Mark Corson

By L. Sebastian. University of Arkansas, Fayetteville. 2018.

Proteasomes can be directly inhibited by oxidative stress [137 generic rulide 150mg amex, 138] and lipofuscin order rulide 150 mg, both of which accumulate with aging [139 generic rulide 150mg on-line, 140]. Inhibition of proteasome activity increases senescence in broblasts [141, 142], and proteasome activity decreases signicantly with age in the lung [143]. Prolonged stress, by contrast, can contribute to apoptosis and the initiation of brotic remodeling [149]. The activation of these pathways may result from altered surfactant protein processing [119, 149, 150]. It is known to play a crucial role in preserving normal mitochondrial function, morphology and mitoph- agy, and also is linked to aging. Several defects in mitochondrial dynamics, including ssion, fusion, biogenesis and mitophagy have been reported in various lung diseases. Whereas the coordinated induction of ssion and autophagy is believed to facilitate the removal of damaged mitochondria through mitophagy, excessive ssion may cause apopto- sis [164]. Conversely, telo- mere erosion versus maintenance and repair can determine cell fate. It is also known that 20 % of the patients with telomerase mutations that cause congenital dyskeratosis also develop pulmonary brosis [178, 179]. Sanchez do not have altered telomere length despite showing markers of senescence such as -galactosidase, suggesting that cell senescence in this case might be driven by stress, rather than exhaustive proliferation [185]. Furthermore, senescence can be induced in vitro by the exposure of broblasts and alveolar epithelial cells to cigarette smoke [186, 187]. Nevertheless, small air- ways, alveolar epithelia and resident broblasts are characterised by different renewal strategies, and telomere dysfunction and cellular senescence could be expected to act differently in these compartments and to be associated to different pathologic outcomes. Variations in methylation of histones H3 and H4, depending on residues, have also been also reported. The tri-methylated lysines 9 and 36 of histone H3 (H3K9me3 and H3K36me3 respectively), and the mono-methylated lysine 20 of histone H4 (H4K20me) can also change as a function of age [202 204]. In theory, the promotion of healthy aging could be pursued by developing epigenetics drugs able to cope with the aged epigenome [205]. Histone modications are involved in the activation of some pro-brotic and repression of anti-brotic genes, while modications at the Fas promoter are responsible for decreased Fas expression and apoptosis resistance in brotic lung broblasts [214 ]. Upregulation of the Wnt/B-catenin signaling has also been associated with a decrease in miR-375 and miR487b [228, 235]. In fact, activation of the Wnt/B-catenin pathway attenuates experimental emphy- sema [236]. Splicing becomes less tightly controlled in aged individuals, based on data from the InChianti study [242]. Disruption in the balance between inammation and immune activation after local and systemic insults contributes to increased morbid- ity and mortality in the elderly [247 249], and older lungs respond to insults in a different manner from that of younger counterparts. Alveolar macrophages, lym- phocytes, senescent epithelial cells, and mesenchymal cells constitute potential candidates. Notably, chronic lung injury, inhaled gases, and particles from cigarette smoke mimic the effects of inammaging [258 264] (Fig. In spite of the observations cited above, the role of inammation in the progres- sion of pulmonary brosis is challenged by the lack of response to anti-inammatory treatments and immunosuppressants. Nevertheless, a pathogenic role for inammation cannot be excluded in the initiation of the disease. M2-activated macrophages secrete cytokines that stimulate col- lagen production in lung broblasts. Moreover, monomeric collagen type I favors the shifting of alveolar macrophages to the probrotic M2 type, which may perpetuate brosis [274 277]. GzmB released from cytotoxic lymphocytes protects against viral infec- tion and it also contributes to extracellular matrix degradation and remodeling and, consequently, the emphysematous phenotype [294, 295 ]. Clara cells are found in the epithelium of bronchioles and secrete surfactants; they may also have functions in maintenance of the bronchiolar epithelium. In pulmonary brosis, epithelial cells release chemokines that recruit inammatory monocytes and neutrophils. This can explain why both pathologies can appear within the same lung specimen [81 ]. Changes in intercellular communication can occur due loss of cell-cell contact, changes in the extracellular matrix, hormones, electrical and chemical signals. It appears, therefore, that decellularized emphysematous scaffolds lack the necessary extracellular matrix architecture to support sustained cell growth [315 ]. Disruption of the 17-estradiol/estrogen receptor alpha signaling pathway is observed in aging. Animal models for acute lung injury and inammation treated with 17-estradiol exhibit reduced lung inammation in a gender-independent, age-dependent manner [323]. A low daily dose of melatonin has been shown to protect lungs from histopathological changes in rabbits exposed to smoke [331]. Unfortunately, our knowledge regarding lung resident stem cells is still emerging, and the changes in these cellular populations during aging and/or age-related diseases of the lung remain to be elucidated. Nevertheless, several stud- ies provide evidence for the existence of human lung epithelial stem/progenitor cells [333 336]. Furthermore, convincing evidence for the existence of resident stem cells comes from a case study that reported compensatory lung growth with an increase in alveolar number in a 33-year-old woman, 15 years after a right-sided pneumonectomy for the treatment of lung adenocarcinoma [337 ].

