The evidence for Mycobacterium avium subspecies paratuberculosis (MAP) as a cause of nonsolar uveal melanoma: a narrative review

Introduction

Uveal melanoma (UvM), also known as intraocular or ocular melanoma, is a rare eye cancer that is distinct from cutaneous melanoma (CM). While both UvM and CM are believed to originate from melanocytes, ultraviolet radiation (UVR) does not have a dominant etiologic role in UvMs that are located in the posterior region of the eye (1,2). The latter area is largely void of sunlight owing to the filtering effect of the cornea, lens, and vitreous (3). This is in contrast to the UV-associated mutational spectrum that characterizes CM, iris cancer (directly exposed to UV-radiation), and epithelial melanomas on the surface skin tissue surrounding the eye (4).

At the molecular level, UvMs are predominately devoid of dipyrimidine site C>T transitions and rarely have mutations in the promoter region of the human telomerase reverse transcriptase (TERT) gene, both of which are attributable to UVR exposure (5). Similar to melanomas presenting in various mucous tissue and non-sun-exposed areas of the body, the etiologic basis of non-solar UvM is unknown.

Several studies have shown an increased rate of eye cancer in farmers (6-12). Zoonoses, infectious diseases that are caused by pathogenic microorganisms and transmitted from animals to humans, have been proposed as possible causes of farming and agriculture associated cancers (13-15). One study showed the highest rate in dairy farmers in particular, although the exact location within the eye was not mentioned (6).

Mycobacterium avium subspecies paratuberculosis (MAP) causes Johne’s disease or paratuberculosis, a chronic enteropathy of dairy and beef cattle and other ruminants (16-19). MAP is a long-suspected cause of Crohn’s disease (20-25). MAP has been implicated in a wide range of autoimmune and neurodegenerative diseases (26-30) and three types of human cancer (31-33).

The literature on the possible relationship between MAP and Crohn’s disease has focused on MAP being transmitted to humans through the ingestion of MAP organisms present in vegetables, raw milk (34,35), and MAP organisms that survive pasteurization (36) and are present in retail milk and other retail dairy products (37-39). However, this route of exposure is negligible compared with more concentrated and direct fecal-borne transmission. MAP is heavily excreted in an infected animal’s feces or manure (17,40). In the case of UvM, near-field exposure to contaminated airborne dust and soil, manure splatter, flies and other insect carriers, and finger-to-eye contact with fecal material containing the pathogen are believed to be the predominant modes of zoonotic spread among farmers and agricultural workers (41). Particularly concerning are subclinical shedders, animals that appear healthy but are shedding MAP in their manure (42). Overall, >60% of infected cattle will go undetected, even with the most sensitive fecal culture techniques (42). Other considerations include inadequately ventilated animal housing units and poor waste removal systems, increasing the exposure to animal excrement and MAP.

The sizable numbers of MAP organisms in dairy cattle feces have not been appreciated. Two milliliters of manure from a dairy cow infected with MAP can contain 1 million MAP organisms, enough to cause infection in a dairy calf (17). An adult dairy animal infected with MAP excretes 12–14 gallons of such heavily contaminated manure per day, or over 23,000 infectious doses of MAP (43).

Large dairy farms, known as confined animal feeding operations, may contain 10,000 animals (44). Approximately 70% of all dairy herds (45,46), and 100% of dairy farms in the United States containing over 200 animals (47) have at least one sub-clinically infected animal with high excretion of MAP in its feces, and within herd prevalence rates can reach 100% (48). Regions of a country with multiple large farms can house over 100,000 dairy animals. The manure output of one such region in the USA was described as “equal to the sewage output of the New York City metro system” (49).

MAP excreted in infected animals’ feces can resist various environmental conditions such as heat, cold, dryness, and acidic conditions (lower pH) (50-52), and remain in soil (51), dirt and dust (53), in a state of nonreplicating persistence, even when other environmental bacteria are present in the environment. MAP is diffusely present in the soil in countries where MAP infections of domestic ruminants is longstanding, “at a higher rate and wider distribution than expected” (54). MAP is present in natural bodies of water contaminated with manure runoff (55,56).

In this narrative review of the literature, we assessed MAP as a possible zoonotic pathogen, examined sources of MAP exposure, and explored routes of transmission from animals to humans. The aim was to present a balanced philosophical perspective of the hypothetical association between MAP exposure and non-solar UvM (herein simply called UvM unless indicated otherwise). We present the following article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2540/rc).

Methods

Based on the several articles documenting an increased rate of eye cancer in farmers (6-11), and particularly dairy farmers (6), a review of the English-language literature from January 1980 to present was conducted to investigate whether there was supporting evidence for MAP excreted in an infected animal’s feces as a risk factor for UvM. We searched PubMed, Scopus, the Cochrane library, and Google on key words to identify locations, occupations, and activities associated with an increased rate or clusters of UvM. We then sought papers illustrating possible connections of these occupations, activities, and locations with dairy cattle. In addition, we deliberately sought connections between occupations with an increased risk of UvM and possible MAP exposure. Studies that used well validated assays such as qPCR and Elisa were specifically targeted when addressing MAP-shedders in this analysis (57).

