Social dimensions of fertility behavior and consumption patterns in the Anthropocene.

We consider two aspects of the human enterprise that profoundly affect the global environment: population and consumption. We show that fertility and consumption behavior harbor a class of externalities that have not been much noted in the literature. Both are driven in part by attitudes and preferences that are not egoistic but socially embedded; that is, each household's decisions are influenced by the decisions made by others. In a famous paper, Garrett Hardin [G. Hardin, Science 162, 1243-1248 (1968)] drew attention to overpopulation and concluded that the solution lay in people "abandoning the freedom to breed." That human attitudes and practices are socially embedded suggests that it is possible for people to reduce their fertility rates and consumption demands without experiencing a loss in wellbeing. We focus on fertility in sub-Saharan Africa and consumption in the rich world and argue that bottom-up social mechanisms rather than top-down government interventions are better placed to bring about those ecologically desirable changes.

Population, Ecological Footprint and the Sustainable Development Goals.

The Anthropocene can be read as being the era when the demand humanity makes on the biosphere's goods and services-humanity's 'ecological footprint'-vastly exceeds its ability to supply it on a sustainable basis. Because the 'ecological' gap is met by a diminution of the biosphere, the inequality is increasing. We deploy estimates of the ecological gap, global GDP and its growth rates in recent years, and the rate at which natural capital has declined, to study three questions: (1) at what rate must efficiency at which Nature's services are converted into GDP rise if the UN's Sustainable Development Goals for year 2030 are to be sustainable; (2) what would a sustainable figure for world population be if global living standard is to be maintained at an acceptably high level? (3) What living standard could we aspire to if world population was to attain the UN's near lower-end projection for 2100 of 9 billion? While we take a global perspective, the reasoning we deploy may also be applied on a smaller scale. The base year we adopt for our computations is the pre-pandemic 2019.

Activation of D2 Dopamine Receptors in CD133+ve Cancer Stem Cells in Non-small Cell Lung Carcinoma Inhibits Proliferation, Clonogenic Ability, and Invasiveness of These Cells.

Lung carcinoma is the leading cause of cancer-related death worldwide, and among this cancer, non-small cell lung carcinoma (NSCLC) comprises the majority of cases. Furthermore, recurrence and metastasis of NSCLC correlate well with CD133+ve tumor cells, a small population of tumor cells that have been designated as cancer stem cells (CSC). We have demonstrated for the first time high expression of D2 dopamine (DA) receptors in CD133+ve adenocarcinoma NSCLC cells. Also, activation of D2 DA receptors in these cells significantly inhibited their proliferation, clonogenic ability, and invasiveness by suppressing extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT, as well as down-regulation of octamer-binding transcription factor 4 (Oct-4) expression and matrix metalloproteinase-9 (MMP-9) secretion by these cells. These results are of significance as D2 DA agonists that are already in clinical use for treatment of other diseases may be useful in combination with conventional chemotherapy and radiotherapy for better management of NSCLC patients by targeting both tumor cells and stem cell compartments in the tumor mass.

A Comparative Study of Transdermal Buprenorphine and Oral Morphine in the Treatment of Chronic Pain of Malignant Origin.

BACKGROUND AND OBJECTIVE: The study was designed to compare the efficacy and adverse effects of buprenorphine transdermal (TD) against oral morphine in pain management of cancer patient. METHODS: A randomized open-labeled prospective study was done in palliative cancer pain clinic in a tertiary care medical college between August 2017 and January 2018, to compare the efficacy (pain assessed by VAS) and adverse events (CTCAEv4) between arm A, buprenorphine TD, (20 µg/h, extended 7 days formulation) and arm B, oral morphine (10mg immediate releasing formulation). Patients with solid tumour malignancies with VAS score >40 (moderate to severe pain) were included in study. RESULTS: 63 patients were analyzed. Commonest primary cancers were breast in females and head and neck in male individuals in both arms. Initial VAS score of arm A and arm B were 81.25 and 82.26 respectively. By 1st week, 11 arm A patients were relieved from pain. Another 17 patients of arm A became pain free by 2nd week, total dose of 40 µg/h. Only 4 patients needed 60 µg/h for pain relief. In arm B, 2 patients were relieved by 1 week with total 30mg/day morphine, 11patients were relieved with 60 mg/day by 2nd week and 12 patients with 90 mg/day. 6 patients were relieved with 120 mg/day dose at the end of 4th week. Nausea and constipation were stastically higher in Arm B compared to that of Arm-A. CONCLUSIONS: TD Buprenorphine had similar efficacy with oral morphine, with better toxicity profile and better compliance.

Activation of Dopamine D1 Receptors in Dermal Fibroblasts Restores Vascular Endothelial Growth Factor-A Production by These Cells and Subsequent Angiogenesis in Diabetic Cutaneous Wound Tissues.

In wound beds, fibroblasts are rich sources of vascular endothelial growth factor A, a cytokine necessary for promoting angiogenesis and thereby the healing of wound tissues. However, in diabetes mellitus, these cells are functionally impaired and produce reduced amounts of vascular endothelial growth factor A, resulting in deficient angiogenesis and delayed wound healing. We here for the first time demonstrate that stimulation of D1 dopamine receptors present in dermal fibroblasts restores vascular endothelial growth factor A production by these cells, resulting in adequate angiogenesis and subsequent healing of cutaneous wounds in both type 1 and type 2 diabetic mice. This action of D1 dopamine receptors was mediated through the protein kinase A pathway. As delayed wound healing or chronic wounds are one of the major health problems in diabetic patients, D1 dopamine receptor agonists, which are already in clinical use for the treatment of other disorders, may be of translational value in the treatment of chronic, nonhealing diabetic wounds.

Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia.

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.

Tumor-derived vascular pericytes anergize Th cells.

Immune evasion within the tumor microenvironment supports malignant growth and is also a major obstacle for successful immunotherapy. Multiple cellular components and soluble factors coordinate to disrupt protective immune responses. Although stromal cells are well-known for their parenchymal supportive roles in cancer establishment and progression, we demonstrate for the first time, to our knowledge, that tumor-derived vascular pericytes negatively influence CD4(+) T cell activation and proliferation, and promote anergy in recall response to Ag by CD4(+)CD44(+) T cells via regulator of G protein signaling 5- and IL-6-dependent pathways. Our data support a new specific role for tumor-derived pericytes in the immune evasion paradigm within the tumor microenvironment and suggest the targeting of these cell populations in the context of successful immunotherapeutics for the treatment of cancer.

On biodiversity conservation and poverty traps.

This paper introduces a special feature on biodiversity conservation and poverty traps. We define and explain the core concepts and then identify four distinct classes of mechanisms that define important interlinkages between biodiversity and poverty. The multiplicity of candidate mechanisms underscores a major challenge in designing policy appropriate across settings. This framework is then used to introduce the ensuing set of papers, which empirically explore these various mechanisms linking poverty traps and biodiversity conservation.

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kruppel-like factor-2 expression in tumor endothelial cells.

Impaired blood flow in the tumor vascular bed caused by structurally and functionally abnormal blood vessels not only hinders the delivery of chemotherapeutic agents but also aggravates tumor hypoxia, making the tumor cells further resistant to antineoplastic drugs. Therefore, normalization of tumor blood vessels may be an important approach to increase therapeutic efficacy in the treatment of cancer patients. As blood vessels are supplied by sympathetic nerves containing dopamine (DA), and DA regulates functions of normal blood vessels through its receptors present in these vessels, we investigated the effect of DA on tumor vasculature. Here we report loss of sympathetic innervation and endogenous DA in abnormal and immature tumor blood vessels in malignant colon and prostate tumor tissues. In contrast, exogenous administration of DA normalizes the morphology and improves the functions of these vessels by acting on pericytes and endothelial cells, the two major cellular components of blood vessels. DA acts through its D(2) receptors present in these cells to up-regulate directly the expression of angiopoietin 1 (Ang1) in pericytes and the expression of the zinc finger transcriptional factor, Krüppel-like factor-2 (KLF2) in tumor endothelial cells. Importantly, this vessel stabilization by DA also significantly increases the concentration of anticancer drug in tumor tissues. These results show a relationship between vascular stabilization and a neurotransmitter and indicate that DA or its D(2) receptor-specific agonists can be an option for the treatment of cancer and disorders in which normalization of blood vessels may have therapeutic benefits.

Economic factors underlying biodiversity loss.

Contemporary economic thinking does not acknowledge that the human economy is embedded in Nature; it instead treats humanity as a customer that draws on Nature. In this paper, we present a grammar for economic reasoning that is not built on that error. The grammar is based on a comparison between our demand for Nature's maintenance and regulating services and her ability to supply them on a sustainable basis. The comparison is then used to show that for measuring economic well-being, national statistical offices should estimate an inclusive measure of their economies' wealth and its distribution, not GDP and its distribution. The concept of 'inclusive wealth' is then used to identify policy instruments that ought to be used to manage such global public goods as the open seas and tropical rainforests. Trade liberalization without heed paid to the fate of local ecosystems from which primary products are drawn and exported by developing countries leads to a transfer of inclusive wealth from there to rich importing countries. Humanity's embeddedness in Nature has far-reaching implications for the way we should view human activities-in households, communities, nations and the world. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

Dark matters: exploitation as cooperation.

The empirical literature on human cooperation contains studies of communitarian institutions that govern the provision of public goods and management of common property resources in poor countries. Scholars studying those institutions have frequently used the Prisoners' Dilemma game as their theoretical tool-kit. But neither the provision of local public goods nor the management of local common property resources involves the Prisoners' Dilemma. That has implications for our reading of communitarian institutions. By applying a fundamental result in the theory of repeated games to a model of local common property resources, it is shown that communitarian institutions can harbour exploitation of fellow members, something that would not be possible in societies where cooperation amounts to overcoming the Prisoners' Dilemma. The conclusion we should draw is that exploitation can masquerade as cooperation.

D1 and D2 dopamine receptor-mediated inhibition of activated normal T cell proliferation is lost in jurkat T leukemic cells.

Dopamine is a catecholamine neurotransmitter, which plays an important role in the regulation of T cell functions. In activated T cells from normal volunteers, stimulation of D(1) and D(2) dopamine receptors inhibit cell proliferation and cytokine secretion. However, there is no report yet regarding the regulatory role of D(1) and D(2) dopamine receptors in abnormally proliferating T cells. The present study investigates the expression and effect of activation of these dopamine receptors in Jurkat cells, a leukemic T cell line showing uncontrolled proliferation. Like normal human T cells, in Jurkat cells, D(1) and D(2) dopamine receptors are also expressed; however, unlike activated normal T cells, stimulation of these dopamine receptors in Jurkat cells fails to inhibit their T cell receptor-induced proliferation. This alteration is due to failure of D(1) dopamine receptor-mediated activation of cyclic AMP signaling and a missense mutation at the third cytoplasmic loop of D(2) dopamine receptors affecting inhibition of phosphorylation of ZAP-70, an important downstream protein transducing signal from the T cell receptor. These results help to understand the biology of abnormal proliferation of T cells in pathophysiological conditions where dopamine plays an important role.

Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization.

Mobilization of endothelial progenitor cells (EPCs) from the bone marrow and their subsequent participation in neovessel formation are implicated in tumor growth and neovascularization. As the neurotransmitter dopamine (DA) modulates adult endothelial cell function, we hypothesized that DA might have a regulatory role in mobilization of EPCs from the bone marrow niche. We show that there was a significant decrease in bone marrow DA content and an increase in EPC mobilization in tumor-bearing mice associated with tumor neovascularization. DA treatment of tumor-bearing mice inhibited EPC mobilization and tumor growth through its D2 receptors, as DA treatment failed to inhibit EPC mobilization in tumor-bearing mice treated with a specific DA D2 receptor antagonist and in tumor-bearing mice lacking the D2 receptor. In addition, we found that DA, through D2 receptors, exerted its inhibitory effect on EPC mobilization through suppression of VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis. These findings reveal a new link between DA and EPC mobilization and suggest a novel use for DA and D2 agents in the treatment of cancer and other diseases involving neovessel formation.

Dopamine, by acting through its D2 receptor, inhibits insulin-like growth factor-I (IGF-I)-induced gastric cancer cell proliferation via up-regulation of Krüppel-like factor 4 through down-regulation of IGF-IR and AKT phosphorylation.

The overexpression of insulin-like growth factor receptor-I (IGF-IR) and the activation of its signaling pathways both play critical roles in the development and progression of gastric cancer. Dopamine (DA), a major enteric neurotransmitter, has been reported to have a wide variety of physiological functions in the gastrointestinal tract, including the stomach. We have previously reported that both DA and tyrosine hydroxylase, the rate-limiting enzyme required for the synthesis of DA, are lost in malignant gastric tissues. The effect of this loss of DA on IGF-IR-induced growth of gastric cancer has not yet been elucidated; we therefore investigated the role of DA, if any, on IGF-IR-induced proliferation of malignant gastric cells. There was a significant increase in the expression of phosphorylated IGF-IR and its downstream signaling molecule AKT in human malignant gastric tissues compared with normal nonmalignant tissues. Furthermore, to determine whether this loss of DA has any effect on the activation of IGF-IR signaling pathways in malignant gastric tumors, in vitro experiments were undertaken, using AGS gastric cancer cells. Our results demonstrated that DA acting through its D(2) receptor, inhibits IGF-I-induced proliferation of AGS cells by up-regulating KLF4, a negative regulator of the cell cycle through down regulation of IGF-IR and AKT phosphorylation. Our results suggest that DA is an important regulator of IGF-IR function in malignant gastric cancer cells.

Effect of carboplatin dose capping on survival in recurrent breast, ovary and head and neck cancers: a single institutional retrospective study.

INTRODUCTION: Carboplatin based regimens are an integral part of chemotherapy regimens for recurrent head and neck cancers (rHNC), triple negative breast cancers (rTNBC) and ovarian cancers (rOC). Dose reduction/capping of carboplatin remains a controversial aspect of such regimens in patients with moderate creatinine clearance (50 ml/min to 125 ml/min), especially in resource limited setting. The authors, therefore, looked into the magnitude of difference in outcome this makes in the above mentioned subsites. METHODS: This single institutional retrospective study was performed with a total of 120 patients divided equally into Group A (patients receiving capped dose) and Group B (patients receiving uncapped dose). Further matching was performed with respect to age, sex, body surface area, weight, and primary malignancy subsite and baseline creatinine clearance. Patients in Group A had received 450 mg (for AUC 6 regimens) and 150 mg (for AUC 2 regimens) of carboplatin while patients in Group B received the actual calculated dose of carboplatin determined by the Calvert formula. Median progression free survival (mPFS) and median overall survival (mOS) were the co-primary outcome measures. RESULTS: At a median follow-up of 24 months, compared to Group A, Group B had a higher mPFS and mOS by 4 months (p < .001) and 5.5 months (p < .001), respectively. Statistically significant difference in outcome favouring Group B extends to all primary tumour subsites, with mPFS difference being 3.1 months (rHNC), 5.1 months (rTNBC) and 4.5 months (rOC) and mOS difference being 4.2 months (rHNC), 3 months (rTNBC) and 5.6 months (rOC). It was also found that capping had a statistically significant detriment in distal failure (p = .042) compared to locoregional failure (p = .842). A higher proportion of hematotoxicity was found in Group B, however, it was not statistically significant and well manageable. CONCLUSIONS: Blatant dose capping of carboplatin should be avoided probably with more caution in patients with distant disease recurrence compared to their counterparts with locoregional failure.

Dopamine Prevents Ultraviolet B-induced Development and Progression of Premalignant Cutaneous Lesions through its D2 Receptors.

Although the role of dopamine (DA) in malignant tumors has been reported, its function in premalignant lesions is unknown. Herein we report that the stimulation of DA D2 receptors in endothelial cells in ultraviolet B (UVB)-induced cutaneous lesions in mice significantly reduced the tumor number, tumor burden, and malignant squamous cell carcinoma in these animals. DA D2 receptor agonist inhibited VEGFA-dependent proangiogenic genes in vitro and in vivo. However, the mice pretreated with selective DA D2 receptor antagonist inhibited the actions of the agonist, thereby suggesting that the action of DA was through its D2 receptors in the endothelial cells. To our knowledge, this study is the first to report DA-mediated regulation of pathogenesis and progression of UVB-induced premalignant skin lesions. PREVENTION RELEVANCE: This investigation demonstrates the role of dopamine and its D2 receptors in UVB induced premalignant squamous cell skin lesions and how DA through its D2 receptors inhibits the development and progression of these lesions and subsequently prevents squamous cell carcinoma of the skin.

RGS5-TGFß-Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth.

Regulator-of-G-protein-signaling-5 (RGS5), a pro-apoptotic/anti-proliferative protein, is a signature molecule of tumor-associated pericytes, highly expressed in several cancers, and is associated with tumor growth and poor prognosis. Surprisingly, despite the negative influence of intrinsic RGS5 expression on pericyte survival, RGS5highpericytes accumulate in progressively growing tumors. However, responsible factor(s) and altered-pathway(s) are yet to report. RGS5 binds with Gαi/q and promotes pericyte apoptosis in vitro, subsequently blocking GPCR-downstream PI3K-AKT signaling leading to Bcl2 downregulation and promotion of PUMA-p53-Bax-mediated mitochondrial damage. However, within tumor microenvironment (TME), TGFß appeared to limit the cytocidal action of RGS5 in tumor-residing RGS5highpericytes. We observed that in the presence of high RGS5 concentrations, TGFß-TGFßR interactions in the tumor-associated pericytes lead to the promotion of pSmad2-RGS5 binding and nuclear trafficking of RGS5, which coordinately suppressed RGS5-Gαi/q and pSmad2/3-Smad4 pairing. The RGS5-TGFß-pSmad2 axis thus mitigates both RGS5- and TGFß-dependent cellular apoptosis, resulting in sustained pericyte survival/expansion within the TME by rescuing PI3K-AKT signaling and preventing mitochondrial damage and caspase activation. This study reports a novel mechanism by which TGFß fortifies and promotes survival of tumor pericytes by switching pro- to anti-apoptotic RGS5 signaling in TME. Understanding this altered RGS5 signaling might prove beneficial in designing future cancer therapy.

Our future in the Anthropocene biosphere.

The COVID-19 pandemic has exposed an interconnected and tightly coupled globalized world in rapid change. This article sets the scientific stage for understanding and responding to such change for global sustainability and resilient societies. We provide a systemic overview of the current situation where people and nature are dynamically intertwined and embedded in the biosphere, placing shocks and extreme events as part of this dynamic; humanity has become the major force in shaping the future of the Earth system as a whole; and the scale and pace of the human dimension have caused climate change, rapid loss of biodiversity, growing inequalities, and loss of resilience to deal with uncertainty and surprise. Taken together, human actions are challenging the biosphere foundation for a prosperous development of civilizations. The Anthropocene reality-of rising system-wide turbulence-calls for transformative change towards sustainable futures. Emerging technologies, social innovations, broader shifts in cultural repertoires, as well as a diverse portfolio of active stewardship of human actions in support of a resilient biosphere are highlighted as essential parts of such transformations.