Kavita Sarin, M.D./ Ph.D., is an Assistant Professor of Dermatology. She has an academic interest in Personalized Medicine, focused on the integration of genetic and clinical patient data to inform disease susceptibility, stratify prognosis, and direct treatments in dermatologic disease. She sees patients in medical dermatology at Portola Valley and directs a specialized Skin Cancer Genetics clinic.
My research encompasses two main areas: 1) Using next-generation RNA, whole genome, and exome sequencing, we are investigating the genetic alterations involved in skin cancer progression, response to therapy, and other clinical outcomes and 2) We are developing and implementing genome-wide genetic risk prediction assessments for skin cancer into clinical use and studying the impact of this information on patient care.
This phase II trial studies how well remetinostat works in treating patients with skin basal cell cancer. Remetinostat may slow the growth of basal cell cancer cells.
The goal of this project is to identify genetic alterations that confer resistance to Smoothened inhibitor therapy in basal cell carcinoma.
PURPOSE: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.PATIENTS AND METHODS: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.RESULTS: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001).CONCLUSION: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.
The letters "Interpretation of the Outputs of Deep Learning Model trained with Skin Cancer Dataset" and "Automated Dermatological Diagnosis: Hype or Reality?" highlight the opportunities, hurdles, and possible pitfalls with the development of tools that allow for automated skin lesion classification. The potential clinical impact of these advances relies on their scalability, accuracy, and generalizability across a range of diagnostic scenarios.
BACKGROUND: Genetic and environmental risk factors have been associated with the development of multiple primary melanomas (MPM). We hypothesized that individuals with MPM may have increased predisposition to developing internal malignancies.OBJECTIVE: To identify the risk of subsequent malignancies in MPM patients.METHODS: Multiple primary standardized incidence ratios were analyzed for individuals with ≥1, ≥2 and ≥3 primary melanomas (PM) in the SEER database from 1973-2014.RESULTS: 223,799 individuals with ≥1, 19,709 with ≥2 and 3,995 with ≥3 PM were identified. Risks of subsequent internal malignancy increased with number of PM, with observed to expected (O/E) ratios of 0.99, 1.14, and 1.23 (p<0.05) for patients with at least one, two and three PM respectively. Internal malignancy was higher in younger MPM patients and those with superficial spreading melanoma. The most common malignancies amongst MPM patients include breast, prostate, thyroid, soft tissue, brain, kidney, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Risk of subsequent cutaneous melanoma increased with O/E ratios of 8.09, to 22.52, to 41.03 (p<0.05) respectively.LIMITATIONS: SEER records limited information about pigmentation phenotypes, histology, and treatments.CONCLUSION: Patients with MPM have increased risk of subsequent internal and cutaneous malignancies and may benefit from tight adherence to age-specific cancer screening.
Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, TGFbeta and fibronectin are found preferentially in infiltrative human BCC. This allowed us to develop in vivo models for the study of infiltrative BCC, which in turn let us confirm the role of TGFbeta in inducing peritumoral fibronectin deposition and tumor infiltration. We then show that fibronectin promotes adhesion and migration of BCC cell lines through integrin alpha5beta1-mediated phosphorylation of focal adhesion kinase (FAK). Fittingly, inhibition of integrin alpha5beta1 and phospho-FAK both prevent fibronectin-induced migration of BCC cells in vitro as well as BCC infiltration in vivo. Altogether our results open important insights into the pathogenesis of aggressive infiltrative BCC, and identify integrin alpha5beta1 or FAK inhibition as promising strategies for the treatment of advanced BCC.
BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk.OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women.METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset.RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma.LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort.CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.
Background: Histopathologic examination alone can be inadequate for diagnosis of certain melanocytic neoplasms. Recently, a 23-gene expression signature was clinically validated as an ancillary diagnostic test to differentiate benign nevi from melanoma. The current study assessed the performance of this test in an independent cohort of melanocytic lesions against clinically proven outcomes.Methods: Archival tissue from primary cutaneous melanomas and melanocytic nevi was obtained from four independent institutions and tested with the gene signature. Cases were selected according to pre-defined clinical outcome measures. Malignant lesions were defined as stage I-III primary cutaneous melanomas that produced distant metastases (metastatic to sites other than proximal sentinel lymph node(s)) following diagnosis of the primary lesion. Melanomas that were metastatic at the time of diagnosis, all re-excisions, and lesions with <10% tumor volume were excluded. Benign lesions were defined as cutaneous melanocytic lesions with no adverse long-term events reported.Results: Of 239 submitted samples, 182 met inclusion criteria and produced a valid gene expression result. This included 99 primary cutaneous melanomas with proven distant metastases and 83 melanocytic nevi. Median time to melanoma metastasis was 18 months. Median follow-up time for nevi was 74.9 months. The gene expression score differentiated melanoma from nevi with a sensitivity of 93.8% and a specificity of 96.2%.Conclusions: The results of gene expression testing closely correlate with long-term clinical outcomes of patients with melanocytic neoplasms.Impact: Collectively, this provides strong evidence that the gene signature adds valuable adjunctive information to aid in the accurate diagnosis of melanoma. Cancer Epidemiol Biomarkers Prev; 26(7); 1107-13. ©2017 AACR.
Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals.In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis. The sonic hedgehog (SHH) pathway inhibitor vismodegib was shown in a placebo-controlled phase III randomized trial to reduce the tumor burden in patients with BCNS. Epidermolysis bullosa (EB) has been classified into four major types and more than 30 subtypes based partly on specific mutations, and best clinical practice guidelines for the management of cutaneous squamous cell carcinoma in EB have been developed. Oculocutaneous albinism (OCA) has been associated with new mutations in genes named OCA5, OCA6, and OCA7, bringing to the total number of culprit genes to seven (OCA1-OCA7).Advances in our understanding of genetic conditions that predispose to childhood skin cancer include new disease classification systems, management guidelines, and treatment options.
DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10(-6) ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10(-6) and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10(-6) ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis.
Genome-wide association studies have identified 21 susceptibility loci associated with melanoma. These loci implicate genes affecting pigmentation, nevus count, telomere maintenance, and DNA repair in melanoma risk. Here, we report the results of a two-stage genome-wide association study of melanoma. The stage 1 discovery phase consisted of 4,842 self-reported melanoma cases and 286,565 controls of European ancestry from the 23andMe research cohort and the stage 2 replication phase consisted of 1,804 melanoma cases and 1,026 controls from the University of Texas M.D. Anderson Cancer Center. We performed a combined meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Our study replicates 20 of 21 previously known melanoma-loci and confirms the association of the telomerase reverse transcriptase, TERT, with melanoma susceptibility at genome-wide significance. In addition, we uncover a novel polymorphism, rs187843643 (OR = 1.96; 95% CI = [1.54, 2.48]; P = 3.53 x 10-8), associated with melanoma. The SNP rs187842643 lies within a noncoding RNA 177kb downstream of BASP1 (brain associated protein-1). We find that BASP1 expression is suppressed in melanoma as compared with benign nevi, providing additional evidence for a putative role in melanoma pathogenesis.