The screening of the literature was independently conducted by two authors (ESP and JTE), with disagreements mediated by a third author (YC). A summary content of the information was compiled by a fourth author (CJ), who also hand-searched the reference lists of the screened articles for relevant papers that were missed in the initial search. The search strategy is summarized in Table 1.

Synthesis of the literature

The circumstantial evidence for the possible association of MAP with UvM

We were able to consistently correlate increased rates and clusters of UvM with possible exposure to MAP. Farmers and agricultural workers are exposed to aerosolized microorganisms present in feces or manure (41). Specifically, dairy farmers are exposed to large numbers of MAP organisms as described above, that are readily aerosolized from manure, and coat indoor surfaces of dairy farms (58-60).

The excretion of MAP in an infected dairy animal’s feces and the subsequent contamination of underlying soil and nearby water may explain the increased rates of UvM in particular geographic areas and some of the clusters of UvM reported in the literature as described below.

Five cities in Lower Mainland and southeastern Vancouver Island in British Columbia have the highest rates of UvM in Canada (61). This is a region with a great concentration of dairy cattle, approximately 140,000 animals (62,63). In the United States, the incidence for UvM increases disproportionately at higher latitudes (less sun exposure), with the latter region being relatively more populated with dairy farms (64). However, it is important to note that lower latitudes are not devoid of dairy farms and the occurrence of UvM.

A recent report describes three clusters or “geospatial accumulations” of UvM in the United States (65). The first mentioned cluster ranged from 5 to 22 cases (65), located in a predominately rural region (66). Three of the cases attended a high school that was built in 2001 (66), but was previously “farmland and open fields” (66). The type of farms in the area were dairy farms (67). Conceivably, this cluster was related to the dense contamination with MAP of the ground underlying the high school, ground that went from being heavily MAP contaminated, but unoccupied, to the site of the school.

The second United States cluster consisted of 14 cases along the northern stretch of the Susquehanna River in the state of New York (65). This stretch of the Susquehanna River houses a dense concentration of dairy cattle, over 110,000 animals (68). On a related note, increased rates and clusters of MAP-associated illnesses, e.g., Crohn’s disease and ulcerative colitis (69), have previously been reported in relation to the presence of possibly MAP-infected dairy cattle, sheep, and non-domestic ruminant animals adjacent to rivers and streams. These clusters have occurred in Cardiff, United Kingdom (56,70), Spokane, Washington (71-73), Northport, Washington (74-77), Plains, Montana (78), and Forest, Virginia (79). The concentration of MAP from natural bodies of water, first by floating to the top of the body of water owing to MAP’s hydrophobic cell wall, and then by the scavenging bubble - jet drop bursting mechanism, has previously been described (78). In particular, the area of British Columbia described above consists of an island surrounded on two sides by narrow straits, across from a section of land with multiple lakes and rivers.

The third United States cluster occurred at a regional university, with the reported number of cases ranging from 6 (65) to 36 (80). Three of the women lived in the same dormitory room, suggesting exposure to a common source of aerosolized MAP, perhaps the shower water (81,82). An idiopathic inflammatory bowel disease (IBD) cluster has previously been described in three college roommates (83). Although the beef and dairy industries have had a historic economic presence (84) and collocation near the university (85), the association with MAP exposure is circumspect. One case was involved in “the reconstruction of dormitories” (65), possibly related to the generation of MAP contaminated dirt and dust when two residence halls were built in the mid-1990s (86). However, it is not clear if, and to what degree MAP exposure occurred, as the individual was not tested for the presence of this organism.

The increased rate of UvM in male athletes and sportsmen (87) is consistent with the presence of MAP in the soil in countries where MAP infection of domestic ruminants is longstanding (54). The increased rates of glioblastoma (32) and amyotrophic lateral sclerosis (28,88) in outdoor athletes associated with possibly MAP contaminated soil has previously been discussed.

There is an increased rate of UvM in welders and metal workers (10,89-93). UVR has been proposed as the cause of the increased rate of UvM in welders (89). However, UVR, either UVA, UVB, or UVC, is unable to reach the choroidal layer of the eye and has not been consistently correlated with UvMs (93,94). A possible explanation may be the presence of MAP in metalworking fluid, which is known to be contaminated with bacteria (95), including mycobacteria (96-99). Aerosolization is a known mechanism of increasing the concentration of mycobacteria present in liquid (100-102).

The increased rate of UvM in occupational cooks (89,103,104) and workers in the leather industry (10,105) and a cluster of three UvM cases in a rural community where a rendering plant was located (106) are consistent with the presence of MAP in an infected animal’s tissues and fluids, including blood (107-114).