The fact that this particular mutational signature is the only type that is strongly correlated with age across many cancer types suggests its accumulation is predominantly time dependent generic 150mg rulide. Since many of the self-renewing cells divide infrequently rulide 150mg visa, the requisite number of mutations needed for malignant conver- sion may necessarily accumulate over years or decades buy generic rulide 150 mg line. An adult human has fewer than 105 such cells that divide very rarely, approximately once every 40 weeks [88]. Presumably, cancer arises through similar The Impact of Aging on Cancer Progression and Treatment 75 mechanisms in other tissues, and in all cases, signicant evidence suggests the period from the earliest stem oncogenic events to full malignant conversion can in some tissues last several decades. In the absence of p53 however, telomere shortening instead causes chro- mosome end-to-end fusions, leading to chromosome breakage during the subse- quent round of cell division, which can result in chromosomal abnormality and aneuploidy [90]. Human somatic cells start with approximately 15 kb of telomere sequence during early embryonic development [91]. In the absence of telomere maintenance mechanisms, each cell division is accompanied by a net loss of 100 200 bp of telomeric sequence. Therefore, age-associated telomere shortening can contribute to increased cancer incidence in the elderly by inducing genomic instability and mutagenesis. Indeed, short telomere length has been associated with signicantly increased risk of several types of human cancers [92, 93], and people with genetic deciencies in telomere maintenance are predis- posed to the development of certain cancers such as leukemia and keratinocytic cancers in addition to exhibiting features of premature aging [88]. For example, common alleles with reduced telomerase activity (and pre- sumably shorter telomeres) appear to increase human risk for the same cancers noted in the syndromes of congenital telomerase deciency (e. Likewise, however, it is becoming clear that somatic stem cell function is compromised with aging in many tissues. This may occur as a result of tumor sup- pressor mechanisms such as senescence, which in turn occurs as a result of telomere 76 S. Importantly, however, the loss of even a fraction of a tissue s somatic stem cell compartment imposes a signicant replicative burden on the remaining stem cells of that tissue. This com- pensatory increase in replication in turn translates into a greater risk of cancer, as well as additional possible stem cell attrition. In fact, it appears that a substantial fraction of human cancers develop specic mechanisms to evade the immune system, thereby allowing for progression into later stages [95]. The ability of the immune system to repress malignancy may be particularly important in certain kinds of cancers that are very immunogenic; for example, those resulting from viral infections or which have tumor neo-antigens. Since the immune system plays an active role in cancer repression throughout life, the waning of immunity with aging, and in particular cellular immunity as mediated by T cells, likely plays an important role in tumori- genesis. For example, an increase in the number of senescent cells in aging tissues is thought to cause a signicant increase in the local concentrations of pro-inammatory cytokines secreted by senescent cells. It should be noted that this model is somewhat contro- versial, with many authors suggesting senescence-related cytokines can also deter tumorigenesis, and therefore the effect of senescent cells with regard to cancer are likely tissue- and context-specic. While our understanding of the molecular basis of cancer and aging continues to grow, it is possible to design strategies to both decrease the incidence of cancer as well as slow the rate of aging. Indeed, it has been shown that quitting smok- ing has a myriad of health benets in both target tissues such as the lung (e. Evidence suggests that tobacco exposure widely promotes aging-like phenotypes in many tissues, and therefore has been argued to represent the prototypical human gerontogen [96, 97]; that is, an environmental exposure that promotes physiological aging. Therefore, nding ways to protect stem cell function