An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single-nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10(-7) and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10(-5) ) for the first time as independently related to BCC risk in meta-analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10(-18) ). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.
Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing.The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing.We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective.We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P < .001), followed by history of sun exposure (odds ratio 1.85, P < .01) and history of skin cancer (odds ratio 0.5, P = .01). Age and family history of skin cancer did not influence this decision. Participants increasingly chose testing if first queried about health behaviors (P < .0001).The decision to pursue hypothetical testing may differ from in-clinic decision-making. Self-selected, online participants may differ from the general population. Surveys may be subject to response bias.The decision to pursue genetic testing for skin cancer is primarily determined by subjective factors, such as anxiety and curiosity. Health factors, including skin cancer history, also influenced decision-making. Priming with consideration of objective health factors can increase the desire to pursue testing.
We describe the case of a 26-year-old woman with a history of congenital ichthyosiform erythroderma (CIE) who initially presented with a stage IIA amelanotic melanoma on her forearm that was surgically excised. We also review the literature on CIE-associated skin cancers and discuss the possible contribution of ichthyosis to the risk of cutaneous malignancies. Our findings emphasize the importance of close lifelong skin cancer screening in individuals with CIE and highlight the unique malignancy risk of these individuals.
Introduction Direct-to-consumer (DTC) teledermatology is radically changing the way patients obtain dermatological care. Now, with a few clicks, patients can obtain dermatological consultations and prescription medications without a prior physician-patient relationship. To analyse all DTC teledermatology services available to US patients. Methods We performed Internet searches to identify DTC teledermatology services available through Internet webpages or through smartphone applications. For each service, the scope of care provided, cost, wait times, prescription policies and other relevant information were recorded. Results Twenty-two DTC teledermatology services are available to US patients in 45 states. Six (27%) services offer care from international physicians. Sixteen (73%) services allow patients to seek care for any reason, while six (27%) limit care to acne or anti-aging. The median reported response time for DTC teledermatology services is 48 hours from the time of patient request. The median consultation fee for companies providing care from US board-certified physicians is US$59. Across all services, consultation fees range from US$1.59 to US$250. Conclusions DTC teledermatology services are readily available to patients in most states. These services may reduce the cost of patient visits, expand access to care and increase patient convenience. However, the presence of services staffed by physicians who are not US board-certified, as well as the use of incautious language regarding prescription medications, is concerning.
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
Basal cell cancers (BCCs) are characterized by up-regulation of Hedgehog pathway through loss of Patched1 or activation of Smoothened, and smoothened-inhibitors such as vismodegib are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with Basal Cell Nevus Syndrome (BCNS) harbor germline defects in Patched1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to Smoothened-inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low-tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high-burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of ultraviolet mutagenesis, increased genomic stability, and harbor fewer functionally resistant Smoothened mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to Smoothened-inhibitors. BCNS-BCCs appear to have reduced mutator phenotype as compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.
The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.
Direct-to-consumer teledermatology is radically changing the way some patients obtain dermatologic care. Many direct-to-consumer teledermatology services offer care to patients younger than 18 years, but policies and standards are nonuniform. For pediatric patients, direct-to-consumer teledermatology is a substantial departure from in-person care. More consensus, standards, and guidelines are necessary.
Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor-treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.Of the 5 patients (mean [SD] age, 52  years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.
To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this investigational, open-label study. Tumor response was determined using the response evaluation criteria in solid tumors. SMO mutations were identified using biopsy samples from the target BCC location.The median duration of treatment with sonidegib was 6 weeks (range, 3-58 weeks). Five patients experienced progressive disease with sonidegib. Three patients experienced stable disease and discontinued sonidegib either due to adverse events (n = 1) or due to election for surgery (n = 2). The response of one patient was not evaluable. SMO mutations with in vitro data suggesting resistance to Hh pathway inhibition were identified in 5 patients, and none of these patients experienced responses while on sonidegib.Patients with advanced BCCs that were previously resistant to treatment with vismodegib similarly demonstrated treatment resistance with sonidegib. Patients who have developed treatment resistance to an SMO inhibitor may continue to experience tumor progression in response to other SMO inhibitors. Clin Cancer Res; 22(6); 1325-9. ©2015 AACR.
Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.
Phenotypic traits, such as red hair and freckling, increase melanoma risk by 2- to 3-fold. In addition, approximately 10% of melanomas are caused by inherited germline mutations that increase melanoma risk from 4- to >1000-fold. This review highlights the key genes responsible for inherited melanoma, with an emphasis on when a patient should undergo genetic testing. Many genetic syndromes associated with increased melanoma risk are also associated with an increased risk of other cancers. Identification of these high-risk patients is essential for preventive behavior reinforcement, genetic counseling, and ensuring other required cancer screenings.
Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nature communications Chahal, H. S., Lin, Y., Ransohoff, K. J., Hinds, D. A., Wu, W., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12048-?
Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.
Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma. Nature communications Chahal, H. S., Wu, W., Ransohoff, K. J., Yang, L., Hedlin, H., Desai, M., Lin, Y., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Hinds, D. A., Tang, J. Y., Han, J., Sarin, K. Y. 2016; 7: 12510-?
Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
IMPORTANCE Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described. OBSERVATIONS We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi. CONCLUSIONS AND RELEVANCE Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a "second hit" during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERT(ci)) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways.


Space Applications centermakes high tech instruments that go into the making of India's best satellites.
The fire started in a store room in the Space Application Center campus.
A minor fire broke out at the Indian Space Research Organisation (ISRO) campus in Ahmedabad, Gujarat.
The fire broke out in a storeroom in ISRO's Space Application Centre, the official said. DK Das, Director of the Space Application Center, told NDTV that the fire started in a non-technical area.
Chief Fire Officer MF Dastur said the fire was brought under control in an hour.
"The fire started in a store room in the SAC campus on Friday morning. Only some old books got burnt in the incident. The fire was brought under control within one hour," he said.
This is the second time in recent times that fire broke out at the facility. Space Applications center makes high tech instruments that go into the making of India's best satellites.


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Home Port Kochi Port tops in maintenance dredging among major ports in country
Kochi Port tops in maintenance dredging among major ports in country
Around 24 MCUM of dredging is done annually at the Kochi Port for maintenance of channels, making it one of the most expensive ports in terms of annual maintenance cost.
Among the major ports in the country, the Kochi Port required the highest quantity of annual maintenance dredging to maintain its draft in the last three years.
According to statistics available with the Ministry of Ports, Shipping and Waterways, around 72.5 million cubic metres (MCUM) was dredged at the port followed by Jawaharlal Nehru Port Authority, Mumbai, (50.16 MCUM), Syama Prasad Mookerjee Port Authority, Kolkata, (25.6 MCUM), and Paradip Port Authority, Odisha, (21.21 MCUM).
Maintenance dredging assumes significance as port administrations need to spend a huge amount for dredging and disposal of dredged material. As per figures, around 24 MCUM of dredging is done annually at the Kochi Port for maintenance of channels, making it one of the most expensive ports in the country in terms of annual maintenance cost.