Possible explanations for the racial difference in patients with UvM

An epidemiologic feature of UvM is their almost exclusive occurrence in non-Hispanic Whites and Hispanic Whites, in persons with white skin (115). Mackintosh proposed that the melanin and melanosomes conferring skin color develop as defenses against bacteria and fungi, in particular noting that “animal husbandry practices…will further determine local parasite pressures” (116). Hurbain and colleagues demonstrated that the individual melanosomes that are the predominant melanosome type in non-white skin function as antibacterial degradative organelles (117). In contrast, the melanosome clusters that are the predominant melanosome type in white skin have no effect on bacteria (117).

Choroidal tuberculomas, a rare location of miliary tuberculosis, are thought to result from hematogenous dissemination after entry of Mycobacterium tuberculosis organisms into the bloodstream at the level of the pulmonary alveoli (118). Miliary tuberculosis occurs at a much higher rate in black than white patients (119). The contrast with white-skinned UvM patients suggests that MAP organisms are getting to the uveal layer of the eye, not from hematogenous dissemination to the eye after the inhalation of aerosolized MAP organisms, but by the penetration of aerosolized MAP organisms through the white skin of the face and eyelid. MAP organisms may be able to penetrate white facial and eyelid skin more easily than non-white facial and eyelid skin. Note that the aerosolized potentially MAP contaminated metalworking fluid is being sprayed right at a welder’s face. Depending on the sport, the faces of outdoor athletes are directly contacting possibly MAP contaminated soil and dirt within their playing fields. On the other hand, given the rarity of UvM, it is not likely that MAP readily penetrates either white or black skin, and that once it has penetrated through skin, there is a paucity of evident suggesting an ocular tropism.

A recent case report hinting that MAP organisms may be getting to the eye from the surface of the face describes an individual living on an animal farm (of “sharps and pigeons”, not dairy cattle) who developed a UvM in his left eye several years after “light blunt trauma” to that eye (120). Nontuberculous mycobacterial ocular infection is associated with surgery of and biomaterials in the cornea and sclera (121), but there are no other reports of UvM associated with trauma to the affected eye.

Once MAP organisms have penetrated through the white skin of the face and reached the uveal layer of the eye possibly within facial blood vessels, MAP organisms may be able to invade the choroidal melanocytes of the eyes of white-skinned persons more easily than the eyes of nonwhite-skinned persons. A frequently cited study (122) demonstrated that the eyes of persons with black skin have a significantly greater amount of protective choroidal melanin than the eyes of persons with white skin. The literature is not clear on the total choroidal melanin in persons of Asian descent, but the low incidence of UvM in Asians suggests a comparably large total choroidal melanin content as in persons with black skin (115).

Mackintosh’s hypothesis regarding melanin and melanosomes as antibacterial substances and organelles also may explain why UvMs often occur in persons with blue eyes. Larger individual melanosomes have more melanin than smaller ones and so are better antibacterial degradative organelles. Brown-eyed choroidal melanocytes have the greatest number of and largest individual melanosomes, blue-eyed choroidal melanocytes the least number of and smallest individual melanosomes (123).

Melanocytes are the malignant cell type in CMs and UvMs (124,125). Studies have demonstrated MAP’s ability to invade human macrophages (126), human enterocytes (127), human monocyte-derived dendritic cells (128), and human small intestinal goblet cells (129,130). However, the ability of MAP to invade human melanocytes and cause their proliferation has not been tested.

Although intermittently reported in the literature (131-133), it is important to rule out CM that has metastasized to the eye when studying UvM, as the former is predominantly associated with sun exposure (134). The differentiation of primary and metastatic melanoma poses difficulties, especially when the diagnosis of UvM may occur up to 15 years following the original skin diagnosis (135,136). In many cases, patients may be asymptomatic, suggesting an under ascertainment of CM that has spread to the eyes (137). On the other hand, mutations in the CDKN2A gene may represent a common genetic predisposition to both CM and UvM (138).

Possible animal models, the implications to humans, and the potential for therapy

Canine melanomas including UvM have been proposed as models of human melanomas (139). The proposed association between MAP and UvM suggests that canine UvMs may be good models for human UvM because canine UvMs also may be caused by MAP. Dogs manifest near-field exposure by putting their noses and faces into MAP contaminated soil, with MAP organisms theoretically penetrating their facial skin. This is analogous to outdoor “athletes and sportsmen” (87) who place their faces into MAP contaminated soil, and dairy farmers exposed to aerosolized MAP contaminated feces spraying their face. The same is true for welders having aerosolized MAP contaminated metalworking fluid reaching their faces.

The proposed association implies that evidence of MAP infection may be present in human UvM lesions and patients. Researchers have developed methods of detecting MAP in human tissue (140), blood (141), and feces (142,143). These identification methods can be applied to human UvM patients. A similar methodology could also be developed to test for MAP in dogs with UvMs.

MAP-associated Crohn’s disease can be treated with anti-MAP antibiotics (144-149). The triple antibiotic drug formulation, known as RHB-104, has been observed to have important bactericidal action against MAP in the treatment of Crohn’s disease (150). However, the therapeutic effect may not be solely attributable to a decrease in MAP viability, as this antibiotic therapy also reverses pro-inflammatory responses in lipopolysaccharide (LPS)-induced macrophages.

Bacterial inflammation and UvM

A key mechanism of bacterial infection as a cause of cancer is the induction of inflammation (151). Regions of persistent inflammation instigate regenerative cell division with an increased occurrence of point mutations, deletions, and/or translocations (152). This ‘disordered cell differentiation’ in the form of inflammation in turn prompts ‘a cycle of cell damage, repair, and compensatory proliferation,’ believed to underlie cancer development (152-154). The microenvironment of UvM in essence is an inflammatory phenotype, characterized by various lymphocytes, macrophages, heightened HLA class I/II expression, and the presence of Tregs, which may explain the lack of an efficient antitumor immune response (155). Additionally, the increased cellular production of macrophage-attraction molecules in UvM leads to an expanded population of myeloid immature cells that suppress immune responses and facilitate the development of new blood vessels needed to nourish tumor growth (156). MAP possesses these bacterial properties and has been proposed to cause the angiogenesis and lymphangiogenesis of Crohn’s disease (157).

MAP also is associated with small-bowel inflammation among cattle, with a trophic affinity for the mucosa of the distal small intestine (158,159). Indeed, there is a striking pathognomic similarity between human Crohn’s disease and paucibacillary Johne’s disease of dairy cattle (and related ruminants), with both regarded as inflammatory paratuberculosis attributable to MAP infection (22,160). While more than 90% of dairy herds in US farms have infected animals, MAP often remains undetected owing to the low sensitivity of diagnostic testing, especially in the case of early-stage disease (161). Farm animals such as dairy cows, sheep, and goats may serve as an unwitting reservoir for frequent and persistent MAP infections. In many cases, infected animals do not manifest clinical symptoms for years, yet shed MAP in their feces (162).

The immediacy of humans with environmental MAP exposure, whether on a farm, in contact with contaminated soil, organic fertilizers, and/or agricultural runoff of fecal material, poses a risk for inflammatory-related cancers such as UvM. Exposure is further exacerbated owing to the spore-like resistance of MAP to disinfectants, chlorination (used to treat municipal water supplies), and pasteurization (159). While the organism has been detected in cow mammary glands, dairy products, and human breast milk, the levels for the most part are minute and relatively insignificant compared with direct fecal sources (which we again posit to primarily underlie UvM risk) (163). Overall, 80–90% of cancers are estimated to be caused by exogenous environmental factors including bacteria, with certain types of cancer more or less susceptible to specific exposures (164).

In addition to producing toxins that induce inflammation and disrupt normal cell growth, bacteria may play a role in directly damaging DNA, mimicking other known carcinogens and tumor promoters (165). Bacteria and similar microbes may act in a “hit-and-run” fashion with the initial cellular transformation occurring years prior to the presentation of cancer (166). Presumably by the time that the cancer first appears, the infection has long been cleared, making it difficult to establish a causal relationship.

Eye lysozyme levels and routes of infection have been explored as another mechanism of relevance to MAP. At the site of infection, lysozyme hydrolyses glycosidic bonds and degrades peptidoglycans in bacterial cell walls. Based on radial immuno-diffusion, increases in the level of lysozyme in inflammatory conditions such as sarcoidosis, latent tuberculosis, and syphilis have been observed in patients with ocular involvement (164). Comparable aspects could underlie the putative association of MAP and UvM.

Limitations

The association of MAP with UvM has not previously been proposed. There are, therefore, no studies documenting the presence of MAP organisms in UvM lesions. The studies mentioned in this perspective were observational in nature. As such, they are prone to various sources of epidemiologic bias (e.g., poor recall, residual confounding, collider effects, or the lack of adjustment for key outcome-related variables). Many of the studies were poorly powered to detect meaningful statistical differences or were inappropriately analyzed with respect to post hoc subsets of the data. Inconsistencies in the literature also may be explained by selection bias, misclassification error, and/or reverse causality.

The association between MAP exposure and UvM, while suggestive, is uncertain. Alternative and equally plausible explanations may underlie the association. For example, the article citing a link between UvM and the leather industry also mentions dry cleaning and glass manufacturing as possible occupations connected with this cancer (105). In the case of welder exposure to bacteria in water, a just as likely risk factor is intense light. Working outdoors and exposure to UV radiation likewise may explain risk attributable to farming and outside athletic activities. However, it is important to note again that sun exposure, in contrast to CM, is an unproven risk factor for UvMs presenting in the posterior region of the eye (9,167). Chemical fertilizers, ammonium nitrate, and various military exposures are other plausible agents that may underlie risk and should be considered when interpreting findings (140-142). The reader is reminded that association does not prove causation.

While examples exist in the noninfectious disease epidemiologic literature of well-recognized clusters, discovery in other cases is usually attributable to chance. The artifactual construction of borders in time and space (104) and multiplicity concerns likely underlie the increased incidence of UvM in reported clusters (94). Clusters of UvM also may be attributable to familial cases BAP1 tumor predisposition syndrome (168-170). However, in comparison with somatic mutations, germline BAP1 mutations in the 3p21 chromosomal region occur infrequently in UvMs (171-173). Barring direct evidence of exposure within multiple clusters, one is advised to carefully interpret the reliability of evidence from MAP-UvM clusters.