in cancer patients may help to reduce the aging-promoting effects of cyto- toxic therapy in this special scenario. Another potential way to reduce cellular damage is through modulating energy metabolism. One possible explanation for this is that decreased cellular energy metabolism may reduce the generation of harmful 78 S. As humans age, the function of the immune system declines sharply, resulting in increased susceptibility of the elderly to external infection. This aging-associated decline in adaptive immune response may also contribute to impaired immune sur- veillance and clearance of damaged or senescent cells from the body, which can contribute to aging and cancer development. On the other hand, an aberrant immune response such as autoimmune diseases also increases with age. Therefore, nding ways to augment the normal immune system function without over-activation in old individuals may ameliorate certain aspects of aging while providing an important anti-cancer defense. Therefore, an important goal of aging research is to nd ways to maintain functional stem cells throughout life. Therefore, reducing the rate of stem cell prolifera- tion may provide a way to slow stem cell aging. Alternatively, providing an exoge- nous source of healthy somatic stem cells, for example through a regenerative medicine approach, could provide a means to reduce both aging and cancer. The choice between these two seemingly distinct outcomes depends on the effectiveness of The Impact of Aging on Cancer Progression and Treatment 79 cellular tumor suppression mechanisms against oncogenic mutation failed tumor suppression results in cancer, while successful tumor suppression causes functional attrition of self-renewing cells, contributing to physiological aging. The increased incidence of cancer with aging reects the time-dependent accumulation of muta- tions in somatic self-renewing cells, as well as waning immune surveillance and possibly pro-oncogenic changes to the tissue milieu with aging. While preventing aging or curing cancer is unlikely, minimizing cellular damage, enhancing immune system function, and maintaining a functional stem cell pool may slow the rate of aging while simultaneously reducing the risk of cancer. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. Runi A, Tucci P, Celardo I, Melino G (2013) Senescence and aging: the critical roles of p53. Campisi J, d Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Samassekou O, Gadji M, Drouin R, Yan J (2010) Sizing the ends: normal length of human telomeres. This opens a new era in cancer care that is chal- lenged with not only enhancing treatment efcacy but also improving the quality of the clinical outcome.

Antibodies to this region of the viral envelope are produced early in the course of infec- tion (31) and are associated with delayed progression of disease (32) and reduced maternal-infant transmission of infection (33) best 150mg rulide. They appear to function by inhibiting coreceptor binding and virus-cell fusion (34) cheap rulide 150mg visa. Several anti-V3 monoclonal antibodies have been created (Table 1) buy 150 mg rulide with amex, but the hypervariability of this region hinders its usefulness as a target for immunologic control by passive or active vaccination strategies (30,36). However, some studies have suggested that some anti-V3 antibod- ies are more broadly neutralizing (37,38). Seventy-two percent of isolates from different clades con- tain this amino acid sequence (45). The monoclonal antibody 2G12 recognizes a discontinuous epitope on gp120 that includes domains in C2, C3, C4, and V4 (46). Synergistic or additive effects were detected when two antibodies tar- geting different epitopes were combined. Two antibody combinations involving b12, 2F5, 2G12, and 694/98D (anti-V3) were most active. The synergistic effects seen in these studies are probably related to their comple- mentary activities at different epitope targets. The b12 anti- body is 10-fold less potent than the best antibodies against poliovirus and influenza A (23). Thus, by using combinations of antibodies, neutralization of virus is made more efficient, and the doses of antibodies needed to achieve maximum virus inhibi- tion are reduced. A single amino acid change in an epitope can result in escape from antibody neutralization (58 60). Thus, this potential treatment appears safe and is likely to proceed to clinical trials. Bispecific Antibodies Another approach to enhance and broaden the activities of antibodies and effector cells is the creation of bispecific antibodies (BsAbs) (79). One is through complement-mediated lysis of free virus or viral-infected cells (80,81). Antibody binding of gp120 expressed on infected cell sur- faces could inhibit fusion of cells, syncytia formation, and cell-to-cell spread to virus (84). The ability of antibodies to protect against infection has been demonstrated in these models, but the results of experiments have not been uni- versally successful. Differences in results may depend on the viral strain tested, the chal- lenge dose, the type of antibody preparation, and the dose of this product. Three of four animals were protected from infection, whereas the two control monkeys who received uninfected monkey serum before challenge became infected. Prechallenge antibody titers in individual animals did not correlate with protection. To study passive immunization against maternal-infant transmission, Van Rompay et al. They sustained low level viremias for up to 4 years after infection but had no detectable plasma viral load and no clinical illness at the time sera were obtained for the hyperimmune serum pool. Untreated neonates all became infected after viral challenge, and most died within 3 months (100). Although both monkeys became infected, one of them maintained a low virus load, with virus isolation achievable only at one time point 2 weeks after challenge (101). They are more resistant to neutralization by antibodies than T-cell laboratory-adapted strains (36,39). On the other hand, by replicating in antigen-presenting cells, they may induce enhanced immune responses when presented as vaccine. Postexposure Protection Studies in Monkeys Using Polyclonal Antibody Preparations Passive immunization has been promoted as a possible strategy for prevention of infection in the immediate postexposure period. Protection Studies in Monkeys Using Monoclonal Antibodies Monoclonal antibodies have also been evaluated in primate protection models. Although the number of ani- mals studied was small, and the progesterone-treated monkey model is not completely comparable to the natural human situation, these experiments suggest that antibody may be more protective against mucosal viral exposure than intravenous challenge (106). Since the monoclonal antibodies used in this experiment were of the IgG1 type, it appears that antibodies of the secretory IgA type are not necessary for mucosal protection from viral infection (107). On the other hand, the immunocompromised nature of these animals does not mimic the natural human state when humans are exposed to virus. Furthermore, most human infections occur via the intravenous or mucosal route, not intraperitoneally. Nonethe- less, with these limitations in mind, several useful observations have been made. Once again, this dose provided serum concentrations corresponding to levels giving 99% in vitro neutralization. It should be noted that in an acute human to mouse xenograft model in which donated human monocytes and lymphocytes are in an activated state, monoclonal anti- bodies with demonstrated in vitro neutralizing activity against primary isolates failed to provide in vivo protection against infection (120). Thus, they might be effective at preventing the establishment of infection even after virus challenge. It was 62% effective when given 5 hours after challenge and 33% effective when given 6 hours or more after challenge. On the other hand, providing com- plement did not change 694/98-D s activity in providing postexposure prophylaxis (114). Sequence analysis of the V3 region of this virus demonstrated amino acid changes in the epitope recognized by 694/98-D and in one amino acid nearby. Thus, mutation leading to escape from neutralization is a risk of therapy with one monoclonal antibody and supports the need for studying com- binations of antibodies. However, statistically nonsignificant trends toward delayed time to opportunistic infection and time to death were noted. No effects on weight, Karnofsky per- formance score, or serum 2-microglobulin levels were seen (127).