Though it is one of the serious problems faced by the ports along the east and west coasts in the country in terms of operational and environmental concerns, the quantity of silt to be dredged will vary from port to port depending upon its geographic location and draft required to be maintained for the passage of vessels, according to senior officer close to the Cochin Ports Authority. Here in the case of Cochin Port, the annual maintenance dredging is relatively high recently compared to other major ports.
First, it is situated in a tidal estuary where tidal forces such as flood tide and ebb tide are the predominantly acting on the port basin. The presence of marine clay along the river mouth is posing serious challenges along with the silt deposited by the Periyar River in harbour basin. However, the cost involved for the maintenance dredging is significantly low here as marine clay has a significant amount of water and the tonnage of silt in marine clay is about fifty per cent lower than other dredged materials such as sand.
Further, the Cochin Port has spent around ₹120-140 crore for the annual maintenance dredging, which is not a big deal considering the 40-million tonne cargo it handles per year, said the sources. In the proposed Vizhinjam international seaport, the maintenance dredging is anticipated almost nil due to its natural drift while it has to undertake a capital dredging of 7 MCUM to arrange infrastructure facilities.
Source : thehindu
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But contrary to popular belief, hair loss is not just a man's issue; around 40 percent of hair loss in the U.S. occurs in women. For both sexes, androgenetic alopecia — also known as male or female pattern baldness — is the most common form of hair loss.
They looked specifically at monthly search volume index (SVI) data for the term "hair loss" between January 2004 and October 2016.
"What is also interesting is that seasonal variations in hair loss also occurs in animals and has been noted in studies with rhesus monkeys, cats, and dogs. In particular, seasonal flank alopecia has been described in dogs," Dr. Kwatra told MNT.
"Future studies should examine physiological changes in human hair during the seasons," Dr. Kwatra told MNT.
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Discussions About the Most Recommended Albums and Songs of All Time
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Treble's Top 200 Songs of the '70s
cuneyt81
Superunknown
Post by cuneyt81 » Tue Aug 14, 2012 4:49 pm
Treble just started a list this week of its Top 200 songs of the 1970s. The first 100 are up right now:
http://www.treblezine.com/features/331.html
Unquestionable Presence
Post by JR » Wed Aug 15, 2012 3:37 pm
Thanks for the heads-up.
Most pleasantly surprised by the No. 112 entry.
150. Pink Floyd, "Money"
149. Led Zeppelin, "Rock and Roll"
148. Dolly Parton, "Jolene"
147. Delta 5, "Mind Your Own Business"
146. Marvin Gaye, "Got to Give It Up"
145. Throbbing Gristle, "Hot on the Heels of Love"
144. The Clash, "Janie Jones"
143. The Runaways, "Cherry Bomb"
142. Badfinger, "Day After Day"
141. The Cure, "Boys Don't Cry"
140. Can, "Spoon"
139. Marianne Faithfull, "Broken English"
138. Plastic Bertrand, "Ça Plane Pour Moi"
137. Judas Priest, "The Ripper"
136. Prince, "I Wanna Be Your Lover"
135. Neil Young, "On the Beach"
134. Dire Straits, "Sultans of Swing"
133. Jimmy Cliff, "The Harder They Come"
132. Pink Floyd, "One of These Days"
131. Roxy Music, "Virginia Plain"
130. The Cars, "Just What I Needed"
129. Ramones, "I Wanna Be Sedated"
128. Donna Summer, "Love to Love You Baby"
127. Pink Floyd, "Another Brick in the Wall, p. 2"
126. Public Image Limited, "Public Image"
125. The Specials, "A Message to You, Rudy"
124. The Pretenders, "Brass In Pocket"
123. Chic, "Le Freak"
122.The Undertones, "Teenage Kicks"
121. Bob Dylan, "Hurricane"
120. James Brown, "The Boss"
119. Bobby Womack, "Across 110th Street"
118. Marvin Gaye, "Inner City Blues (Makes Me Wanna Holler)"
117. Magazine, "Shot by Both Sides"
116. David Bowie, "Ziggy Stardust"
115. Gram Parsons, "Return of the Grievous Angel"
114. Suicide, "Frankie Teardrop"
113. Sugarhill Gang, "Rapper's Delight"
112. The Bee Gees, "How Deep Is Your Love?"
111. Devo, "Gut Feeling/Slap Your Mammy"
110. Herbie Hancock, "Chameleon"
109. Grateful Dead, "Uncle John's Band"
108. The Police, "Roxanne"
107. Steely Dan, "Show Biz Kids"
106. Serge Gainsbourg, "Cargo Culte"
105. David Bowie, "Rebel Rebel"
104. Bob Marley and the Wailers, "No Woman No Cry"
103. The Who, "Won't Get Fooled Again"
102. Kraftwerk, "Autobahn"
101. George Harrison, "What Is Life"
Re: Treble's Top 200 Songs of the '70s
Post by Zorg » Fri Aug 17, 2012 12:55 am
Fanfanfanfanfantastic list so far.
Post by Romain » Fri Aug 17, 2012 6:56 am
Zorg wrote: Fanfanfanfanfantastic list so far.
I agree. Absolutely perfect for the moment. And I just discovered Delta 5 - Mind Your Own Business...very good song.
100-51...
Post by JR » Fri Aug 17, 2012 8:07 pm
100. Bob Dylan, "Shelter from the Storm"
99. Gil Scott-Heron & Brian Jackson, "The Bottle"
98. Tubeway Army, "Are `Friends' Electric"
97. Led Zeppelin, "Kashmir"
96. Siouxsie and the Banshees, "Hong Kong Garden"
95. Can, "Oh Yeah"
94. Allman Brothers, "Midnight Rider"
93. The B-52s, "Rock Lobster"
92. Curtis Mayfield, "Superfly"
91. Elvis Costello and the Attractions, "No Action"
90. T. Rex, "Bang A Gong (Get It On)"
89. Isaac Hayes, "Theme from Shaft"
88. Peter Gabriel, "Solsbury Hill"
87. Suicide, "Cheree"
86. America, "A Horse With No Name"
85. Grateful Dead, "Friend of the Devil"
84. Wire, "I Am the Fly"
83. Talking Heads, "Life During Wartime"
82. Joy Division, "Shadowplay"
81. Elvis Costello, "Alison"
80. Marvin Gaye, "Let's Get It On"
79. Rolling Stones, "Can't You Hear Me Knocking"
78. Kate Bush, "Wuthering Heights"
77. The Clash, "(White Man) In Hammersmith Palais"
76. Lou Reed, "Walk on the Wild Side"
75. Roxy Music,"Love Is the Drug"
74. Gil Scott-Heron, "The Revolution Will Not Be Televised"
73. Rod Stewart, "Maggie May"
72. The Beatles, "Let It Be"
71. Bauhaus, "Bela Lugosi's Dead"
70. The Beach Boys, "Surf's Up"
69. Sex Pistols, "Anarchy in the UK"
68. Lou Reed, "Satellite of Love"
67. Fleetwood Mac, "Dreams"
66. David Bowie, "Sound and Vision"
65. Iggy Pop, "Lust For Life"
64. The Clash, "Train In Vain (Stand by Me)"
63. Sly and the Family Stone, "Family Affair"
62. Bill Withers, "Ain't No Sunshine"
61. Cheap Trick, "Surrender"
60. Gang Of Four, "Natural's Not In It"
59. Joy Division, "Disorder"
58. Al Green, "Let's Stay Together"
57. Neil Young, "Heart of Gold"
56. The Damned, "New Rose"
55. T. Rex, "20th Century Boy"
54. Fela Kuti, "Zombie"
53. Neu! "Hallogallo"
52. Big Star, "Thirteen"
51. Fleetwood Mac, "The Chain"
50-1...