Although UV radiation is the most likely cause of iris tumors located in the anterior region of the eye, this does not preclude MAP as a risk factor. However, if this bacteria is involved in the development of iris cancer, one would expect a relatively higher frequency than for posteriorly located UvMs, given the closer proximity of the former to surface of the eye (implying more direct exposure to the microbe). However, iris cancers only account for 3% of UvMs (174). In general, a spatial predilection for cancer is poorly understood, with tissue heterogeneity, genetics, sex, and race being possible underlying explanatory factors (175-178). A temporal causal dominance of UV radiation over MAP exposure also might explain the etiology of iris cancer, although supportive proof for this theory is not evident in the literature.

The intermixing eyelid, orbital, and intraocular cancers in studies of UvM is another potential limitation. While primary intraocular cancers in adult patients are predominately melanomas, eyelid and orbital malignancies may include lymphomas, keratinocyte carcinomas, and other histologic subtypes (179).

Conclusions

To date, there is a paucity of data to support a cause-and-effect basis for MAP in the etiology of non-solar UvMs located in the posterior (dark) region of the eye. Neither animal nor human studies provide sufficient proof, vis-à-vis direct exposure, for such an association. MAP infection has never been observed in the posterior region of the eye nor ‘conclusively’ proven to cause cancer in any organ system. Furthermore, the literature is largely void of evidence that MAP can persist in this immune privileged site and subsequently induce malignant mutations in effector cell types (i.e., melanocytes of the eye).

Oncologic inflammatory responses evoked by MAP likely are co-incidental versus inductive. Equating immune reactivity during tumorigenesis with chronic immune dysregulation remains dubious—with the latter being pathognomonic of the mucosal instability and uncontrolled immunological stasis in IBD. Unlike CM, UvM remain relatively resistant to immune checkpoint blockade drugs (3). A reverse causality explanation also cannot be ruled out, wherein UvM might induce inflammation antecedent to infection.

Doubts persist and a precautionary approach to MAP exposure continues to be a prudent strategy in the prevention of UvM. Conceivably, factors associated with UvM could interact in a multifactorial and synergistic fashion with MAP, to evoke or reinforce a carcinogenic effect. Genetics and metabolomics may play a contributory role, with UvMs manifesting driver mutations in GNAQ and GNA11, rather than BRAF mutations (146,180). Additionally, miR-155 (an endogenously expressed, noncoding RNA) is believed to function as a tumor promotor in UvM, potentially increasing cell proliferation and tumor invasion autonomous of solar exposure (181).

However, with the exception of tumors restricted to the iris (which account for only ~3% of cases) and those driven by germline MBD4 mutations, most UvMs are sporadic and have a low mutational burden (4,174). A unified UV-related pathogenetic basis for UvMs, comparable to CM, has yet to be elucidated for this cancer (182,183). Interestingly, ciliochoroidal UvMs are predominately associated with light-colored eyes and typically manifest A>T mutations, characteristic of a pigment dependent etiology (2).

Posteriorly located UvMs of the eye may be characteristic of non-sun exposed, primary gastric melanomas (184). Melanomas also are known to occur on the soles of feet, subungual areas, and various mucous membranes. These sites manifest divergent mutation patterns and other features that are independent of, or less susceptible, to solar radiation (185,186). Nonetheless, it remains difficult to believe that a bacterial infection invading from the outside environment would be able to affect the choroid, cause an inflammatory response, and be involved in the development of UvM without histologic evidence of granulomatous inflammation or mycobacteria. Additional study is needed to better delineate this possibility, in light of the extensive vascular supply of the choroid.

The association of MAP with non-solar UvMs remains an unanswered question. In this paper, we aimed to provide a thought-provoking synthesis of the literature, with the intent of generating future research ideas and questions. New directions and the development of novel approaches to this topic are welcome. This will aid the understanding of neoplastic disease etiology and further elucidate the role of bacterial infections on human health and life. However, until new proof is forthcoming, there is a paucity of methodologically rigorous evidence to support either a direct or indirect causal link between MAP exposure and UvM, as well as any other infectious agent.

Acknowledgments

ESP gratefully acknowledges the assistance of Dr. Beth Hill at the Providence Sacred Heart Medical Center and Children’s Hospital’s Health Sciences Library in Spokane, Washington, U.S.A. as well as the other libraries that participated in the FreeShare Library Group within the DOCLINE National Network of Libraries of Medicine.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2540/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2540/coif). YMC is a non-stock holding employee of Signify Health, a private sector healthcare corporation with a mission of building trusted relationships to make people healthier. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Disclaimer: The views and opinions expressed in this article are those of the authors and do not necessarily reflect those of their respective institutions or the United States Federal Government.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Eye Cancer Causes, Risk Factors, and Prevention. American Cancer Society. Available online: www.cancer.org/aboutus/policies/content-usage.html (Accessed Nov 1, 2022).
2. de Lange MJ, Razzaq L, Versluis M, et al. Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism. PLoS One 2015;10:e0138002. [Crossref] [PubMed]
3. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers 2020;6:24. [Crossref] [PubMed]
4. Johansson PA, Brooks K, Newell F, et al. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. Nat Commun 2020;11:2408. [Crossref] [PubMed]
5. Amaro A, Gangemi R, Piaggio F, et al. The biology of uveal melanoma. Cancer Metastasis Rev 2017;36:109-40. [Crossref] [PubMed]
6. Saftlas AF, Blair A, Cantor KP, et al. Cancer and other causes of death among Wisconsin farmers. Am J Ind Med 1987;11:119-29. [Crossref] [PubMed]
7. Gallagher RP. Ocular melanoma in farmers. Am J Ind Med 1988;13:523-5. [Crossref] [PubMed]
8. Blair A, Dosemeci M, Heineman EF. Cancer and other causes of death among male and female farmers from twenty-three states. Am J Ind Med 1993;23:729-42. [Crossref] [PubMed]
9. Vajdic CM, Kricker A, Giblin M, et al. Sun exposure predicts risk of ocular melanoma in Australia. Int J Cancer 2002;101:175-82. [Crossref] [PubMed]
10. Ajani UA, Seddon JM, Hsieh CC, et al. Occupation and risk of uveal melanoma. An exploratory study. Cancer 1992;70:2891-900. [Crossref] [PubMed]
11. Keller JE, Howe HL. Case-control studies of cancer in Illinois farmers using data from the Illinois State Cancer Registry and the U.S. Census of Agriculture. Eur J Cancer 1994;30A:469-73. [Crossref] [PubMed]
12. Fleming LE, Bean JA, Rudolph M, et al. Mortality in a cohort of licensed pesticide applicators in Florida. Occup Environ Med 1999;56:14-21. [Crossref] [PubMed]
13. Efird JT, Davies SW, O'Neal WT, et al. Animal viruses, bacteria, and cancer: a brief commentary. Front Public Health 2014;2:14. [Crossref] [PubMed]
14. Zur Hausen H. The search for infectious causes of human cancers: where and why. Virology 2009;392:1-10. [Crossref] [PubMed]
15. Pearce N, Reif JS. Epidemiologic studies of cancer in agricultural workers. Am J Ind Med 1990;18:133-48. [Crossref] [PubMed]
16. Clarke CJ. The pathology and pathogenesis of paratuberculosis in ruminants and other species. J Comp Pathol 1997;116:217-61. [Crossref] [PubMed]
17. Tiwari A, VanLeeuwen JA, McKenna SL, et al. Johne's disease in Canada Part I: clinical symptoms, pathophysiology, diagnosis, and prevalence in dairy herds. Can Vet J 2006;47:874-82. [PubMed]
18. McKenna SL, Keefe GP, Tiwari A, et al. Johne's disease in Canada part II: disease impacts, risk factors, and control programs for dairy producers. Can Vet J 2006;47:1089-99. [PubMed]
19. Garvey M. Mycobacterium Avium Paratuberculosis: A Disease Burden on the Dairy Industry. Animals (Basel) 2020.
20. Chiodini RJ. Crohn's disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev 1989;2:90-117. [Crossref] [PubMed]
21. Hermon-Taylor J, Bull TJ, Sheridan JM, et al. Causation of Crohn's disease by Mycobacterium avium subspecies paratuberculosis. Can J Gastroenterol 2000;14:521-39. [Crossref] [PubMed]
22. Kuenstner JT, Naser S, Chamberlin W, et al. The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017. Front Public Health 2017;5:208. [Crossref] [PubMed]
23. Agrawal G, Aitken J, Hamblin H, et al. Putting Crohn's on the MAP: Five Common Questions on the Contribution of Mycobacterium avium subspecies paratuberculosis to the Pathophysiology of Crohn's Disease. Dig Dis Sci 2021;66:348-58. [Crossref] [PubMed]
24. Dow CT. Hermon-Taylor: M. paratuberculosis and Crohn's Disease-The Book of Revelation According to John. Pathogens 2021; [Crossref] [PubMed]