The second and third bunches were tagged by tying insulated electric wire of the best-visible colours proven 150 mg rulide, viz cheap rulide 150 mg amex. For obtaining pre-treatment population data buy rulide 150mg on-line, the third nutlet from the bottom of the bunch was sampled from the fourth and fth bunches. Following the pre- treatment sampling, all the bunches were treated with the specic spray uid (2 l/palm) using a portable, lightweight, hand-compression sprayer (3. All the spray uids were prepared in plain water and applied thrice as sprays at fortnightly intervals during early mornings. The post-treatment population count of the mite was recorded in all the palms 6 weeks after the rst round of treatment. Population counts were made on two nuts, one each from both the tagged bunches, in the same way as pre-treatment analysis. Finally, during the pre- harvest stage, both the tagged bunches were cut off entirely from the palm and brought down for grading. The nuts were separated from the short peduncles from each bunch separately and were graded individually based on the damage caused by the mite. Data analysis All laboratory experiments were performed twice and the eld trial once. For the labo- ratory experiments, the results from only one trial are presented because a similar trend was observed between the trials with homogeneity of variances determined with Bartlett s test. Prior to analysis, the data from conidial counts were subjected to log(x)-transformation to improve homogeneity of variances. Data on colony counts on the lter paper and pathogenicitypwere square-root- p p transformed x. The pre-treatment x and post-treatment x 0:5 data from the eld trial were also subjected to square-root transformation. Diseases of Mites and Ticks 175 Results Effect of adjuvants on the growth characteristics of Hirsutella thompsonii The number of fungal colonies formed on the lter paper by H. Hyphal development and extension occurred in less than 24 h only in glycerol treatment. In other treatments, it took anywhere between 24 and 48 h, except in the case of gelatine and nutrient broth, both of which took longer. Several test adjuvants were able to take sporulation levels much higher than the untreated control (F9,20 = 15. Gelatine was the least effective among all the treatments with the lowest 4 numbers of conidia (2. In terms of conidia density generated on a 20-mm-diameter mycelial mat, the treatments varied signicantly. In the second method, wherein pellets were added to the adjuvant solution (F9,20 = 46. Growth and conidiation of mycelial pellets on excised parts of the coconut palm Conidiation of adjuvant-treated mycelial pellets occurred on various parts of the coconut palm but the progress of growth and conidiation was not uniform on all (Table 3). The progress of fresh fungal growth out of the pellets was the best on the nut surface or exocarp (green portion of tender nut). An unexpected shrinkage of the mycelial pellets was observed on the short peduncle as well as on the adaxial and abaxial surfaces of the leaet. Effect of simulated sunlight on the conidiation of Hirsutella thompsonii Irradiance with simulated sunlight for 1 h resulted in reduced conidiogenesis by H. Better conidiation was observed under alternating light dark regime than under total darkness in all the treatments (F3,32 = 39. The three adjuvants shielded the pellets from adverse sunlight to certain extent and helped retain enough moisture to be able to undergo conidiogenesis successfully (F3,32 = 19. Pathogenicity of adjuvant-treated pellets Prior to eld-testing of the fungus, the adjuvant-treated pellets were tested for pathoge- nicity towards the coconut mite. Glycerol-treated pellets were the most effective in terms of the mortality caused, a 16. Field trial 2 The pre-treatment counts of live mites per mm of the nut surface just below the perianth ranged from 6. A signicant reduction in the post-treatment population of the coconut mite was observed in nut samples collected from the tagged bunch 1 (F4,55 = 19. The fungus was able to cause disease in the mite on all the sprayed palms as evidenced during the post-treatment sampling. In terms of the pre-harvest damage grades, all the fungal treatments were on a par with the chemical and superior to control in both the tagged bunch 1 (F4,55 = 18. Several adjuvants have been found to have an additive effect on the performance of the fungus against the coconut mite. The laboratory studies also indicated that not all substances with recognised nutrient or humectant qual- ities would augment the performance of H. For example, skimmed milk powder, gelatine and nutrient broth were either ineffective or only slightly better than control. Assigning the exact reason for the difference in performance of each of these test adjuvants seems impossible because of the differences in their macro- and micronutrient contents and their availability to the fungus. Later, McCoy and Couch (1982) demonstrated the utility of certain adjuvants to stimulate conidiation of H. The fungus was able to put forth new hyphae and conidiate profusely on several plant parts, more so on the nut surface, indicating the possible additive effect of the treatments under the actual eld situation (Table 3). However, the variations could be explained as the impact of the texture of the plant surface as well as the interaction of the resident microora with the fungus. Tank-mixed nutrients enable biopesticide fungi to grow and sporulate on the plant parts thus aiding continual infection of surviving mites. The fungus treated with selected adjuvants in fact caused higher mortality of the mite in the laboratory experiment (Fig.

The Record of the Hair The hair shaft records repeated cosmetic practices the so-called record of the hair (7) rulide 150mg free shipping. Newly emerging hair has properties that are different from those of the hair tips buy rulide 150mg free shipping. Genetic evidence suggests that Homo sapiens originated only 200 order 150mg rulide,000 250,000 years ago somewhere in the East African savannah. Despite their apparent phenotypic variation, today s world population is potentially derived from as few as 1,000 to 10,000 individuals. Descendants of these modern humans migrated out of Africa when the climate improved and populated the earth. This is due in the most part to the gross reduction in breeding pairs in the late Pleistocene era. This core of humanity, survived near-extinction and went on to populate the entire world in less than 5000 genera- tions. In less than 100 generations and 2000 years, world population has risen from 3 million to 6 billion. Of the remainder, 14% live in the Americas, 13% in Africa, and 12% in Europe with only 0. Hair form arose from these clans and, as much as skin color, denotes local origins. Despite serial migrations, the original groups have been preserved largely on a regional basis. Bands, which are the simplest form of human society, and still exist (Inuit, indigenous Australians) expanded into clans and sub- sequently tribes. Until the advent of global agriculture some 7,000 ago, genetic lineages were probably tightly maintained. Where and when the emergence of the archetypal hair forms that are described in the literature occurred is not known. Similarly, knowledge of the hair phenotype of early humans and whether the tightly curled hair of today s equatorial Africa or a more wavy appearance predominated is speculative (Figs. Demonstrat- ing that environmental selective pressures shaped specic physical features is difcult, since such features may have resulted from sexual selection for individuals. These terms not only have a pejorative ring but from a practical standpoint are scientically inac- curate and no longer employed by publishers. Hair Morphology Studies Human hair morphology varies from the at to the round (Fig. Her hair displays varied phenotypic adaptability straight hair when pregnant and tightly coiled in the nonpregnant state. Curiously she is a doppleganger for the proposed African Eve published in Newsweek (see Fig. In many parts of the world, groups have mixed in such a way that many individuals have relatively recent ancestors from widely separated regions. Although genetic analyses of large numbers of loci can produce estimates of the percentage of a person s ancestors coming from various continental populations (10,11), these estimates may assume a false distinctiveness of the parental populations since human groups have exchanged mates from local to continental scales throughout history (12). Even with large numbers of markers, information for estimat- ing admixture proportions of individuals or groups is limited and estimates typically will have wide condence intervals (13). The alleged relationship between the cross-sectional shape of the hair shaft and the form of the hair, e. Three-dimensional computer-aided reconstructions have documented that the follicle form determines the appearance of the hair, e. In vitro growth of curly hair follicles was slightly slower than that of Caucasian follicles but, more importantly, the curvature was maintained in the hair shaft produced in vitro. Immu- nohistochemistry revealed that the proliferative matrix compartment of curly hair follicles was asymmetrical, with Ki-67-labeled cells more numerous on the convex side and extending above the Auber line. The authors concluded that hair curliness is programmed from the bulb and is linked to asymmetry in differentiation programs. The differences in the patterns between the inner and the outer sides of the curvature were successfully detected (16). The analysis of the equatorial and azi- muthal scattering intensity proles showed that the arrangement of the intermediate laments was different between the inner and the outer sides of the curvature. From the analogy with Merino and Romny wool, it is suggested that different types of cortices exist in human hair. It is concluded that, regardless of the ethnic origins, the macroscopic curl shape of the hair ber originates from the nonhomogeneity of the internal nanostructure, arising from unhomoge- neous distribution of two types of cortices. Adaptive Changes in Hair Morphology Since Africa is the home of humankind, it is appropriate to commence here with a discussion of hair morphology. The classical hair of equatorial Africa is also seen in equatorial regions of Indonesia and Australia. Many of the populations of northeastern Africa have looser, less tightly coiled hair than most other Africans. Andamanese peoples, the Negrito, are phenotypically African but are in fact a recent Asian branch. Their small stature, heavily pigmented skin, and tightly coiled hair represent a recent adaptation to equatorial existence. Indigenous Australian peoples exhibit the same phenotype and some Aboriginal infants are born with blonde hair. It is characterized by extremely frizzy and wiry hair that looks almost wooly in appearance. The syndrome usually lessens in adulthood, when wavy hair often takes the place of wooly hair.