50. Shuggie Otis, "Strawberry Letter 23"
49. The Pop Group, "She is Beyond Good and Evil"
48. Joy Division, "She's Lost Control"
47. XTC, "Making Plans for Nigel"
46. Nick Drake, "Pink Moon"
45. Bee Gees, "Stayin' Alive"
44. Big Star, "September Gurls"
43. Brian Eno, "Needles In the Camel's Eye"
42. John Lennon, "Imagine"
41. Curtis Mayfield, "Pusherman"
40. Buzzcocks, "What Do I Get?"
39. Marvin Gaye, "What's Going On"
38. Wire, "Map Ref. 41º N 93º W"
37. Modern Lovers, "Roadrunner"
36.Richard Hell and the Voidoids, "Blank Generation"
35. Al Green, "Love and Happiness"
34. Queen, "Bohemian Rhapsody"
33. Elvis Costello and the Attractions, "Pump It Up"
32. Pink Floyd, "Wish You Were Here"
31. Miles Davis, "Pharaoh's Dance"
30. Led Zeppelin, "When the Levee Breaks"
29. Blue Öyster Cult, "Don't Fear the Reaper"
28. Michael Jackson, "Don't Stop Till You Get Enough"
27. Fleetwood Mac, "Go Your Own Way"
26. Creedence Clearwater Revival, "Lookin' Out My Back Door"
25. Bruce Springsteen, "Born to Run"
24. Buzzcocks, "Ever Fallen In Love (With Someone You Shouldn't've)"
23. Curtis Mayfield, "Move On Up"
22. Rolling Stones, "Wild Horses"
21. The Police, "Message in a Bottle"
20. Can, "Vitamin C"
19. Black Sabbath, "Paranoid"
18. Gang of Four, "Damaged Goods"
17. Ramones, "Blitzkrieg Bop"
16. Patti Smith, "Gloria"
15. Funkadelic, "Maggot Brain"
14. Donna Summer, "I Feel Love"
13. The Who, "Baba O'Riley"
12. Iggy Pop, "The Passenger"
11. Bob Dylan, "Tangled Up in Blue"
10. Blondie, "Heart of Glass"
9. Iggy and the Stooges, "Search and Destroy"
8. The Clash, "London Calling"
7. David Bowie, "Heroes"
6. Television, "Marquee Moon"
5. Stevie Wonder, "Superstition"
4. Joy Division, "Transmission"
3. Talking Heads, "Psycho Killer"
2. Velvet Underground, "Sweet Jane"
1. David Bowie, "Life on Mars?"
Die Mensch Maschine
Post by Moonbeam » Sun Aug 19, 2012 11:07 am
Pretty excellent list. So happy to see "Editions of You" make an appearance!
Post by Romain » Mon Aug 20, 2012 12:39 pm
For sure one of the best song list ever.
Full of Fire
Re: 50-1...
Post by Jackson » Wed Aug 22, 2012 12:36 pm
JR wrote: 49. The Pop Group, "She is Beyond Good and Evil"
Fantastic list, glad to see these and others get a boost (I agree on "Editions of You" too, Moonbeam). That top 5 is both really unique for a 70s list yet doesn't stray too far from what you might expect.
Location: Älvsjö, Stockholm, Sweden
Contact Henrik
Post by Henrik » Fri Jul 12, 2013 7:51 pm
Jackson wrote: (I agree on "Editions of You" too, Moonbeam)
That song is not on the list. What are you guys talking about?
Everyone you meet fights a battle you know nothing about. Be kind. Always.
Poliuks
Post by Poliuks » Fri Jul 12, 2013 8:07 pm
It's number 177; only first 150 of total 200 songs were posted here. If you want me to do it, I may complete the list.
Post by Henrik » Fri Jul 12, 2013 11:36 pm
Poliuks wrote: It's number 177; only first 150 of total 200 songs were posted here. If you want me to do it, I may complete the list.
Oh, yes please!
Post by Poliuks » Sat Jul 13, 2013 8:49 am
http://www.treblezine.com/trebles-top-2 ... s-200-151/
200. Neil Young, "My My Hey Hey (Out of the Blue)"
199. ABBA, "Dancing Queen"
198. Stevie Wonder, "Higher Ground"
197. Pere Ubu, "Final Solution"
196. Derek and the Dominos, "Layla"
195. Michael Jackson, "Rock With You"
194. Rolling Stones, "Beast of Burden"
193. Joe Jackson, "Is She Really Going Out With Him?"
192. Freda Payne, "Band of Gold"
191. Carole King, "It's Too Late"
190. Gene Clark, "No Other"
189. Brian Eno, "Everything Merges With the Night"
188. Wire, "The 15th"
187. The Slits, "Typical Girls"
186. Black Sabbath, "Supernaut"
185. Kermit the Frog, "Rainbow Connection"
184. Throbbing Gristle, "Hamburger Lady"
183. The Kinks, "Strangers"
182. Crosby, Stills, Nash & Young, "Helpless"
181. X-Ray Spex, "Oh Bondage Up Yours!"
180. Alice Coltrane, "Journey in Satchidananda"
179. T. Rex, "Jeepster"
178. Lynyrd Skynyrd, "Free Bird"
177. Roxy Music, "Editions of You"
176. Al Green, "Call Me"
175. Creedence Clearwater Revival, "Have You Ever Seen the Rain"
174. The Ramones, "Sheena Is a Punk Rocker"
173. Mott the Hoople, "All the Young Dudes"
172. Joni Mitchell, "Blue"
171. Leonard Cohen, "Last Year's Man"
170. Jorge Ben, "Ponta de Lança Africano (Umbabarauma)"
169. Sex Pistols, "God Save the Queen"
168. John Lennon, "Instant Karma"
167. Patti Smith, "Because the Night"
166. Lou Reed, "Perfect Day"
165. Black Sabbath, "Iron Man"
164. ABBA, "Fernando"
163. Fela Kuti, "Expensive Shit"
162. Kraftwerk, "The Model"
161. Gary Numan, "Cars"
160. Gerry Rafferty, "Baker Street"
159. James Brown, "(Get Up I Feel Like Being a) Sex Machine"
158. Wire, "Ex-Lion Tamer"
157. Tom Petty and the Heartbreakers, "American Girl"
156. The Saints, "Know Your Product"
155. Cat Stevens, "The Wind"
154. Althea and Donna, "Uptown Top Ranking"
153. Bruce Springsteen, "Thunder Road"
152. Neil Young, "Don't Let It Bring You Down"
151. Kraftwerk, "Trans Europe Express"
Post by Henrik » Sat Jul 13, 2013 12:35 pm
Thanks Poliuks!
Post by JR » Sat Jul 13, 2013 8:50 pm
I don't know why I didn't post 200-151.
"Rainbow Connection" made the list.
Sweepstakes Ron
Location: Here, There, and Everywhere
Post by Sweepstakes Ron » Sun Jul 14, 2013 1:40 am
JR wrote: Rainbow Connection" made the list.
That's awesome! Does anyone know if it's shown up on any other critic's lists?
Splish splash, I was raking in the cash
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Psychologists and anthropologists explore how only some "conspiracy theories" fail tests of reason; and discuss the problems and potential of "conspiracy theory" for social movements.


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Home » Library » Historical Library » John Locke Locke 3 11
John Locke Locke 3 11
Of the Remedies of the Foregoing Imperfections
and Abuses of Words
1. Remedies are worth seeking The natural and improved imperfections of languages we have seen above at large: and speech being the great bond that holds society together, and the common conduit, whereby the improvements of knowledge are conveyed from one man and one generation to another, it would well deserve our most serious thoughts to consider, what remedies are to be found for the inconveniences above mentioned.
2. Are not easy to find. I am not so vain as to think that any one can pretend to attempt the perfect reforming the languages of the world, no not so much as of his own country, without rendering himself ridiculous. To require that men should use their words constantly in the same sense, and for none but determined and uniform ideas, would be to think that all men should have the same notions, and should talk of nothing but what they have clear and distinct ideas of: which is not to be expected by any one who hath not vanity enough to imagine he can prevail with men to be very knowing or very silent And he must be very little skilled in the world, who thinks that a voluble tongue shall accompany only a good understanding; or that men's talking much or little should hold proportion only to their knowledge.
3. But yet necessary to those who search after truth. But though the market and exchange must be left to their own ways of talking, and gossipings not be robbed of their ancient privilege: though the schools, and men of argument would perhaps take it amiss to have anything offered, to abate the length or lessen the number of their disputes; yet methinks those who pretend seriously to search after or maintain truth, should think themselves obliged to study how they might deliver themselves without obscurity, doubtfulness, or equivocation, to which men's words are naturally liable, if care be not taken.
4. Misuse of words the great cause of errors. For he that shall well consider the errors and obscurity, the mistakes and confusion, that are spread in the world by an ill use of words, will find some reason to doubt whether language, as it has been employed, has contributed more to the improvement or hindrance of knowledge amongst mankind. How many are there, that, when they would think on things, fix their thoughts only on words, especially when they would apply their minds to moral matters? And who then can wonder if the result of such contemplations and reasonings, about little more than sounds, whilst the ideas they annex to them are very confused and very unsteady, or perhaps none at all; who can wonder, I say, that such thoughts and reasonings end in nothing but obscurity and mistake, without any clear judgment or knowledge?
5. Has made men more conceited and obstinate. This inconvenience, in an ill use of words, men suffer in their own private meditations: but much more manifest are the disorders which follow from it, in conversation, discourse, and arguings with others. For language being the great conduit, whereby men convey their discoveries, reasonings, and knowledge, from one to another, he that makes an ill use of it, though he does not corrupt the fountains of knowledge, which are in things themselves, yet he does, as much as in him lies, break or stop the pipes whereby it is distributed to the public use and advantage of mankind. He that uses words without any clear and steady meaning, what does he but lead himself and others into errors? And he that designedly does it, ought to be looked on as an enemy to truth and knowledge. And yet who can wonder that all the sciences and parts of knowledge have been so overcharged with obscure and equivocal terms, and insignificant and doubtful expressions, capable to make the most attentive or quick-sighted very little, or not at all, the more knowing or orthodox: since subtlety, in those who make profession to teach or defend truth, hath passed so much for a virtue: a virtue, indeed, which, consisting for the most part in nothing but the fallacious and illusory use of obscure or deceitful terms, is only fit to make men more conceited in their ignorance, and more obstinate in their errors.
6. Addicted to wrangling about sounds. Let us look into the books of controversy of any kind, there we shall see that the effect of obscure, unsteady, or equivocal terms is nothing but noise and wrangling about sounds, without convincing or bettering a man's understanding. For if the idea be not agreed on, betwixt the speaker and hearer, for which the words stand, the argument is not about things, but names. As often as such a word whose signification is not ascertained betwixt them, comes in use, their understandings have no other object wherein they agree, but barely the sound; the things that they think on at that time, as expressed by that word, being quite different.
7. Instance, bat and bird. Whether a bat be a bird or no, is not a question, Whether a bat be another thing than indeed it is, or have other qualities than indeed it has; for that would be extremely absurd to doubt of. But the question is, (1) Either between those that acknowledged themselves to have but imperfect ideas of one or both of this sort of things, for which these names are supposed to stand. And then it is a real inquiry concerning the nature of a bird or a bat, to make their yet imperfect ideas of it more complete; by examining whether all the simple ideas to which, combined together, they both give the name bird, be all to be found in a bat: but this is a question only of inquirers (not disputers) who neither affirm nor deny, but examine: Or, (2) It is a question between disputants; whereof the one affirms, and the other denies that a bat is a bird. And then the question is barely about the signification of one or both these words; in that they not having both the same complex ideas to which they give these two names, one holds and the other denies, that these two names may be affirmed one of another. Were they agreed in the signification of these two names, it were impossible they should dispute about them. For they would presently and clearly see (were that adjusted between them), whether all the simple ideas of the more general name bird were found in the complex idea of a bat or no; and so there could be no doubt whether a bat were a bird or no. And here I desire it may be considered, and carefully examined, whether the greatest part of the disputes in the world are not merely verbal, and about the signification of words; and whether, if the terms they are made in were defined, and reduced in their signification (as they must be where they signify anything) to determined collections of the simple ideas they do or should stand for, those disputes would not end of themselves, and immediately vanish. I leave it then to be considered, what the learning of disputation is, and how well they are employed for the advantage of themselves or others, whose business is only the vain ostentation of sounds; i.e. those who spend their lives in disputes and controversies. When I shall see any of those combatants strip all his terms of ambiguity and obscurity, (which every one may do in the words he uses himself), I shall think him a champion for knowledge, truth, and peace, and not the slave of vain-glory, ambition, or a party.
8. Remedies. To remedy the defects of speech before mentioned to some degree, and to prevent the inconveniences that follow from them, I imagine the observation of these following rules may be of use, till somebody better able shall judge it worth his while to think more maturely on this matter, and oblige the world with his thoughts on it.
First remedy: To use no word without an idea annexed to it. First, A man shall take care to use no word without a signification, no name without an idea for which he makes it stand. This rule will not seem altogether needless to any one who shall take the pains to recollect how often he has met with such words as instinct, sympathy, and antipathy, &c., in the discourse of others, so made use of as he might easily conclude that those that used them had no ideas in their minds to which they applied them, but spoke them only as sounds, which usually served instead of reasons on the like occasions. Not but that these words, and the like, have very proper significations in which they may be used; but there being no natural connexion between any words and any ideas, these, and any other, may be learned by rote, and pronounced or writ by men who have no ideas in their minds to which they have annexed them, and for which they make them stand; which is necessary they should, if men would speak intelligibly even to themselves alone.
9. Second remedy: To have distinct, determinate ideas annexed to words, especially in mixed modes. Secondly, It is not enough a man uses his words as signs of some ideas: those he annexes them to, if they be simple, must be clear and distinct; if complex, must be determinate, i.e. the precise collection of simple ideas settled in the mind, with that sound annexed to it, as the sign of that precise determined collection, and no other. This is very necessary in names of modes, and especially moral words; which, having no settled objects in nature, from whence their ideas are taken, as from their original, are apt to be very confused. Justice is a word in every man's mouth, but most commonly with a very undertermined, loose signification; which will always be so, unless a man has in his mind a distinct comprehension of the component parts that complex idea consists of: and if it be decompounded, must be able to resolve it still on, till he at last comes to the simple ideas that make it up: and unless this be done, a man makes an ill use of the word, let it be justice, for example, or any other. I do not say, a man needs stand to recollect, and make this analysis at large, every time the word justice comes in his way: but this at least is necessary, that he have so examined the signification of that name, and settled the idea of all its parts in his mind, that he can do it when he pleases. If any one who makes his complex idea of justice to be, such a treatment of the person or goods of another as is according to law, hath not a clear and distinct idea what law is, which makes a part of his complex idea of justice, it is plain his idea of justice itself will be confused and imperfect. This exactness will, perhaps, be judged very troublesome; and therefore most men will think they may be excused from settling the complex ideas of mixed modes so precisely in their minds. But yet I must say, till this be done, it must not be wondered, that they have a great deal of obscurity and confusion in their own minds, and a great deal of wrangling in their discourse with others.
10. And distinct and conformable ideas in words that stand for substances. In the names of substances, for a right use of them, something more is required than barely determined ideas. In these the names must also be conformable to things as they exist; but of this I shall have occasion to speak more at large by and by. This exactness is absolutely necessary in inquiries after philosophical knowledge, and in controversies about truth. And though it would be well, too, if it extended itself to common conversation and the ordinary affairs of life; yet I think that is scarce to be expected. Vulgar notions suit vulgar discourses: and both, though confused enough, yet serve pretty well the market and the wake. Merchants and lovers, cooks and tailors, have words wherewithal to dispatch their ordinary affairs: and so, I think, might philosophers and disputants too, if they had a mind to understand, and to be clearly understood.
11. Third remedy: To apply words to such ideas as common use has annexed them to. Thirdly, it is not enough that men have ideas, determined ideas, for which they make these signs stand; but they must also take care to apply their words as near as may be to such ideas as common use has annexed them to. For words, especially of languages already framed, being no man's private possession, but the common measure of commerce and communication, it is not for any one at pleasure to change the stamp they are current in, nor alter the ideas they are affixed to; or at least, when there is a necessity to do so, he is bound to give notice of it. Men's intentions in speaking are, or at least should be, to be understood; which cannot be without frequent explanations, demands, and other the like incommodious interruptions, where men do not follow common use. Propriety of speech is that which gives our thoughts entrance into other men's minds with the greatest ease and advantage: and therefore deserves some part of our care and study, especially in the names of moral words. The proper signification and use of terms is best to be learned from those who in their writings and discourses appear to have had the clearest notions, and applied to them their terms with the exactest choice and fitness. This way of using a man's words, according to the propriety of the language, though it have not always the good fortune to be understood; yet most commonly leaves the blame of it on him who is so unskilful in the language he speaks, as not to understand it when made use of as it ought to be.
12. Fourth remedy: To declare the meaning in which we use them. Fourthly, But, because common use has not so visibly annexed any signification to words, as to make men know always certainly what they precisely stand for: and because men in the improvement of their knowledge, come to have ideas different from the vulgar and ordinary received ones, for which they must either make new words, (which men seldom venture to do, for fear of being though guilty of affectation or novelty), or else must use old ones in a new signification: therefore, after the observation of the foregoing rules, it is sometimes necessary, for the ascertaining the signification of words, to declare their meaning; where either common use has left it uncertain and loose, (as it has in most names of very complex ideas); or where the term, being very material in the discourse, and that upon which it chiefly turns, is liable to any doubtfulness or mistake.
13. And that in three ways. As the ideas men's words stand for are of different sorts, so the way of making known the ideas they stand for, when there is occasion, is also different. For though defining be thought the proper way to make known the proper signification of words; yet there are some words that will not be defined, as there are others whose precise meaning cannot be made known but by definition: and perhaps a third, which partake somewhat of both the other, as we shall see in the names of simple ideas, modes, and substances.
14. I. In simple ideas, either by synonymous terms, or by showing examples. First, when a man makes use of the name of any simple idea, which he perceives is not understood, or is in danger to be mistaken, he is obliged, by the laws of ingenuity and the end of speech, to declare his meaning, and make known what idea he makes it stand for. This, as has been shown, cannot be done by definition: and therefore, when a synonymous word fails to do it, there is but one of these ways left. First, Sometimes the naming the subject wherein that simple idea is to be found, will make its name to be understood by those who are acquainted with that subject, and know it by that name. So to make a countryman understand what feuillemorte colour signifies, it may suffice to tell him, it is the colour of withered leaves falling in autumn. Secondly, but the only sure way of making known the signification of the name of any simple idea, is by presenting to his senses that subject which may produce it in his mind, and make him actually have the idea that word stands for.
15. II. In mixed modes, by definition. Secondly, Mixed modes, especially those belonging to morality, being most of them such combinations of ideas as the mind puts together of its own choice, and whereof there are not always standing patterns to be found existing, the signification of their names cannot be made known, as those of simple ideas, by any showing: but, in recompense thereof, may be perfectly and exactly defined. For they being combinations of several ideas that the mind of man has arbitrarily put together, without reference to any archetypes, men may, if they please, exactly know the ideas that go to each composition, and so both use these words in a certain and undoubted signification, and perfectly declare, when there is occasion, what they stand for. This, if well considered, would lay great blame on those who make not their discourses about moral things very clear and distinct. For since the precise signification of the names of mixed modes, or, which is all one, the real essence of each species is to be known, they being not of nature's, but man's making, it is a great negligence and perverseness to discourse of moral things with uncertainty and obscurity; which is more pardonable in treating of natural substances, where doubtful terms are hardly to be avoided, for a quite contrary reason, as we shall see by and by.
16. Morality capable of demonstration. Upon this ground it is that I am bold to think that morality is capable of demonstration, as well as mathematics: since the precise real essence of the things moral words stand for may be perfectly known, and so the congruity and incongruity of the things themselves be certainly discovered; in which consists perfect knowledge. Nor let any one object, that the names of substances are often to be made use of in morality, as well as those of modes, from which will arise obscurity. For, as to substances, when concerned in moral discourses, their divers natures are not so much inquired into as supposed: v.g. when we say that man is subject to law, we mean nothing by man but a corporeal rational creature: what the real essence or other qualities of that creature are in this case is no way considered. And, therefore, whether a child or changeling be a man, in a physical sense, may amongst the naturalists be as disputable as it will, it concerns not at all the moral man, as I may call him, which is this immovable, unchangeable idea, a corporeal rational being. For, were there a monkey, or any other creature, to be found that had the use of reason to such a degree, as to be able to understand general signs, and to deduce consequences about general ideas, he would no doubt be subject to law, and in that sense be a man, how much soever he differed in shape from others of that name. The names of substances, if they be used in them as they should, can no more disturb moral than they do mathematical discourses; where, if the mathematician speaks of a cube or globe of gold, or of any other body, he has his clear, settled idea, which varies not, though it may by mistake be applied to a particular body to which it belongs not.
17. Definitions can make moral discourses clear. This I have here mentioned, by the by, to show of what consequence it is for men, in their names of mixed modes, and consequently in all their moral discourses, to define their words when there is occasion: since thereby moral knowledge may be brought to so great clearness and certainty. And it must be great want of ingenuousness (to say no worse of it) to refuse to do it: since a definition is the only way whereby the precise meaning of moral words can be known; and yet a way whereby their meaning may be known certainly, and without leaving any room for any contest about it. And therefore the negligence or perverseness of mankind cannot be excused, if their discourses in morality be not much more clear than those in natural philosophy: since they are about ideas in the mind, which are none of them false or disproportionate; they having no external beings for the archetypes which they are referred to and must correspond with. It is far easier for men to frame in their minds an idea, which shall be the standard to which they will give the name justice; with which pattern so made, all actions that agree shall pass under that denomination, than, having seen Aristides, to frame an idea that shall in all things be exactly like him; who is as he is, let men make what idea they please of him. For the one, they need but know the combination of ideas that are put together in their own minds; for the other, they must inquire into the whole nature, and abstruse hidden constitution, and various qualities of a thing existing without them.
18. And is the only way in which the meaning of mixed modes can be made known. Another reason that makes the defining of mixed modes so necessary, especially of moral words, is what I mentioned a little before, viz. that it is the only way whereby the signification of the most of them can be known with certainty. For the ideas they stand for, being for the most part such whose component parts nowhere exist together, but scattered and mingled with others, it is the mind alone that collects them, and gives them the union of one idea: and it is only by words enumerating the several simple ideas which the mind has united, that we can make known to others what their names stand for; the assistance of the senses in this case not helping us, by the proposal of sensible objects, to show the ideas which our names of this kind stand for, as it does often in the names of sensible simple ideas, and also to some degree in those of substances.
19. III. In substances, both by showing and by defining. Thirdly, for the explaining the signification of the names of substances, as they stand for the ideas we have of their distinct species, both the forementioned ways, viz. of showing and defining, are requisite, in many cases, to be made use of. For, there being ordinarily in each sort some leading qualities, to which we suppose the other ideas which make up our complex idea of that species annexed, we forwardly give the specific name to that thing wherein that characteristical mark is found, which we take to be the most distinguishing idea of that species. These leading or characteristical (as I may call them) ideas, in the sorts of animals and vegetables, are (as has been before remarked, ch. vi. SS 29, and ch. ix. SS 15) mostly figure; and in inanimate bodies, colour; and in some, both together. Now,
20. Ideas of the leading qualities of substances are best got by showing. These leading sensible qualities are those which make the chief ingredients of our specific ideas, and consequently the most observable and invariable part in the definitions of our specific names, as attributed to sorts of substances coming under our knowledge. For though the sound man, in its own nature, be as apt to signify a complex idea made up of animality and rationality, united in the same subject, as to signify any other combination; yet, used as a mark to stand for a sort of creatures we count of our own kind, perhaps the outward shape is as necessary to be taken into our complex idea, signified by the word man, as any other we find in it: and therefore, why Plato's animal implume bipes latis unguibus should not be a good definition of the name man, standing for that sort of creatures, will not be easy to show: for it is the shape, as the leading quality, that seems more to determine that species, than a faculty of reasoning, which appears not at first, and in some never. And if this be not allowed to be so, I do not know how they can be excused from murder who kill monstrous births, (as we call them), because of an unordinary shape, without knowing whether they have a rational soul or no; which can be no more discerned in a well-formed than ill-shaped infant, as soon as born. And who is it has informed us that a rational soul can inhabit no tenement, unless it has just such a sort of frontispiece; or can join itself to, and inform no sort of body, but one that is just of such an outward structure?
21. And can hardly be made known otherwise. Now these leading qualities are best made known by showing, and can hardly be made known otherwise. For the shape of a horse or cassowary will be but rudely and imperfectly imprinted on the mind by words; the sight of the animals doth it a thousand times better. And the idea of the particular colour of gold is not to be got by any description of it, but only by the frequent exercise of the eyes about it; as is evident in those who are used to this metal, who will frequently distinguish true from counterfeit, pure from adulterate, by the sight, where others (who have as good eyes, but yet by use have not got the precise nice idea of that peculiar yellow) shall not perceive any difference. The like may be said of those other simple ideas, peculiar in their kind to any substance; for which precise ideas there are no peculiar names. The particular ringing sound there is in gold, distinct from the sound of other bodies, has no particular name annexed to it, no more than the particular yellow that belongs to that metal.
22. The Ideas of the powers of substances are best known by definition. But because many of the simple ideas that make up our specific ideas of substances are powers which lie not obvious to our senses in the things as they ordinarily appear; therefore, in the signification of our names of substances, some part of the signification will be better made known by enumerating those simple ideas, than by showing the substance itself. For, he that to the yellow shining colour of gold, got by sight, shall, from my enumerating them, have the ideas of great ductility, fusibility, fixedness, and solubility in aqua regia, will have a perfecter idea of gold than he can have by seeing a piece of gold, and thereby imprinting in his mind only its obvious qualities. But if the formal constitution of this shining, heavy, ductile thing, (from whence all these its properties flow), lay open to our senses, as the formal constitution or essence of a triangle does, the signification of the word gold might as easily be ascertained as that of triangle.
23. A reflection on the knowledge of corporeal things possessed by spirits separate from bodies. Hence we may take notice, how much the foundation of all our knowledge of corporeal things lies in our senses. For how spirits, separate from bodies, (whose knowledge and ideas of these things are certainly much more perfect than ours), know them, we have no notion, no idea at all. The whole extent of our knowledge or imagination reaches not beyond our own ideas limited to our ways of perception. Though yet it be not to be doubted that spirits of a higher rank than those immersed in flesh may have as clear ideas of the radical constitution of substances as we have of a triangle, and so perceive how all their properties and operations flow from thence: but the manner how they come by that knowledge exceeds our conceptions.
24. IV Ideas of substances must be conformable to things. Fourthly, But, though definitions will serve to explain the names of substances as they stand for our ideas, yet they leave them not without great imperfection as they stand for things. For our names of substances being not put barely for our ideas, but being made use of ultimately to represent things, and so are put in their place, their signification must agree with the truth of things as well as with men's ideas. And therefore, in substances, we are not always to rest in the ordinary complex idea commonly received as the signification of that word, but must go a little further, and inquire into the nature and properties of the things themselves, and thereby perfect, as much as we can, our ideas of their distinct species; or else learn them from such as are used to that sort of things, and are experienced in them. For, since it is intended their names should stand for such collections of simple ideas as do really exist in things themselves, as well as for the complex idea in other men's minds, which in their ordinary acceptation they stand for, therefore, to define their names right, natural history is to be inquired into, and their properties are, with care and examination, to be found out. For it is not enough, for the avoiding inconveniences in discourse and arguings about natural bodies and substantial things, to have learned, from the propriety of the language, the common, but confused, or very imperfect, idea to which each word is applied, and to keep them to that idea in our use of them; but we must, by acquainting ourselves with the history of that sort of things, rectify and settle our complex idea belonging to each specific name; and in discourse with others, (if we find them mistake us), we ought to tell what the complex idea is that we make such a name stand for. This is the more necessary to be done by all those who search after knowledge and philosophical verity, in that children, being taught words, whilst they have but imperfect notions of things, apply them at random, and without much thinking, and seldom frame determined ideas to be signified by them. Which custom (it being easy, and serving well enough for the ordinary affairs of life and conversation) they are apt to continue when they are men: and so begin at the wrong end, learning words first and perfectly, but make the notions to which they apply those words afterwards very overtly. By this means it comes to pass, that men speaking the language of their country, i.e. according to grammar rules of that language, do yet speak very improperly of things themselves; and, by their arguing one with another, make but small progress in the discoveries of useful truths, and the knowledge of things, as they are to be found in themselves, and not in our imaginations; and it matters not much for the improvement of our knowledge how they are called.
25. Not easy to be made so. It were therefore to be wished, That men versed in physical inquiries, and acquainted with the several sorts of natural bodies, would set down those simple ideas wherein they observe the individuals of each sort constantly to agree. This would remedy a great deal of that confusion which comes from several persons applying the same name to a collection of a smaller or greater number of sensible qualities, proportionably as they have been more or less acquainted with, or accurate in examining, the qualities of any sort of things which come under one denomination. But a dictionary of this sort, containing, as it were, a natural history, requires too many hands as well as too much time, cost, pains, and sagacity ever to be hoped for; and till that be done, we must content ourselves with such definitions of the names of substances as explain the sense men use them in. And it would be well, where there is occasion, if they would afford us so much. This yet is not usually done; but men talk to one another, and dispute in words, whose meaning is not agreed between them, out of a mistake that the significations of common words are certainly established, and the precise ideas they stand for perfectly known; and that it is a shame to be ignorant of them. Both which suppositions are false; no names of complex ideas having so settled determined significations, that they are constantly used for the same precise ideas. Nor is it a shame for a man not to have a certain knowledge of anything, but by the necessary ways of attaining it; and so it is no discredit not to know what precise idea any sound stands for in another man's mind, without he declare it to me by some other way than barely using that sound, there being no other way, without such a declaration, certainly to know it. Indeed the necessity of communication by language brings men to an agreement in the signification of common words, within some tolerable latitude, that may serve for ordinary conversation: and so a man cannot be supposed wholly ignorant of the ideas which are annexed to words by common use, in a language familiar to him. But common use being but a very uncertain rule, which reduces itself at last to the ideas of particular men, proves often but a very variable standard. But though such a Dictionary as I have above mentioned will require too much time, cost, and pains to be hoped for in this age; yet methinks it is not unreasonable to propose, that words standing for things which are known and distinguished by their outward shapes should be expressed by little draughts and prints made of them. A vocabulary made after this fashion would perhaps with more ease, and in less time, teach the true signification of many terms, especially in languages of remote countries or ages, and settle truer ideas in men's minds of several things, whereof we read the names in ancient authors, than all the large and laborious comments of learned critics. Naturalists, that treat of plants and animals, have found the benefit of this way: and he that has had occasion to consult them will have reason to confess that he has a clearer idea of apium or ibex, from a little print of that herb or beast, than he could have from a long definition of the names of either of them. And so no doubt he would have of strigil and sistrum, if, instead of currycomb and cymbal, (which are the English names dictionaries render them by,) he could see stamped in the margin small pictures of these instruments, as they were in use amongst the ancients. Toga, tunica, pallium, are words easily translated by gown, coat, and cloak; but we have thereby no more true ideas of the fashion of those habits amongst the Romans, than we have of the faces of the tailors who made them. Such things as these, which the eye distinguishes by their shapes, would be best let into the mind by draughts made of them, and more determine the signification of such words, than any other words set for them, or made use of to define them. But this is only by the bye.
26. V. Fifth remedy: To use the same word constantly in the same sense. Fifthly, If men will not be at the pains to declare the meaning of their words, and definitions of their terms are not to be had, yet this is the least that can be expected, that, in all discourses wherein one man pretends to instruct or convince another, he should use the same word constantly in the same sense. If this were done, (which nobody can refuse without great disingenuity,) many of the books extant might be spared; many of the controversies in dispute would be at an end; several of those great volumes, swollen with ambiguous words, now used in one sense, and by and by in another, would shrink into a very narrow compass; and many of the philosophers, (to mention no other) as well as poets works, might be contained in a nutshell.
27. When not so used, the variation is to he explained. But after all, the provision of words is so scanty in respect to that infinite variety of thoughts, that men, wanting terms to suit their precise notions, will, notwithstanding their utmost caution, be forced often to use the same word in somewhat different senses. And though in the continuation of a discourse, or the pursuit of an argument, there can be hardly room to digress into a particular definition, as often as a man varies the signification of any term; yet the import of the discourse will, for the most part, if there be no designed fallacy, sufficiently lead candid and intelligent readers into the true meaning of it; but where there is not sufficient to guide the reader, there it concerns the writer to explain his meaning, and show in what sense he there uses that term.


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Acupuncture & Wellness Center of Rhode Island, 1681 Cranston Street Suite H, Cranston, RI, 02920-5000
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Acupuncture & Wellness Center of Rhode Island
Company Name: Acupuncture & Wellness Center of Rhode Island
County: Providence
City: Cranston
Address: 1681 Cranston Street Suite H
Contact Owner: Erin Balt
SIC code:	804999 Industry group: Health Services, Business category: Offices Of Health Practitioners Nec, Subcategory: Offices Of Health Practitioners Nec
Description: Acupuncture & Wellness Center of Rhode Island is a business categorized under offices of health practitioners nec, which is part of the larger category offices of health practitioners nec. Acupuncture & Wellness Center of Rhode Island is located at the address 1681 Cranston Street Suite H in Cranston, Rhode Island 02920-5000. The Owner is Erin Balt who can be contacted at (401)946-7734.
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