25. Hruska K, Sechi LA. Long History of Queries about Bovine Paratuberculosis as a Risk Factor for Human Health. Pathogens 2021; [Crossref] [PubMed]
26. Garvey M. Mycobacterium avium subspecies paratuberculosis: A possible causative agent in human morbidity and risk to public health safety. Open Vet J 2018;8:172-81. [Crossref] [PubMed]
27. Sechi LA, Dow CT. Mycobacterium avium ss. paratuberculosis Zoonosis - The Hundred Year War - Beyond Crohn's Disease. Front Immunol 2015;6:96. [Crossref] [PubMed]
28. Pierce ES. How did Lou Gehrig get Lou Gehrig's disease? Mycobacterium avium subspecies paratuberculosis in manure, soil, dirt, dust and grass and amyotrophic lateral sclerosis (motor neurone disease) clusters in football, rugby and soccer players. Med Hypotheses 2018;119:1-5. [Crossref] [PubMed]
29. Dow C. Parkinson’s - Just another Infectious Disease. J Neuroinfect Dis 2015;6:2.
30. Okuni JB, Hansen S, Eltom KH, et al. Paratuberculosis: A Potential Zoonosis and a Neglected Disease in Africa. Microorganisms 2020; [Crossref] [PubMed]
31. Pierce ES. Could Mycobacterium avium subspecies paratuberculosis cause Crohn's disease, ulcerative colitis...and colorectal cancer? Infectious Agents and Cancer 2018;13:1. [Crossref] [PubMed]
32. Pierce ES. Baseballs, tennis balls, livestock farm manure, the IDH1 mutation, endothelial cell proliferation and hypoxic pseudopalisading (granulomatous) necrosis: Mycobacterium avium subspecies paratuberculosis and the epidemiology, cellular metabolism and histology of diffuse gliomas, including glioblastoma. Open Vet J 2019;9:5-12. [Crossref] [PubMed]
33. Pierce ES. Mycobacterium avium subspecies paratuberculosis and goblet cells: are Barrett's esophagus and esophageal adenocarcinoma zoonotic infectious diseases? J Infectiol 2018;1.
34. Grant IR, Ball HJ, Rowe MT. Incidence of Mycobacterium paratuberculosis in bulk raw and commercially pasteurized cows' milk from approved dairy processing establishments in the United Kingdom. Appl Environ Microbiol 2002;68:2428-35. [Crossref] [PubMed]
35. Foddai AC, Grant IR. A novel one-day phage-based test for rapid detection and enumeration of viable Mycobacterium avium subsp. paratuberculosis in cows’ milk. Appl Microbiol Biotechnol 2020;104:9399-412. [PubMed]
36. Soltani M. Identification of Mycobacterium avium subspecies paratuberculosis in raw and pasteurized milk samples using culture, IS900 PCR and IS900 nested PCR methods. Food Hygiene 2021;11:23-35.
37. Donaghy JA, Johnston J, Rowe MT. Detection of Mycobacterium avium ssp. paratuberculosis in cheese, milk powder and milk using IS900 and f57-based qPCR assays. J Appl Microbiol 2011;110:479-89. [Crossref] [PubMed]
38. Monif GR. The Hruska postulate of Crohn's disease. Med Hypotheses 2015;85:878-81. [Crossref] [PubMed]
39. Botsaris G, Swift BM, Slana I, et al. Detection of viable Mycobacterium avium subspecies paratuberculosis in powdered infant formula by phage-PCR and confirmed by culture. Int J Food Microbiol 2016;216:91-4. [Crossref] [PubMed]
40. Durst P, Grooms D. Johne's disease-causing bacteria are around the farm. Michigan State University (MSU) Extension. 2011. Available online: http://www.canr.msu.edu/news/johnes_disease_causing_bacteria_are_around_the_farm (Accessed Nov 1, 2022).
41. The Center for Food Security & Public Health. Transmission Routes of Zoonotic Diseases of Livestock. Iowa State University. 2017. Available online: http://www.cfsph.iastate.edu/Zoonoses/assets/English/zoonotic_dz_transmission.pdf (Accessed November 1, 2020).
42. Animal and Plant Health Inspection Service. U.S. Department of Agriculture. 2020. Accessed Nov 1, 2022.
43. Pierce ES. Manure as the major source and aerosolization as the major route of infection of Mycobacterium avium subspecies paratuberculosis (MAP) from infected animals to humans: implications for disease etiologies and infection diagnosis and monitoring. A presentation for the 2017 Philadelphia MAP conference. 2017. Available online: http://vimeo.com/215736675/fd48f623cc (Accessed November 1, 2020).
44. Arizona Farm Bureau. The most interesting facts about Arizona dairies you'll ever read. Available online: http://www.azfb.org/Article/The-Most-Interesting-Facts-about-Arizona-Dairies-Youll-Ever-Read (Accessed November 1, 2020).
45. Lombard JE, Gardner IA, Jafarzadeh SR, et al. Herd-level prevalence of Mycobacterium avium subsp. paratuberculosis infection in United States dairy herds in 2007. Prev Vet Med 2013;108:234-8. [Crossref] [PubMed]
