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This is likely to drive the perturbations of the above-mentioned biological pathways. Dissociation of native retinal tissue and 3D-culture retinal aggregates: the dissociation of mouse retinas and 3D retinal aggregates was inspired by the protocol of Macosko et al. Singlecell trajectory inference and pseudo-time analysis was conducted with Monocle2 cole-trapnell-lab. All corresponding scripts and datasets are freely available from bigcloud19. Page 18 of 46 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 libraries, respectively. Page 19 of 46 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 Downstream analyses. This was repeated 1,000 times yielding a measure of clique diversity akin to (1-entropy). Pathway analyses: Pathway enrichment analyses were conducted using the on-line Reactome analysis tools (Fabregat et al. A pathway is enriched in a list of genes if it contains more components of the pathway than expected by chance (given the number of genes in the list). The same pathway can be enriched in two gene lists due to the same, distinct or partially overlapping sets of "found entities". For each gene, the data were summarized as (i) the total number of occurrences, and (ii) the mean number of occurrences per peak (i. We then checked - for each of the 336 binding motifs separately - whether the number ("total" in Suppl. Table 2) of motifs differed significantly between genes that were upregulated versus downregulated in every one of the 13 cliques. Differential expression analyses to identify genes that are up- and downregulated in specific cliques were performed with the Findmarkers function in Seurat satijalab. The statistical significance of the difference in number and density of binding motifs between up- and downregulated genes was computed using Wilcoxon rank-based test implemented with the Georges et al. Page 21 of 46 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 wilcox. The results of these analyses are summarized in 2 x (total and mean) 336 graphs (similar to Fig. All corresponding scripts and datasets are freely available from big-cloud19. Page 23 of 46 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 Bassett et al. Belliveau & Cepko (1999) Extrinsic and intrinsic factors control the genesis of amacrine cells and cone cells in the rat retina. Page 24 of 46 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 Chow et al. Page 25 of 46 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 Fabregat et al. Page 26 of 46 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 Heine et al. Page 27 of 46 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 mouse induced pluripotent stem cells as a research tool. An intron control region differentially regulates expression of thyroid hormone receptor B2 in the cochlea, pituitary and cone photoreceptors. Page 28 of 46 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 Kuwahara et al. Molecular signatures of retinal ganglion cells revealed through single cell profiling. Page 29 of 46 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 Martersteck et al. The Spalt family transcription factor Sall3 regulates the development of cone photoreceptors and retinal horizontal interneurons. Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina. Page 30 of 46 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 Nelson et al. The Fox gene family in Xenopus laevis: FoxI2, FoxM1 and FoxP1 in early development. Page 31 of 46 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 Saelens et al. A B Photoreceptor Cells Bipolar Cells C Amacrine Cells D Ganglion Cells Page 33 of 46 Georges et al. Cells in undifferentiated state are circumferential, "domed shaped" and surrounded by a luminous halo (white arrow). Some unstable colonies tend to differentiate; they have a fibroblastic morphology instead of round shape (red arrow). After dissection, the retinal neuroepithelium/evaginating tissue is isolated from the dark/pigmented inner cell mass. Cells from retinal neuro-epithelium are dissociated into a homogenous solution of single cells (no doublets). Page 40 of 46 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 Figure 4: (A) Expression profiles in 12 cliques of 7,292 genes that are dynamically regulated during in vivo retinal development (i. Y-axis: Reactome pathways are colored by "top level" system (cell cycle, gene expression, signal transduction, metabolism, cell biology and development) and sub-level therein. Tiles mark the pathways that are significantly enriched in the corresponding contrast and cell type/clique. The colors of the tiles reflect similarity in gene content ("found entities") as described in (C). All overlaps are highly significant (p < 10-6) assuming random sampling from 2,365 reactome pathways. Shown are a hypothetical precursor (blue) and derived differentiated (orange) cell. The genes (horizontal rectangles) are subdivided in genes that define the precursor state (blue rectangles), genes that define the derived state (orange rectangles), and genes that do not participate in the differentiation (grey rectangles). Differential expression analysis between precursor cells and differentiated cells reveals (i) the genes that are upregulated in precursor cells (and consequently downregulated in differentiated cells)(large blue arrows), and (ii) the genes that are upregulated in differentiated cells (and consequently downregulated in precursor cells)(large orange arrows). One can predict that genes activated in the precursor cell state will be enriched in binding motifs for Ap (labelled as ap) and depleted in binding motifs for Ip (labelled as ip), but (given their expression pattern in differentiated cells) also enriched in binding motifs for Id (labelled as id) and depleted in binding motifs for Ad (labelled as ad) (and vice versa). The p-values of the corresponding enrichment (positive value) or depletion (negative value) are given when p < 0. Page 46 of 46 1131 1132 1133 1134 1135 1136 1137 1138 1139 Table 1: Candidate constituents of regulatory toggles operating in the mouse retina (NaR). Cancer is a group of more than 100 different diseases characterized by the uncontrolled, abnormal growth of cells. Because it takes years for mutations to accumulate, cancer is primarily a disease of aging. Benign Versus Malignant Tumors Major Classes of Cancer Carcinomas begin in the skin or in tissues covering glands or major organs (80-90% of all cancers; e. Lymphomas begin in the lymphatic system, a network of glands and vessels that carries lymph and white blood cells (e. Risk Factors for Cancer Certain environmental and lifestyle factors can cause genetic changes (mutations) that lead to growth of cancer.

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Cell 148: 873-885 this pilot study shows the initial characterization of the cancer genome at the single-cell, single-nucleotide level. Illumina Technology: HiSeq 2000 system with 100 bp paired-end reads and 1M genotyping arrays Falconer E. Genome Med 3: 31 48 Stem Cells and Cell Cultures Cultured cell lines are versatile tools to study biological processes. When cell lines are cultured over a long period of time, they can be expected to accumulate mutations. Also, the genetic bottlenecks that result from population reduction during the culturing process can significantly accelerate the accumulation of mutations. Recent studies used deep sequencing to show that as many as 50% of the genomic variants that are seen in cell lines derive from low-frequency somatic genomic variants that are present in the parental fibroblasts. They found differentially expressed genes encoding for proteins that are associated with a number of signaling pathways. Examinees should refer to the test specifications for each examination for more information about which parts of the outline will be emphasized in the examination for which they are preparing. What is the Difference Between Vision Screening with Eye Charts and Vision Screening Devices? Predictive value of photoscreening and traditional screening of preschool children. This document and its associated attachments are subject to United States Freedom of Information Act Exemption 4. The study will enroll approximately 150 patients in 2:1 randomization (100 patients in abemaciclib and 50 patients in docetaxel). Investigators will report resource utilization such as concomitant medications, transfusions, radiation therapy, surgery, and treatment-related hospitalization days. Biomarkers: Whole blood, plasma, and tissue samples will be tested for biomarkers relevant to the cell cycle pathway, abemaciclib, docetaxel, and/or the pathogenesis of lung cancer and to correlate these markers to clinical outcomes. Historical information will be incorporated into the control arm during the primary analysis by using a Bayesian approach. Under a frequentist design, this sample size yields roughly 75% power with 1-sided type I error of 0. Safety: All safety summaries and analyses will be based upon the Safety Population as defined as all enrolled patients receiving at least 1 dose of any study drug. Overall exposure to study drug, the numbers of patients completing each cycle, and the dose intensity will be summarized using descriptive statistics. Incidence rates of these events will be compared between treatment arms using Chi-square test. Biomarkers: Correlative analyses will be performed to investigate the associations between biomarkers and clinical outcomes. Other Study Conditions: Surgery (or Equally Considered Procedure) During Study Treatment Phase. Efficacy, Health Outcome/Quality of Life Measures, Safety Evaluations, Sample Collection and Testing, and Appropriateness of Measurements. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The period between study completion and end of trial during which patients on [investigational product[s] or study treatment] who continue to experience clinical benefit and no undue risks may continue to receive [investigational product[s] or study treatment] until one of the criteria for discontinuation is met. Patients who are enrolled in the trial are those who have been assigned to a treatment. Informed consent is documented by means of a written, signed, and dated informed consent form. An interim analysis is an analysis of clinical trial data, separated into treatment groups, that is conducted before the final reporting database is created/locked. A pharmaceutical form of an active ingredient substance or placebo being tested, or used as a reference, in a clinical trial A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. It has the consequence that patients allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance to the planned course of treatment. Global safety database that tracks and reports serious adverse and spontaneous events occurring while using a drug/drug delivery system. The final reporting database is used to produce the analyses and output reports for interim or final analyses of data. In this study, screening involves invasive or diagnostic procedures and/or tests (for example, diagnostic psychological tests, x-rays, blood draws). Introduction Lung cancer is the most common cancer worldwide, with an estimated 1. Clinical studies have demonstrated that patients with squamous histology have poorer outcomes, with a 1-year survival rate of approximately 14. However, even with treatment, the majority of patients relapse, with a median time to progression of 3 to 6 months after initiating chemotherapy (Schiller et al. Recent clinical trials suggest that approximately 40% to 50% of patients are eligible for second-line chemotherapy (Socinski et al. Those with squamous histology have challenges for treatment options because of the lack of driver mutations associated with response to approved agents (Garon et al. A total of 1253 patients were randomized, with 628 assigned to ramucirumab plus docetaxel and 625 patients assigned to placebo plus docetaxel, with the squamous population being 157 and 171, respectively. A subgroup analysis of patients with squamous histology showed a longer survival for those receiving ramucirumab compared to the control arm (9. In the CheckMate 017 study, 272 patients received either nivolumab (135 patients) or docetaxel (137 patients). Abemaciclib appears to have singleagent activity based upon preliminary efficacy data and a safety profile that is manageable and amenable to chronic administration. Study Population Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened. The following patients may be eligible for rescreening if any of the following circumstances: Patients who have become eligible to enroll in the study as the result of a protocol amendment. Patient status has changed such that the eligibility criterion that caused the patient to screen fail would no longer cause the patient to screen fail again. Patients who complete screening and meet all inclusion and exclusion requirements but are unable to be enrolled due to extenuating circumstances (such as severe weather, death in family, or child illness). Prospective approval of protocol deviations to recruitment and enrollment criteria (also known as protocol waivers or exemptions) is not permitted. This sample should be the most recent available sample containing adequate material. No other anticancer agents (for example, chemotherapy, radiotherapy) are permitted as prior therapy. The time from completion of the last cycle of adjuvant or neoadjuvant therapy to progression must be less than 6 months. For radiotherapy for locally advanced disease with curative intent with chemotherapy (platinum-based therapy), the time of completion of chemotherapy or radiotherapy, whichever finishes last, to progression must be less than 6 months to count as a line of therapy. May not have received docetaxel as monotherapy or in combination with platinum therapy in first-line setting, or in the neoadjuvant/adjuvant setting a. Prior paclitaxel therapy as monotherapy or in combination is permitted (for example, single-agent neoadjuvant/adjuvant setting or combination in first line). Patients must have recovered from the acute toxic effects of the radiotherapy treatment prior to the first dose of study treatment.

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However, the approach to planning for energy differs substantially from planning for other nutrients. The situation for energy is quite different because for individuals who consume energy above their requirements and needs over long periods of time, weight gain will occur. They are only a starting point because energy expenditures vary from one individual to another even though their characteristics may be similar. These errors in estimation would eventually lead to a gain or loss in body weight, which would be undesirable when the goal is to maintain a healthy weight. Developing Dietary Plans for an Individual Once appropriate nutrient intake goals have been identified for the individual, these must be translated into a dietary plan that is acceptable to the individual. This is most frequently accomplished using nutrient-based food guidance systems such as national food guides. The requirement for zinc may be as much as 50 percent greater for vegetarians, particularly for strict vegetarians whose major food staples are grains and legumes. Average requirements for iron may range from 30 to 70 percent above those for normally active individuals. Vitamin B12 for those older than 50 years of age Smoking Vitamin C Bioavailability in vegetarian diets Iron Zinc Age of menstruation Iron (it is assumed that girls younger than 14 years do not menstruate and that girls 14 years and older do menstruate) Athletes engaged in regular intense exercise Iron Recommendation set according to reference weight Recommendation set per 1,000 kcal Protein Fiber Recommendation is 14 g/1,000 kcal. In all cases, individual assessments should be cautiously interpreted, preferably in combination with other information on factors that can affect nutritional status, such as anthropometric data, biochemical measurements, dietary patterns, lifestyle habits, and the presence of disease. Examples of such groups include nursing home residents, research study participants, and children attending residential schools. How to Assess the Nutrient Intakes of a Group the goal of assessing the nutrient intakes of groups is to determine the prevalence of inadequate (or excessive) nutrient intakes within a particular group of individuals (see Box 1 for definitions). To accurately determine the proportion of a group that has a usual intake of a nutrient that is less than their requirement, information on both the distribution of usual intakes and the distribution of requirements in the group is needed. Several characteristics of dietary intake data make estimating the distribution of usual intakes for a group challenging. When single 24-hour recalls or diet records are obtained from members of a group, the variability of the nutrient intakes will reflect both differences between individuals as well as differences within individuals (i. To obtain a distribution of usual intakes for a group, the distribution of observed intakes (i. To do this, at least two 24-hour recalls or diet records obtained on nonconsecutive days (or at least three days of data from consecutive days) are needed from a representative subsample of the group. If intake distributions are not properly adjusted, the prevalence of nutrient inadequacy will be incorrectly estimated and is usually overestimated (see Figure 5). Although these methods will adjust for variability in day-to-day intakes, they do not make up for inaccuracies in reported or observed intakes. This method depends on two key assumptions: that intakes and requirements are independent and thus no correlation exists between usual intakes and requirements (this is thought to be true for most nutrients, although it is not known to be true for energy) and that the distribution of requirements for the nutrient in question is known. This method then uses statistical equations to estimate the prevalence of inadequacy. Case studies one and two at the end of the chapter illustrate the use of the probability approach. Blood (and therefore iron) losses during menstrual flow greatly vary among women, and some women have unusually high losses. Note, however, that the assumption that intakes are more variable than requirements might not hold for groups of similar individuals who were fed similar diets (e. When the requirement distribution is symmetrical, when intakes are more variable than requirements, and when intakes and requirements are independent, the proportion of the group described in item 1 cancels out the proportion described in item 2. For example, as shown in Box 3, women 51 to 70 years of age had a median dietary vitamin B6 intake of 1. For this reason, it is simply not possible to determine the proportion of a group with intakes below requirements. Accordingly, only limited inferences can be made about the adequacy of group intakes. The distribution has been adjusted for individual variability using the method developed by the National Research Council. For some nutrients, such as fluoride, phosphorus, and vitamin C, the distribution of usual intakes would need to include intake from all sources. For others, such as magnesium, folate, niacin, and vitamin E, only the distribution of usual intakes from synthetic sources added to foods and from supplements (and in the case of magnesium, medications) would be needed. If significant proportions of the population fall outside the range, concern could be heightened for possible adverse consequences. This is because empirical evidence indicates a strong correlation between energy intake and energy requirement. This correlation most likely reflects either the regulation of energy intake to meet needs or the adjustment of energy expenditure to be consistent with intakes. This can be challenging because the amount and selection of foods that group individuals eat will vary, even if the same meal is offered. Situations where group planning occurs include residential schools, prisons, military garrisons, hospitals, nursing homes, child nutrition programs, and food assistance programs. When planning for groups, a practitioner should aim for a low prevalence of inadequate intakes. An important caveat: By focusing explicitly on the distribution of nutrient intakes of a group as the goal of group planning, the framework presented here is, in many respects, a new paradigm, and it should be tested before being implemented in large-scale group-feeding situations. To apply the framework presented here, an acceptable prevalence of inadequacy must be defined (a critical step on the part of the planner) and the distribution of usual intakes in the group must be estimated. As previously stated, this is accomplished by determining the distribution of reported or observed intakes, and performing a statistical adjustment to estimate the distribution of usual intakes. In most cases, planning group intakes is an ongoing process, in which planners set goals for usual intake, implement the plan, assess whether the goals have been achieved, and then accordingly modify their planning procedures. Suppose a practitioner is interested in planning a group diet with a high probability of nutrient adequacy (e. To achieve this goal of a low prevalence of nutrient inadequacy, it may be necessary to modify the baseline usual nutrient intake distribution. The change may be as simple as a shift (up or down) of the entire baseline distribution or it may include changes in both the location and the shape of the distribution. In either case, the appropriate changes to the baseline usual nutrient intake distribution are intended to result in the desired distribution of usual intakes. This desired distribution is referred to as the target usual nutrient intake distribution. The simplest approach to determining the target usual nutrient intake distribution is to shift the baseline distribution, with the assumption that there will be no change in its shape. Panel A shows the baseline usual nutrient intake distribution with 30 percent prevalence of inadequate intakes. When it is known that the usual intake distribution of the group being assessed approximates normality, as depicted in all panels of Figure 7, the position of the target usual nutrient intake distribution can be estimated very simply with a table of selected areas under the normal distribution. On the other hand, if a 5 percent prevalence of inadequacy were chosen, the calculated median intake would be 80 (80 = 50 + [1. However, in most cases, the usual intakes within a group are not normally distributed. Further details are provided in the sections that follow and in the case studies at the end of the chapter. For energy, the estimated energy requirement of a reference individual or an average of estimated maintenance energy needs for the group members can be used in planning energy intake of groups. One can estimate energy requirements for the reference person or obtain an average of estimated maintenance energy needs for the group members.

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Usually, immunotherapies using single-agent have been not successful in metastatic prostate cancer, as well as in other genitourinary neoplasia, such as bladder cancer and renal cancer. Thus, although some cancer patients respond to therapy with Pembrolizumab monotehrapy, the response rate is significantly lower than that observed in other genitourinary tumors, such as kidney (~40% of responding patients) or bladder cancer (~ 25% of responding patients). In fact, studies of manipulation of androgen activity either with androgen inhibitors or by castration, striongly support the view that androgens have an immunosuppressive effect [378]. The results of this study support to further explore the therapeutic potential of immunocheck inhibitors in combination with androgen deprivation. A recent study explored the mechanisms responsible for resistance of prostate cancer to Ipilimumab. Immune responses generated in the tumor microenvironment influence the response of prostate cancer to androgen deprivation therapy. Thus, various studies have shown that the immunosuppressive microenvironment of prostate tumors decreases the response to androgen deprivation therapy. These findings imply the existence of a multitude of immune suppressor mechanisms present in prostate cancers that need to be countered via appropriate combination therapies. Immunotherapy is a promising area for a subset of prostate cancers, but many challenges seem to limit its development [413]. Hormonal Regulation of Prostate Cancer the prostate is a hormonally regulated gland. There is some evidence to suggest that in prostate cancer development an important pathogenetic event could be related to abnormal steroid receptor signaling at the level of the stem cell compartment. Prostate hormonal carcinogenesis triggered by combined testosterone and estradiol treatment for several months has been established in murine models. Recent studies have shown a carcinogenic effect of steroids using human prostate regeneration models. In addition to androgen and estrogen, prolactin also through activation of Stat5 signaling may affect prostate cancer development though a direct effect on the basal stem-like compartment of prostate cells [436]. Sustained Stat5 activation was associated with the development of abnormal clusters of basal/stem cells in prostate epithelium of transgenic mice overexpressing prolactin at the level of the prostatic tissue and with the amplification of a luminal progenitor cell population, seemingly originated from amplified basal/stem cells [437]. Stat5 plays an important role in the transition of prostate cancer to its castrate-resistant state. Pharmacologic treatment of Stat5 is an efficient approach to delay castrate-resistant progression, due to the cooperation between Stat5 and Androgen Receptor to promote prostate cancer progression [438]. Jak2-Stat5 signaling inhibitors potently suppress the growth and induce apoptosis of primary prostate cancer cells and castrate-resistant prostate cancer cells, this inhibitory effect was observed in 75% of primary tumors grown ex vivo in organ explant cultures [439]. Studies in experimental models support the concept that Stat5 signaling promotes metastatic progression of prostate cancer by inducing epithelial to mesenchymal transition and stem cell properties in prostate cancer cells [441]. The role of Stat5 in prostate cancer progression is supported by two clinical observations: (i) active nuclear Stat5 had a predictive value for early disease recurrence of localized prostate cancer treated with radical prostatectomy [442]; (ii) the Stat5 gene locus undergoes amplification during prostate cancer progression, conferring a growth advantage in prostate cancer cells [443]. A key event in prostate cancer progression is represented by the development of castration resistance and the mechanisms responsible for this phenomenon are not completely understood. However, in spite these limitations studies carried out during these last years have shown that a high proportion of prostate cancers progress to androgen resistance through mechanisms involving the maintenance of androgen receptor-dependent signaling, such as (i) androgen receptor overexpression (amplification of androgen receptor gene copy number) and (ii) growth factor-regulated androgen Medicines 2019, 6, 82 61 of 136 receptor activation (usually due to gain of function mutations of the androgen receptor that confer greater sensitivity to androgens or ligand-independent activation); de novo autocrine/intracrine androgen production [162,445,446]. Androgen resistance is not related only to androgen receptor reactivation, but also to mechanisms related to tumor heterogeneity. Studies on advanced prostate cancers indicate that these tumors are heterogeneous, being composed by islets of cells that overexpress androgen receptors and other islets of cells that do not express androgen receptors [447,448]. The cellular mechanisms underlying the emergence of castration resistance in prostate cancer are not clearly defined. In this context, two hypotheses have been proposed: the first, based on an adaptative mechanism, implies genetic/epigenetic changes at the level of tumor cells previously androgen-dependent, and the second, based on clonal selection model, argues the emergence of castration resistance in consequence of the proliferation of a previously quiescent rare population of castration-resistant cells within an otherwise androgen-dependent tumor. In line with this last hypothesis, it was shown that early (stage I) human prostate adenocarcinomas harbor androgen-independent cancer cells with stem/progenitor-like properties [451]. Abnormalities of Metabolism in Prostate Cancer Prostate cancer, as well as other tumors, display metabolic alterations essential for tumor development, survival of tumor cells in various environmental conditions, tumor progression, and resistance to therapy [452]. This topic was reviewed [452,454] and here are just outlined the most relevant studies, providing findings leading to the identification of metabolic vulnerabilities and of potential therapeutic targets. Several other recent studies have shown that a dysregulated lipid metabolism plays an oncogenetic role in prostate cancer. The dysregulation of lipid metabolism observed in prostate cancer is complex and involves elevated de novo lipogenesis, including steroid hormone biosynthesis and beta oxidation of fatty acids [455]. This property distinguishes prostate cancer cells from normal prostate cells that rely mostly on diet-derived lipids [242]. Another recent study defined a peculiar metabolic abnormality sustaining lipogenesis in prostate cancer cells. Prostate cancer cells exhibit increased de novo synthesis of fatty acids and use fatty acids as the major source of carbons for lipid synthesis, while the contribution of glucose and glutamine is only minoritary [457]. This study showed also the heterogeneity of prostate cancer cells in their utilization of fatty acids [457]. Prostate cancer progression is characterized by increased rates of de novo fatty acid synthesis, independent of circulatory lipid levels [458]. A recent study addressed another abnormality involving pyruvate mitochondrial metabolism in pyruvate cancer cells. The findings of this study again support the concept of the possible links between alterations in cellular metabolism with prostate cancer cell biology. Prostate cancer hypoxia contributes to the development of tehrapy resistance mechanisms. Interestingly, targeting hypoxia reduction may represent a strategy to restore T cell infiltration and to sensitize prostate cancer cell to immunotherapy with immune check inhibitors [471]. Thus, reprogramming of cell metabolism is a hallmark of prostate cancer, as well as of other malignancies. These recent observations support the importance of metabolic studies because the identification of metabolic vulnerabilities of prostate cancer cells may open new avenues for novel personalized diagnostic and therapeutic approaches [452]. Each glandular subunit is composed by a complex branching of stratified epithelia, composed by three cell types: basal, luminal, and neuroendocrine cells. The putative prostate stem cells are localized at the level of the basal compartment, in strict contact with the basal lamina on one side and with the stromal cells on the other side. The intermediate cells located at the Medicines 2019, 6, 82 65 of 136 level of the basal compartment have been termed transit-amplifying cells. Neuroendocrine epithelial cells express markers, such as chromogenin A and synaptolysin. The existence of prostate stem cells was proposed when Isaacs and colleagues found that a fraction of prostate cells remain after castration-induced involution and were capable of regenerating the full gland with all different cell types [473]. In the normal prostate, luminal cells are androgen-dependent and undergo apoptosis following androgen deprivation, while basal and neuroendocrine cells are castration-resistant. On the other hand, the observations made on prostate cancer patients undergoing androgen ablation therapy allowed to postulate that certain prostate cancer cells share properties with normal adult prostate stem cells and have the capacity to survive androgen therapy and subsequently to regenerate the tumor with a more aggressive phenotype [474]. In adults, prostate epithelium is quiescent and, therefore, there is no apparent need for the activity of stem cell to maintain the normal hemostasis of this tissue. However, prostate stem cells play a key role in the context of androgen-mediated prostate regeneration. In fact, following androgen deprivation the prostate tissue regresses; however, when physiologically normal androgen levels are restored, the prostate gland regenerates back to its original size [475]. This observation is compatible with the idea that normal adult prostate stem cells exist under steady-state conditions in a completely quiescent state but are triggered to cycle and to repair when prostate tissue is damaged. Various methods have been developed for the identification and propagation of prostate stem cells and to determine their location within the normal prostate. These methods involve the study of the expression of various luminal and basal-specific cell markers, cell lineage tracing experiments, prostate sphere (protaspheres) cultures, and organoid cultures. To try to identify normal prostate stem cells various approaches have been attempted, providing different types of evidences. Basically, flow cytometry and tissue reconstitution studies have led to the identification of basal stem cells, while a genetic lineage-marking approach has identified luminal stem cells [476]. The characterization of prostate stem/progenitor cells was based on in vitro and ex vivo functional assays. A first approach is based on cell culture, involving prostasphere formation in suspension culture, to evaluate the self-renewal and differentiation potential of cell populations isolated by flow cytometry. A limitation of the prostasphere assay is that it allows the growth of only basal cells and not of luminal cells [432].

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At the beginning of the 20th century, 38% of the labor force was needed for farm work, which was hard and often dangerous. By 2000, research in plant and animal genetics, nutrition, and husbandry together with innovation in machinery had transformed farm life. Those advances have reduced the farm labor force to less than 3% of the population. The visible products of research, however, are made possible by a large 4National Research Council. The 20th century saw dramatic reductions in disease incidence in the United States. All that activity, and its sustaining public support, fuels the steady flow of knowledge and provides the mechanism for converting information into the products and services that create jobs and improve the quality of modern life. Maintaining that vast and complex enterprise during an age of competition and globalization is challenging, but it is essential to the future of the United States. The knowledge density of modern economies has steadily increased, and the ability of a society to produce, select, adapt, and commercialize knowledge is critical for sustained economic growth and improved quality of life. Although most early studies focused on agriculture, recent work shows high rates of return for academic science research in the 7R. The economy grew faster and employment rose more than had seemed possible without 9E. Policy-makers previously focused almost entirely on changes in demand as the determinant of inflation, but the surge in productivity showed that changes on the supply side of the economy could be just as important and in some cases even more important. The Doctrine Was Not to Have One; Greenspan Will Leave No Road Map to His Successor. The report notes that "the growth of economies throughout the world since the industrial revolution began has been driven by continual technological innovation through the pursuit of scientific understanding and application of engineering solutions. Those "social rates of return"16 on investments in R&D are reported to range from 20 to 100%, with an average of nearly 50%. For example, Table 2-3 shows the large number of jobs and revenues created by information-technology manufacturing and services-an industry that did not exist until the recent past. The value of public and private investment in research is so important that it has been 16"Social rate of return" is defined in C. The return can then be thought of as a sum of a dividend and a capital gain (or loss). First, the additional knowledge directly raises the productivity of capital and labor in the economy. Second, the additional knowledge changes the productivity of future R&D investment because of either knowledge spillovers or because subsequent ideas are more difficult to discover. Starr Center for Applied Economics, New York University Department of Economics, August 1993. Nadiri adds, "The channels of diffusion of the spillovers vary considerably and their effects on productivity growth are sizeable. The potential of those developments for health and healthcare is only beginning to be realized. Studies of the interaction of light with atoms led to the prediction of stimulated emission of coherent radiation. That, together with the quest for a device to produce high-frequency microwaves, led to the development of 19Council of Economic Advisers. Enormous economic gains can be traced to research in harnessing electricity, which grew out of basic research (such as that conducted by Michael Faraday and James Maxwell) and applied research (such as that by Thomas Edison and George Westinghouse). In virtually all those examples, the original researchers did not-or could not-foresee the consequences of the work they were performing, let alone its economic implications. The fundamental research typically was driven by the desire to answer a specific question about nature or about an application of technology. Life expectancy has increased in the United States, particularly in the last century. The development of lithium as a mental-health treatment, for example, saves $9 billion in health costs each year. Hip-fracture prevention in postmenopausal women at risk for osteoporosis saves $333 million annually. Weather satellites, global positioning systems, and airborne-particle measurement technologies also have helped us to monitor and mitigate unexpected environmental problems. Unfortunately, some of these problems have been the consequence of unexpected side-effects of technological advances. Fortunately, in many cases additional technological understanding was able to overcome unintended consequences without forfeiting the underlying benefits. Water Quality Early in the 20th century, when indoor plumbing was rare, wastewater often was dumped directly into streets and rivers. Waterborne diseases- cholera, typhoid fever, dysentery, and diarrhea-were rampant and among the leading causes of death in the United States. Research and engineering for modern sewage treatment and consequent improvements in water quality have dramatically affected public and environmental health. Waterpollution controls have mitigated declines in wildlife populations, and research into wetlands and riparian habitats has informed the process of engineering water supplies for our population. Automobiles and Gasoline In the 1920s, engineers discovered that adding lead to gasoline caused it to burn more smoothly and improved the efficiency of engines. The widespread use of leaded gasoline resulted in harmful concentrations of lead in the air,28 and by the 1970s the danger was apparent. New formulations developed by petrochemical researchers not requiring the use of lead 27W. Parallel advances in petroleum refining and the adoption and improvement of catalytic converters increased engine efficiency and removed harmful byproducts from the combustion process. Those achievements have reduced overall automobile emissions by 31%, and carbon monoxide emissions per automobile are 85% lower than in the 1970s. The consequences could be long-lasting and severe, including increased cancer rates and global warming. Agricultural Mechanization Advances in agriculture have vastly increased farm productivity and food production. However, injudicious application of mechanization also led to increased soil erosion. Urban sprawl, desertification, and over-fertilization have reduced the amount of arable land by 20%. Advances in agricultural biotechnology have further reduced soil erosion and water contamination because they have reduced the need for tilling and for use of pesticides. The result has been a general enhancement in the quality of life in the United States as viewed by most observers. In 1900, less than 10% of the nation was electrified; now virtually every home in the United States is wired (Figure 2-11). Transportation As workers left farms to move to cities, transportation systems developed to get them to work and home again. Improvements in refrigeration put a refrigerator in virtually every home, and the ability to ship food across the country made it possible to keep those refrigerators stocked. The increasing speed, safety, and reliability of aircraft spawned yet another global industry that spans commercial airline service and overnight package delivery. Communication At the beginning of the 20th century slightly more than 1 million telephones were in use in the United States. The dramatic increase in telephone calls per capita over the following decades was made possible by advances in cable bundling, fiber optics, touch-tone dialing, and cordless communication (Figure 2-13). Cellular-telephone technology and voice-over-Internet protocols have added even more communication options. At the beginning of the 21st century, there were more than 300 million telephone communication devices and cellular telephone lines in the United States. Radio and television revolutionized the mass media, but the Internet has provided altogether new ways of communicating. Interoperability between systems makes it possible to use one device to communicate by telephone, over the Internet, in pictures, in voice, and in text.

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The two eyelids are separated medially by a triangular space, the lacrimal lake or lacus lacrimalis. A fleshy raised body, the lacrimal caruncle, is located in the lacus lacrimalis on the medial side of the plica. On the top of the papilla is the lacrimal punctum which leads the tears to the lacrimal canaliculus. Layers of the Eyelid Each eyelid from outer to inner aspect has following layers (Fig. A horizontal fold is present in the skin of the upper lid which becomes prominent on the upward gaze, the superior palpebral sulcus or lid crease. The anterior border of the lid margin is round, while the posterior is sharp and lies closely in contact with the eyeball. The skin is loosely attached to the underlying structures; this loose attachment permits easy accumulation of edematous fluid or blood. Layer of striated muscle is composed of fibers of palpebral part of the orbicularis oculi. The orbital part is arranged in a concentric manner around the orbital margin covering the tarsus. The preseptal portion overlies the orbital septum and the pretarsal portion of orbital part of orbicularis oculi muscle lies anterior to the tarsus. An incision at the gray line (a line between the anterior and posterior margins of the lid) splits the lid through the plane into an anterior and a posterior portion. It has two parts, a thick central part, the tarsal plate and a thin peripheral part, the orbital septum or septum orbitale. The lateral palpebral ligament attaches the lateral ends of the tarsi to the Whitnall tubercle, while the medial ends of the tarsi are attached by the medial palpebral ligament to the lacrimal crest. It is thicker on the lateral side than on the medial and in the upper lid than in the Diseases of the Lids 387 Fig. In the upper lid the septum is in contact with the orbital fat which separates it from the levator palpebrae superioris. They are believed to help in the retraction of eyeball and elevation of the upper lid. Glands of the Eyelid the glands of Zeis are situated at the lid margin in close association with the cilia. The glands secrete oily secretion which lubricates the eye and prevents evaporation of tears from the cornea. They form two main arcades: the superior peripheral arcade lying between the upper part of the tarsus and the orbicularis, and the inferior peripheral arcade, nearly 3 mm above the lid margin (Fig. The superior arcade is reinforced by the branches from the superficial temporal, lacrimal and supraorbital arteries, while the inferior by the transverse facial and facial arteries. Each lid is drained by the pretarsal and the posttarsal plexus into the subcutaneous and ophthalmic veins, respectively. Lymphatics from most of the upper lid and lateral half of the lower lid drain into the preauricular lymph nodes and the medial portions of both the lids drain into the submandibular lymph nodes. The sensory supply to the upper lid comes from the ophthalmic division of the trigeminal nerve. The lower lid is supplied through the infraorbital nerve, a branch of the maxillary division of the trigeminal nerve. Cryptophthalmos is a rare anomaly in which a fold of skin passes from the eyebrow over the malformedeye to the cheek. It gives an appearance of pseudoconvergent strabismus and disappears as the nose develops. Distichiasis is a congenital anomaly of eyelashes wherein an extra posterior row of cilia is present. This additional row of the lashes occupies the position of meibomian glands which are reduced to ordinary sebaceous glands. It can be managed by cryo application to the posterior lid margin after splitting the eyelid along the gray line. Incomplete closure of the embryonic facial cleft and pressure of the amniotic bands are implicated in the etiology of the coloboma. Inflammatory edema is often found in acute conjunctivitis, tarsitis, dacryocystitis and orbital cellulitis. Passive edema of the eyelid is a common feature of cavernous sinus thrombosis, congestive heart failure, nephrotic syndrome, hypoproteinemia and anemia. Clinically, it occurs in two forms, squamous blepharitis and ulcerative blepharitis. Squamous Blepharitis Squamous blepharitis is characterized by the presence of small white scales at the root of the lashes (Fig. Etiology the blepharitis is common in children who suffer from dandruff of the scalp. The squamous blepharitis is essentially a metabolic disorder and often associated with seborrhea. Perhaps, certain organisms produce lipolytic co-enzymes that split the neutral lipids into free fatty acids which irritate the lid margins and the conjunctiva. A pustule on the lid may develop as a result of inoculation from the recently vaccinated arm of a baby. If the scales are removed the underlying area is found to be hyperemic but not ulcerated. Certain parasites such as crab louse and Demodex folliculorum can cause the disease. Clinical Features Intense itching, swelling and redness of lid margins, falling of lashes, watering and photophobia are common symptoms of ulcerative blepharitis. The ulcerative blepharitis has a chronic course and is often accompanied with chronic conjunctivitis, the two together are known as blepharoconjunctivitis. The presence of nits at the roots of eyelashes is diagnostic of parasitic blepharitis. Complications Squamous blepharitis rarely causes complications, but constant irritation due to free fatty acids may lead to chronic papillary conjunctivitis and punctate epithelial erosions of the cornea. Ulcerative Blepharitis Ulcerative blepharitis is an infective condition of the lid margin characterized by the deposition of yellow crusts at the roots of eyelashes, swelling of the lid margins and falling of the eyelashes (Fig. Complications When blepharitis persists for a long time, the ulcerative process extends deeply and destroys the hair follicles resulting in falling of cilia. The cilia are often not replaced, and if they regrow only a few distorted ones come. The shallow ulcers of blepharitis heal by fibrosis, the contraction of fibrous tissue may cause misdirection of a few eyelashes which rub against the cornea, the Etiology Ulcerative blepharitis is common in debilitated children with poor personal hygiene. Staphylococcus aureus (coagulase positive) is the most Diseases of the Lids 391 cornea, catarrhal marginal corneal ulcers and, rarely, phlyctenulosis. Basic differences in the clinical features of squamous and ulcerative blepharitis are listed in Table 24. Treatment Treatment of blepharitis consists of proper removal of the crust, application of specific antibiotic ointment depending on the sensitivity of the organism and massage of the lid margin so that the drug may reach the follicles of eyelashes where organisms lie hidden. The crust can be softened and removed through bathing with warm 3% sodium bicarbonate lotion or hydrogen peroxide. Mechanical expression of the meibomian glands is particularly helpful in controlling squamous blepharitis because the procedure reduces the vicarious secretion from the glands. Associated seborrheic dermatitis and dandruff need special care and should be managed by medicated shampoo. The excessive fibrosis of the lid margin leads to its thickening known as tylosis. Occasionally the contraction of the scar tissue pulls the conjunctiva of the lower lid making the acute posterior border more or less rounded so that its capillary action is disturbed resulting in epiphora. The constant moistening of the skin leads to eczema of the lower eyelid which eventually causes ectropion. The ulcerative blepharitis may also be associated with recurrent styes and angular conjunctivitis.


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In the same way, public-policy decisions about the supply of scientists and engineers should not be guided by an attempt to provide a guaranteed high level of income for every recipient of an advanced degree. It is also important that scientists and engineers tend, through innovation, to create new jobs not only for themselves but also for workers throughout the economy. Some economists believe that there might be a transition phase in some fields during which wages fall, but they assert that there is no reason to believe that such a dip would be permanent, because the global economic pie keeps growing. We need people who have been prepared for the kinds of knowledge-intensive occupations in which the nation must excel. Yet the United States has for a number of decades fallen short in making the kinds of investments that will be essential in a global economy. Loss of Human Capital An educated, innovative, motivated workforce-human capital-is the most precious resource of any country in this new, flat world. A recent Gallup poll30 asked respondents, "Overall, how satisfied are you with the quality of education students receive in kindergarten through grade twelve in the United States today-would you say you are completely satisfied, somewhat satisfied, somewhat dissatisfied or completely dissatisfied? According to the poll results, the critical required change would be to produce better educated, higher-quality teachers. By far the highest leverage to be found in our education system resides with teachers, if for no other reason than that they influence such a large number of future workers. Students in the United States are not keeping up with their counterparts in other countries. About 6% of our undergraduates major in engineering; that percentage is the second lowest among developed countries. Engineering students make up about 12% of undergraduates in most of Europe, 20% in Singapore, and more than 40% in China. Students throughout much of the world see careers in science and engineering as the path to a better future. Higher Education as a Private Good Our culture has always considered higher education a public good-or at least we have seemed to do so. We have agreed as a society that educated citizens benefit the whole society; that the benefit accrues to us all and not just to those who receive the education. Now, however, funding for state universities is dwindling, tuition is rising, and students are borrowing more than they receive in grants. These seem to be indications that our society increasingly sees higher education as a private good, of value only to the individual receiving it. College has been a traditional path for upward mobility-and this has been particularly true in the field of engineering for students who were first in their family to attend college. One reason might be the challenge of capturing the results of research investments within one company or even a single nation on a long-term basis. The companies and nation can, however, capture high-technology discoveries at least for the near term (510 years) and enhance the importance of innovation in jobs. As a result, corporate funding of certain applied research has been enhanced at such companies as Google and Intel and at many biotechnology companies. Nonetheless, the increasing pressure on corporations for short-term results has made investments in research highly problematic. Funding for Research in the Physical Sciences and Engineering Although support for research in the life sciences increased sharply in the 1990s and produced remarkable results, funding for research in most physical sciences, mathematics, and engineering has declined or remained relatively flat-in real purchasing power-for several decades. Even to those whose principal interest is in health or healthcare, that seems short-sighted: Many medical devices and procedures-such as endoscopic surgery, "smart" pacemakers, kidney dialysis, and magnetic resonance imaging- are the result of R&D in the physical sciences, engineering, and mathematics. The need is to strengthen investment in the latter areas while not disinvesting in those areas of the health sciences that are producing promising results. A recent National Academies study37 revealed that the average age at which a principal investigator receives his or her first grant is 42 years-partly because of requirements for evidence of an extensive "track record" to reduce risk to the grant-makers. History also suggests that young researchers make disproportionately important discoveries. These relate to the events of 9/11, which profoundly changed our world and made it necessary to re-examine national security issues in an entirely new context. This re-examination led to changes in visa policies, export controls, and the treatment of "sensitive but unclassified" information. There appears today to be a need to better balance security concerns with the benefits of an open, creative society. New Visa Policies Much has been written about new immigration and visa policies for students and researchers. Some promising students wait a year or more for visas; some senior scholars are subjected to long and sometimes demeaning review processes. Those cases, not the shorter average processing time, are emphasized in the international press. The United States is portrayed less as a welcoming land of opportunity than as a place that is hostile to foreigners. As a result, we are damaging the image of our country in the eyes of much of the world. Some observers are also concerned that encouraging international students to come to the United States will ultimately fill jobs that could be occupied by American citizens. Others worry that such visitors will reduce the compensation that scientists and engineers receive-diminishing the desire of Americans to enter those professions. Studies show, however, that the financial impact is minimal, especially at the PhD level. Furthermore, scientists and engineers tend to be creators of new jobs and not simply consumers of a fixed set of existing jobs. If Americans make up a larger percentage of a graduating class, a larger percentage of Americans will be hired by corporations. In the end, the United States needs the smartest people, wherever they come from throughout the world. The United States will be more prosperous if those people live and work in the United States rather than elsewhere. The Use of Export Controls Export controls were first instituted in the United States in 1949 to keep weapons technology out of the hands of potential adversaries. The export of controlled technology requires a license from the Department of Commerce or from the Department of State. Since 1994, the disclosure of information regarding a controlled technology to some foreign na- Copyright National Academy of Sciences. Some recent reports40 suggest that implementation of the rules that govern deemed exports should be tightened even further-for example, by altering or eliminating the exemption for basic research and by broadening the definition of "access" to controlled technology. Given that 55% of the doctoral students in engineering in the United States are foreign-born and that many of these students currently remain in the United States after receiving their degrees, the effect could be to drastically reduce our talent pool. By putting up overly stringent barriers to the exchange of information about basic research, we isolate ourselves and impede our own progress. The current fear that foreign students in our universities pose a security risk must be balanced against the great advantages of having them here. It is, of course, prudent to control entry to our nation, but as those controls become excessively burdensome they can unintentionally harm us. As an example, see Bureau of Industry and Security, Office of Inspections and Program Evaluations. Some foreign-born students do return home to work as competitors, but others join in international collaborations that help us move faster in the development and adaptation of new technology and thereby create new jobs. Yet, Section 214b of the Immigration and Nationality Act requires applicants for student or exchange visas to provide convincing evidence that they plan to return to their home countries-a challenging requirement. There is little doubt that the United States would profit from a serious discussion about what kinds of information should be classified, but such a discussion is not occurring. In recent months, polls have indicated persistent concern not only about the war in Iraq and issues of terrorism but also, and nearly equally, about jobs and the economy. On the eve of the 2004 presidential election, the Gallup organization asked respondents what issues concerned them most. Terrorism was first, ranked "extremely important" by 45% of respondents; next came the economy (39%), health care (33%), and education (32%). The numbers who are worried about outsourcing are second only to the numbers who are worried about the price of energy, according to a July 2005 Gallup poll on investor concerns.

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Dehiscence of an abdominal wound can be a lifethreatening complication, in some studies carrying a mortality as high as 30%. An incisional hernia, usually of the abdominal wall, refers to a defect caused by poor wound healing following surgery into which the intestines protrude. Ulceration: Wounds ulcerate because of an inadequate intrinsic blood supply or insufficient vascularization during healing. For example, leg wounds in persons with varicose veins or severe atherosclerosis typically ulcerate. Nonhealing wounds also develop in areas devoid of sensation because of persistent trauma. Such trophic or neuropathic ulcers are occasionally seen in patients with leprosy, diabetic peripheral neuropathy and in tertiary syphilis from spinal involvement (in tabes dorsalis). Excessive Scar Formation An excessive deposition of extracellular matrix at the wound site results in a hypertrophic scar or a keloid (See Figure 4-5 and 4-6). Keloid Formation An excessive formation of collagenous tissue results in the appearance of a raised area of scar tissue called keloid. Genetic predisposition, repeated trauma, and irritation caused by foreign body, hair, keratin, etc. However, hypertrophic scar never gets worse after 6 months unlike keloid, which gets worse even after a year and some may even progress for 5 to 10 years. Excessive contraction A decrease in the size of a wound depends on the presence of myofibroblasts, development of cell-cell contacts and sustained cell contraction. An exaggeration of these processes is termed contracture (cicatrisation) and results in severe deformity of the wound and surrounding tissues. Contracture (cicatrisation) is also said to arise as a result of late reduction in the size of the wound. Interestingly, the regions that normally show minimal wound contraction (such as the palms, the soles, and the anterior aspect of the thorax) are the ones prone to contractures. Contractures of the skin and underlying connective tissue can be severe enough to compromise the movement of joints. Cicatrisation is also important in hollow viscera such as urethra, esophagus, and intestine. In the alimentary tract, a contracture (stricture) can result in an obstruction to the passage of food in the esophagus or a block in the flow of intestinal contents. Several diseases are characterized by contracture and irreversible fibrosis of the superficial fascia, including Dupuytren disease (palmar contracture), plantar contracture (Lederhosen disease), and Peyronie disease (contracture of the cavernous tissues of the penis). In these diseases, there is no known precipitating injury, even though the basic process is similar to the contracture in wound healing. Miscellaneous Implantation (or epidermoid cyst: Epithelial cells which flow into the healing wound may later sometimes persist, and proliferate to form an epidermoid cyst. Fracture Healing the basic processes involved in the healing of bone fractures bear many resemblances to those seen in skin wound healing. Unlike healing of a skin wound, however, the defect caused by a fracture is repaired not by a fibrous "scar" tissue, but by specialized boneforming tissue so that, under favorable circumstances, the bone is restored nearly to normal. Depending on the arrangement of the collagen fibers, there are two histological types of bone: 1. Woven, immature or non-lamellar bone this shows irregularity in the arrangement of the collagen bundles and in the distribution of the osteocytes. Lamellar or adult bone In this type of bone, the collagen bundles are arranged in parallel sheets. Immediately following the injury, there is a variable amount of bleeding from torn vessels; if the periosteum is torn, this blood may extend into the surrounding muscles. The tissue damage excites an inflammatory response, the exudate adding more fibrin to the clot already present. The inflammatory changes differ in no way from those seen in other inflamed tissues. Macrophages invade the clot and remove the fibrin, red cells, the inflammatory exudate, and debris. Any fragments of bone, which have become detached from their blood supply, undergo necrosis, and are attacked by macrophages and osteoclasts. Following this phase of demolition, there is an ingrowth of capillary loops and mesenchymal cells derived from the periosteum and the endosteum of the cancellous bone. The mesenchymal "osteoblasts" next differentiate to form either woven bone or cartilage. The term "callus", derived from the Latin and meaning hard, is often used to describe the material uniting the fracture ends regardless of its consistency. When this is granulation tissue, the "callus" is soft, but as bone or cartilage formation occurs, it becomes hard. The dead calcified cartilage or woven bone is next invaded by capillaries headed by osteoclasts. As the initial scaffolding ("provisional callus") is removed, osteoblasts lay down osteoid, which calcifies to form bone. Its collagen bundles are now arranged in orderly lamellar fashion, for the most part concentrically around the blood vessels, and in this way the Haversian systems are formed. Adjacent to the periosteum and endosteum the lamellae are parallel to the surface as in the normal bone. The final remodeling process involving the continued osteoclastic removal and osteoblastic laying down of bone results in the formation of a bone, which differs remarkably little from the original tissue. The external callus is slowly removed, the intermediate callus becomes converted into compact bone containing Haversian systems, while the internal callus is hollowed out into a marrow cavity in which only a few spicules of cancellous bone remain. S Israel; General Pathology, Churchill Livingston Edinburgh and London, 4th edition, 1974 4. Macfarlane, Reid, callander, Illustrated Pathology, Churchill Livingstone, 5th edition, 2000. Learing objectives Upon completion of this chapter, students should be able to: 1. Explain how fluid balance is maintained across the arteriolar & venular end of the vasculature by Starling forces 2. Know the pathologic conditions occurring when the balance between the above forces is disrupted across the vascular wall under different conditions, i. Understand and explain the cause and pathogenesis of clinical conditions like myocardial infarction, deep venous thrombosis, pulumonary thromboembolism, etc. Know the pathogenesis of edema of congestive heart failure, nephrotic syndrome, cirrosis, and other clinical conditions 5. Have the basic knowledge about various types of shock, their pathogenesis, manifestations, and complications. Introduction the health and well-being of cells & tissues depend not only on an intact circulation to deliver nutrients but also on normal fluid hemostasis. Edema Definition: Edema is increased fluid in the interstitial tissue spaces or it is a fluid accumulation in the body cavities in excessive amount. Mechanism of edema formation: Approximately 60% of the lean body weight is water, two-thirds of which is intracellular with the remainder in the extracellular compartment. The capillary endothelium acts as a semipermeable membrane and highly permeable to water & to almost all solutes in plasma with an exception of proteins. Proteins in plasma and interstial fluid are especially important in controlling plasma & interstitial fluid volume. Normally, any outflow of fluid into the interstitium from the arteriolar end of the microcirculation is nearly balanced by inflow at the venular end. Edema formation is determined by the following factors: 1) 2) 3) 4) 5) Hydrostatic pressure Oncotic pressure Vascular permeability Lymphatic channels Sodium and water retention We will discuss each of the above sequentially. There are four primary forces that determine fluid movement across the capillary membrane. Each of them can be listed under the above two basic categories, the hydrostatic pressure & the oncotic pressure. The capillary hydrostatic pressure (Pc) this pressure tends to force fluid outward from the intravascular space through the capillary membrane to the interstitium.

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Studies of persons exposed environmentally as a result of the Chernobyl disaster or as a re- months at very low dose rates or with fractionated exposures. The cumulative effect of multiple low doses of less than 10 mGy delivered over extended periods has to be explored further. Research Need 4: Identification of molecular mechanisms for postulated hormetic effects at low doses Definitive experiments that identify molecular mechanisms are necessary to establish whether hormetic effects exist for radiation-induced carcinogenesis. Research Need 5: Tumorigenic mechanisms Further cytogenetic and molecular genetic studies are necessary to reduce current uncertainties about the specific role of radiation in multistage radiation tumorigenesis. Research Need 6: Genetic factors in radiation cancer risk Further work is needed in humans and mice on gene mutations and functional polymorphisms that influence radiation response and cancer risk. In humans, the problem can be explored using genomic databases and knowledge of mechanisms of origin of radiation-induced deletions to predict regions that may be particularly prone to radiationinducible deletions. With respect to epidemiology, studies on the genetic effects of radiotherapy for childhood cancer should be encouraged, especially when they can be coupled with modern molecular techniques (such as array-based comparative genomic hybridization). Research Need 8: Future medical radiation studies Most studies of medical radiation should rely on exposure information collected prospectively, including cohort studies as well as nested case-control studies. Future studies should continue to include individual dose estimation for the site of interest, as well as an evaluation of the uncertainty in dose estimation. Studies of populations with high- and moderate-dose medical exposures are particularly important for the study of modifiers of radiation risks. Because of the high level of radiation exposure in these populations, they are also ideally suited to study the effects of gene-radiation interactions, which may render particular subsets of the population more sensitive to radiation-induced cancer. It is important that follow-up for mortality and cancer incidence continue for the 45% of the cohort who remained alive at the end of 2000. Doseresponse analyses that make use of this evaluation should thus be conducted to account for dosimetry uncertainties. Specifically, methods that draw on both data for the specific site and data for broader cancer categories could be useful. Is ionizing radiation a unique insult to cells, or are its effects lost in the ocean of naturally occurring metabolic reaction products? Can cells detect and respond to low doses of ionizing radiation because of detectable qualitative and quantitative differences from endogenous reaction products? Different Types of Ionizing Radiation Ionizing radiation, by definition, contains enough energy to displace electrons and break chemical bonds. Charged particles, such as high-energy electrons, protons, -particles, or fast heavy ions, are termed directly ionizing because, while they traverse the cell, they ionize numerous molecules by direct collisions with their electrons. Electromagnetic radiations, such as X- and -rays, consist of photons that can travel relatively large distances in tissue without interaction. This term is also applied to fast neutrons, because they too traverse large distances in tissue without interaction but can, in occasional collisions, transfer much of their energy to atomic nuclei that in turn produce the main part of the ionizations. In addition to the distinction between indirectly ionizing and directly ionizing (i. It is seen that electrons are generally sparsely ionizing while protons are, at moderate energies, densely ionizing. However it is also noted that very energetic protons, as they occur in altitudes relevant to aviation and in space, are sufficiently fast to be sparsely ionizing. The reason is that a small fraction of the absorbed dose to A-bomb survivors was due not to the predominant high-energy -rays, but to fast neutrons. Because of the greater effectiveness of these fast neutrons, this small dose component must be taken into consideration. Photon Spectral Distributions the absorption and scattering of photons depends on their energy. The -rays from radioactive decay consist of monoenergetic photons that do not exceed several million electronvolts (MeV) in energy; -rays that result from the fission of uranium or plutonium have a spectrum of energies with a maximum of 2 MeV. Higher-energy -rays, up to 7 MeV, can be generated by inelastic scattering, as occurred in the neutron-nitrogen interaction from the atomic bomb explosions in Hiroshima and Nagasaki. Artificially produced X-rays have a wide spectrum of energies resulting from the deceleration of electrons as they traverse high-atomic-number materials. A continuous distribution of photon energies is generated, with a mean energy of about one-third the maximal energy of the accelerated electrons. Discrete energy "spikes" also occur in the X-ray spectrum; these spikes originate in the ejection of electrons from atoms of the affected element, which is followed by the transition of electrons from outer shells to inner shells of the atom releasing photons of discrete energy. Conventional Xrays, used for diagnostic radiology, are commonly produced with accelerating voltages of about 200 kV. For mammography, where high contrast is sought and only a moderate thickness of tissue must be traversed by the X-rays, the low acceleration voltage of 29 kV is usually employed. There are three different types of energy-transfer processes whereby photons of sufficient energy eject electrons from an atom, which can then interact with other atoms and molecules to produce a cascade of alterations that ultimately lead to observable biological effects. A photon interacts with and ejects an electron from one of the inner shells of an atom. The photon is extinguished, and most of its energy is imparted to the ejected electron as kinetic energy. In this case the energy of the incoming photon is converted into the kinetic energy of an ejected electron and a secondary "scattered" photon. The scattered photon has less energy than the primary photon and can undergo further Compton scattering until its energy is sufficiently degraded for the photoelectric process to occur. A photon interacts with an atomic nucleus, and the photon energy is converted into a positron and an electron. The positron ultimately interacts with another electron, and this results in an "annihilation" event in which the mass is extinguished and two 0. To compare the penetration depth of photon radiation with that of electron radiation, the mean range of electrons of specified energy is given in the same diagram. It is seen that the electrons released by photons are always considerably less penetrating than the photons themselves. Figure 1-3 compares in terms of the distributions of photon energy fluence the -rays from the A-bomb explosions with the distributions of photon energy for orthovoltage Xrays and low-energy mammography X-rays. There are, nevertheless, differences in effectiveness and possibly also differences in the risk for late effects due to these radiations. Track Structure the passage of fast electrons through tissue creates a track of excited and ionized molecules that are relatively far apart. The distributions of the energy fluence relative to the logarithmic scale of energy are plotted, because they represent roughly the fractional contribution of incident photons of specified energy to the dose absorbed by a person. For lower-energy X-rays the photon energy is further reduced, and the photo effect (i. The -rays from the atomic bomb explosions had average energies between 2 and 5 MeV at the relevant distances (Straume 1996). With regard to mutations in Tradescantia, aberrations in human lymphocytes, and killing of mouse oocytes (Bond and others 1978), conventional 200 kV Xrays have been found to be about twice as effective at low doses as high-energy -rays. Edwards and others (1982) have obtained the data for dicentrics in human lymphocytes listed in Table 1-1 for 15 MeV electrons, 60Co -rays, and 250 kV X-rays. Sasaki and colleagues (1989; Sasaki 1991) have determined the yields of dicentrics in human lymphocytes over a broad range of photon energies. The upper panel of Figure 16 gives the linear coefficients (and standard errors) from linear-quadratic fits to the dose dependencies. The closed circles relate to -rays and to broad X-ray spectra; the squares, to characteristic X-rays and monoenergetic photons from synchrotron radiation. The diagram demonstrates that there is a substantial decrease of the yield of dicentrics from conventional X-rays to -rays. The photon energies below 20 keV are of special interest with regard to biophysical consideration, but are less relevant to exposure situations in radiation protection. However, the difference has to be noted whenever risk estimates are derived from exposures to -rays and then applied to X-rays. Since the dose dependence for solid tumors among A-bomb survivors indicates little curvature, the dependence of risk on photon energy may be similarly weak for tumor induction in man. It is of interest to compare the biophysical information and the experimental results to the radioepidemiologic evidence for health effects.