunosuppressive potential of these cells was confirmed by expression of Arginase 1 (ARG1), which is pivotal for T-cell suppression. These findings are important for developing therapeutic modalities to target mechanisms employed by immunosuppressive cells that generate an immune-permissive environment for the progression of cancer.

Background Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGF) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression. Methods Immunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n  = 181; for metastatic tumors n  = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset ( n  = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed. Results We showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-3β and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1α, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR. Conclusions Our findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.

In the present study, we unrevealed the effect of tamoxifen on ERα and PIP5K1α/AKT that are responsible for prostate cancer growth and invasion. Tamoxifen in combination treatment with PIP5K1α inhibitor, ISA‐2011B, led to tumor regression in xenograft mice. We found that depletion of tumor‐associated macrophages using clodronate sensitized the inhibitory effect of tamoxifen on prostate cancer. Selective ERα modulator, tamoxifen, is well tolerated in a heavily pretreated castration‐resistant prostate cancer (PCa) patient cohort. However, its targeted gene network and whether expression of intratumor ERα due to androgen deprivation therapy (ADT) may play a role in PCa progression is unknown. In this study, we examined the inhibitory effect of tamoxifen on castration‐resistant PCa in vitro and in vivo. We found that tamoxifen is a potent compound that induced a high degree of apoptosis and significantly suppressed growth of xenograft tumors in mice, at a degree comparable to ISA‐2011B, an inhibitor of PIP5K1α that acts upstream of PI3K/AKT survival signaling pathway. Moreover, depletion of tumor‐associated macrophages using clodronate in combination with tamoxifen increased inhibitory effect of tamoxifen on aggressive prostate tumors. We showed that both tamoxifen and ISA‐2011B exert their on‐target effects on prostate cancer cells by targeting cyclin D1 and PIP5K1α/AKT network and the interlinked estrogen signaling. Combination treatment using tamoxifen together with ISA‐2011B resulted in tumor regression and had superior inhibitory effect compared with that of tamoxifen or ISA‐2011B alone. We have identified sets of genes that are specifically targeted by tamoxifen, ISA‐2011B or combination of both agents by RNA‐seq. We discovered that alterations in unique gene signatures, in particular estrogen‐related marker genes are associated with poor patient disease‐free survival. We further showed that ERα interacted with PIP5K1α through formation of protein complexes in the nucleus, suggesting a functional link. Our finding is the first to suggest a new therapeutic potential to inhibit or utilize the mechanisms related to ERα, PIP5K1α/AKT network, and MMP9/VEGF signaling axis, providing a strategy to treat castration‐resistant ER‐positive subtype of prostate cancer tumors with metastatic potential.

Regulatory T cells (Tregs) can be antitumorigenic or pro-tumorigenic in colorectal cancer (CRC) depending on the presence of different Treg subsets with various immunosuppressive molecules. Some studies reported the phenotypic characteristics of tumor-infiltrating immune cells in CRC, but limited studies have focused on the co-expression of suppressive molecules on immune cells. The aim of this study was to characterize immune cells in the tumor microenvironment (TME), compared to paired adjacent non-tumor colon tissue of CRC patients. Additionally, we investigated co-expression of immunosuppressive molecules on different Treg subsets in the TME, normal colon tissue, and peripheral blood of CRC patients and healthy donors. In this preliminary study, we report that the majority of CD3 T cells in the TME are CD4 T cells with high co-expression of programmed death 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/CD39 molecules. Levels of CD4 FoxP3 Helios Tregs were significantly increased in the TME. Furthermore, we observed increased levels of PD-1/CTLA-4 and PD-1/CD39 co-expressing cells within FoxP3 Helios and FoxP3 Helios Treg subsets, indicative of their potent immunosuppressive potential. These results suggest synergistic associations between PD-1/CTLA-4 and PD-1/CD39 in dampening T-cell activation and function along with suppressing tumor-specific immune responses, suggesting that dual blockade of these molecules could be a more effective strategy for inducing antitumor immune responses in CRC.

Factors Required to Predict Postoperative Pulmonary Complications Factors Postoperative respiratory failure prediction Postoperative pneumonia prediction Type of surgery  Anorectal X X  Aortic X X  Bariatric X X  Brain X X  Breast X X  Cardiac X X  Ears, nose, throat X X  Foregut/hepatopancreatobiliary X X  Gallbladder, appendix, adrenal, and spleen X X  Hernia (ventral, inguinal, femoral) X X  Intestinal X X  Neck (thyroid and parathyroid) X X  Nonesophageal thoracic X X  Obstetric/gynecologic X X  Orthopedic and nonvascular extremity X X  Other abdominal X X  Peripheral vascular X X  Skin X X  Spine X X  Urologic X X  Vein X X American Society of Anesthesiology class*  Normal healthy patient X X  Patient with mild systemic disease X X  Patient with severe systemic disease X X  Patient with severe systemic disease that is a constant threat to life X X  Moribund patient who is not expected to survive without the surgery X X Functional status†  Totally dependent X X  Partially dependent X X  Totally independent X X Sepsis  Preoperative systemic inflammatory response syndrome X X  Preoperative septic shock X X  Preoperative sepsis X X  None X X Emergency case  Yes X  No X Age (in years) X COPD  GOLD stage 2–4 X  Without COPD X Smoking  Yes (prior to surgery) X  No X Note: This table is based on risk assessment tools from the American College of Surgeons National Surgical Quality Improvement Program. Other risk scores not discussed in this article include the LAS VEGAS tool, Surgical Lung Injury Prediction model, and Score for Prediction of Postoperative Respiratory Complications.11–13 Applying the Evidence A 54-year-old woman with a body mass index of 42 kg per m2 presents for a preoperative assessment before elective bariatric surgery. Because obstructive sleep apnea is not included in the NSQIP tools, there is a potential that her postoperative pulmonary risk is underestimated.

Abstract Identifying the causes and consequences of natural variations in ocean acidification and atmospheric CO 2 due to complex earth processes has been a major challenge for climate scientists in the past few decades. Recent developments in the boron isotope (δ 11 B) based seawater pH and pCO 2 (or pCO 2 sw ) proxy have been pivotal in understanding the various oceanic processes involved in air-sea CO 2 exchange. Here we present the first foraminifera-based δ 11 B record from the north-eastern Arabian Sea (NEAS) covering the mid-late Holocene (~ 8–1 ka). Our record suggests that the region was overall a moderate to strong CO 2 sink during the last 7.7 kyr. The region behaved as a significant CO 2 source during two short intervals around 5.5–4 ka and 2.8–2.5 ka. The decreased pH and increased CO 2 outgassing during those abrupt episodes are associated with the increased upwelling in the area. The upwelled waters may have increased the nutrient content of the surface water through either increased supply or weaker export production. This new dataset from the coastal NEAS suggests that, as a potential result of changes in the strength of the El-Nino Southern Oscillation, the region experienced short episodes of high CO 2 outgassing and pre-industrial ocean acidification comparable to or even greater than that experienced during the last ~ 200 years.

Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation.