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'.

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.

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.

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.

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.

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.

Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice.

BACKGROUND: Although vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2-3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated. METHODS: CIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo. RESULTS: Significant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice. CONCLUSION: CI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.

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.

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 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.

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.

Efficacy of a standardized herbal preparation (Roidosanal(®)) in the treatment of hemorrhoids: A randomized, controlled, open-label multicentre study.

BACKGROUND: Catechins and epicatechins are monomers of naturally occurring proanthocyanidins, which have been reported with free radical scavenging, antioxidant, antiinflammatory, antiallergic, and vasodilatory properties. Plant parts rich in proanthocyanidins have been used for years in treatment of various ano-rectal diseases. This study compares the efficacy of two herbal preparations, Daflon(®) 500 mg and Roidosanal(®), in ameliorating the signs and symptoms associated with hemorrhoids. OBJECTIVE: To evaluate the safety and to compare the efficacy of a herbal preparation, Roidosanal(®) versus Daflon(®) 500 mg, on signs and symptoms of hemorrhoidal disease. MATERIALS AND METHODS: In this pilot, active controlled, open-labeled multicentre study, 73 patients with proctoscopy proven hemorrhoids (Grade I to III) were randomly assigned to receive either Roidosanal(®) (Gr R; n = 37) or Daflon(®) 500 mg (Gr D; n = 36), for 15 days, at three centers in India. Assessment of hemorrhoidal symptoms was carried out in all patients at different time points. Intent-to-treat analysis was performed for both primary and secondary endpoints. RESULTS: Baseline characteristics were comparable between the two groups. Both products were found to be equally effective in improving the ano-rectal conditions in Grade I and Grade II hemorrhoids; however, Roidosanal(®) demonstrated better efficacy in patients with Grade III hemorrhoids. Hemorrhoids associated symptoms like bleeding, pain, etc., improved in both groups, although intergroup comparisons were comparable. CONCLUSION: Both Roidosanal(®) and Daflon(®) 500 mg were equally effective in resolving signs and symptoms of hemorrhoids. Roidosanal(®) can be tried as a safe and effective treatment option for treatment of hemorrhoids. Further randomized, double-blind and large multicentre studies are recommended.

Variation of adverse drug reaction profile of platinum-based chemotherapy with body mass index in patients with solid tumors: an observational study.

OBJECTIVES: Toxicity of cancer chemotherapy may be affected by nutritional status of patients which is reflected in the body mass index (BMI). We sought to assess whether the adverse drug reaction (ADR) profile of platinum-based chemotherapy varies with BMI status. MATERIALS AND METHODS: Adult patients of either sex, suffering from a solid tumor (lung, head and neck, ovary, gall bladder, stomach, colon) and started on platinum-based chemotherapy as initial treatment were included. BMI at chemotherapy commencement was obtained from medical records. Events were recorded and graded as per Eastern Co-operative Oncology Group Common Toxicity Criteria-patients' complaints; clinically evident signs and laboratory reports were considered. Frequencies of individual adverse events were compared between low BMI (<18.5 kg/m(2)) and satisfactory BMI groups. Similar comparisons were done for events with grades 2 or 3 severities. RESULTS: A total of 50 patients were observed over a 3-month period of whom 17 (34%) belonged to the low BMI group. Nausea, vomiting, diarrhea, stomatitis, anemia, alopecia, tinnitus and paresthesia were the commonly observed ADRs. The frequencies of anemia (P = 0.152) and vomiting (P = 0.140) and severity of grades of nausea (P = 0.066), anemia (P = 0.120) and paresthesia (P = 0.128) showed a higher trend in the low BMI group though differences were not statistically significant. The frequencies of tinnitus (P = 0.021) and paresthesia overall (P = 0.036) were significantly higher in the low BMI group. CONCLUSION: ADR profile of primary platinum-based chemotherapy appears to be partly influenced by BMI. This suggests the importance of maintaining adequate nutrition in patients and the need for greater vigilance in those with low BMI.

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.

Pervasive externalities at the population, consumption, and environment nexus.

Growing concerns that contemporary patterns of economic development are unsustainable have given rise to an extensive empirical literature on population growth, consumption increases, and our growing use of nature's products and services. However, far less has been done to reach a theoretical understanding of the socio-ecological processes at work at the population-consumption-environment nexus. In this Research Article, we highlight the ubiquity of externalities (which are the unaccounted for consequences for others, including future people) of decisions made by each of us on reproduction, consumption, and the use of our natural environment. Externalities, of which the "tragedy of the commons" remains the most widely discussed illustration, are a cause of inefficiency in the allocation of resources across space, time, and contingencies; in many situations, externalities accentuate inequity as well. Here, we identify and classify externalities in consumption and reproductive decisions and use of the natural environment so as to construct a unified theoretical framework for the study of data drawn from the nexus. We show that externalities at the nexus are not self-correcting in the marketplace. We also show that fundamental nonlinearities, built into several categories of externalities, amplify the socio-ecological processes operating at the nexus. Eliminating the externalities would, therefore, require urgent collective action at both local and global levels.