46. Lombard JE, Wagner BA, Smith RL, et al. Evaluation of environmental sampling and culture to determine Mycobacterium avium subspecies paratuberculosis distribution and herd infection status on US dairy operations. J Dairy Sci 2006;89:4163-71. [Crossref] [PubMed]
47. Pillars RB, Grooms DL, Woltanski JA, et al. Prevalence of Michigan dairy herds infected with Mycobacterium avium subspecies paratuberculosis as determined by environmental sampling. Prev Vet Med 2009;89:191-6. [Crossref] [PubMed]
48. Raizman EA, Wells SJ, Muñoz-Zanzi CA, et al. Estimated within-herd prevalence (WHP) of Mycobacterium avium subsp. paratuberculosis in a sample of Minnesota dairy herds using bacterial culture of pooled fecal samples. Can J Vet Res 2011;75:112-6. [PubMed]
49. Pierce ES. Could a zoonosis cause some cases of anencephaly? Mycobacterium avium subspecies paratuberculosis inhaled from aerosolized dairy cow manure and the Washington State rural anencephaly cluster. In: J Rare Emerg Dis. 2018. Available online: http://www.boffinaccess.com/journal-emerging-rare-diseases/could-a-zoonosis-2-114/jer-2-114.pdf (Accessed November 1, 2020).
50. Collins M, Stabel J. Diseases of Dairy Animals Infectious Diseases: Johne’s Disease. Encyclopedia of Dairy Sciences 2011:174-18.
51. Fecteau ME, Hovingh E, Whitlock RH, et al. Persistence of Mycobacterium avium subsp. paratuberculosis in soil, crops, and ensiled feed following manure spreading on infected dairy farms. Can Vet J 2013;54:1083-5. [PubMed]
52. Slana I, Pribylova R, Kralova A, et al. Persistence of Mycobacterium avium subsp. paratuberculosis at a farm-scale biogas plant supplied with manure from paratuberculosis-affected dairy cattle. Appl Environ Microbiol 2011;77:3115-9. [Crossref] [PubMed]
53. Eisenberg SW, Nielen M, Santema W, et al. Detection of spatial and temporal spread of Mycobacterium avium subsp. paratuberculosis in the environment of a cattle farm through bio-aerosols. Vet Microbiol 2010;143:284-92. [Crossref] [PubMed]
54. Rhodes G, Henrys P, Thomson BC, et al. Mycobacterium avium subspecies paratuberculosis is widely distributed in British soils and waters: implications for animal and human health. Environ Microbiol 2013;15:2761-74. [PubMed]
55. Sousa T, Costa M, Sarmento P, et al. DNA-based detection of Mycobacterium avium subsp. paratuberculosis in domestic and municipal water from Porto (Portugal), an area of high IBD prevalence. AIMS Microbiol 2021;7:163-74. [Crossref] [PubMed]
56. Rhodes G, Richardson H, Hermon-Taylor J, et al. Mycobacterium avium Subspecies paratuberculosis: Human Exposure through Environmental and Domestic Aerosols. Pathogens 2014;3:577-95. [Crossref] [PubMed]
57. Hosseiniporgham S, Cubeddu T, Rocca S, et al. Identification of Mycobacterium avium subsp. paratuberculosis (MAP) in Sheep Milk, a Zoonotic Problem. Microorganisms 2020; [Crossref] [PubMed]
58. Eisenberg SW, Koets AP, Hoeboer J, et al. Presence of Mycobacterium avium subsp. paratuberculosis in environmental samples collected on commercial Dutch dairy farms. Appl Environ Microbiol 2010;76:6310-2. [Crossref] [PubMed]
59. Eisenberg S, Nielen M, Hoeboer J, et al. Mycobacterium avium subspecies paratuberculosis in bioaerosols after depopulation and cleaning of two cattle barns. Vet Rec 2011;168:587. [Crossref] [PubMed]
60. Eisenberg SW, Nielen M, Koets AP. Within-farm transmission of bovine paratuberculosis: recent developments. Vet Q 2012;32:31-5. [Crossref] [PubMed]
61. Ghazawi FM, Darwich R, Le M, et al. Uveal melanoma incidence trends in Canada: a national comprehensive population-based study. Br J Ophthalmol 2019;103:1872-6. [Crossref] [PubMed]
62. Province of British Columbia. Dairy Industry. 2021. Available online: http://www2.gov.bc.ca/gov/content/industry/agriculture-seafood/animals-and-crops/animal-production/dairy#:~:text=British%20Columbia%20ranks%20first%20in,and%20north%20Okanagan%2DShuswap%20area (Accessed November 1, 2022).
63. British Columbia Ministry of Agriculture. Farm Practices - Dairy. 2014. Available online: http://www2.gov.bc.ca/assets/gov/farming-natural-resources-and-industry/agriculture-and-seafood/agricultural-land-and-environment/strengthening-farming/farm-practices/870218-7_dairy.pdf (Accessed November 1, 2020).
64. Yu GP, Hu DN, McCormick SA. Latitude and incidence of ocular melanoma. Photochem Photobiol 2006;82:1621-6. [Crossref] [PubMed]
65. Orloff M, Brennan M, Sato S, et al. Unique Geospatial Accumulations of Uveal Melanoma. Am J Ophthalmol 2020;220:102-9. [Crossref] [PubMed]
66. North Carolina Department of Health and Human Services Division of Public Health. Ocular Melanoma Investigation in Mecklenburg County, North Carolina. 2015. Available online: http://epi.publichealth.nc.gov/oee/docs/OcularMelanomaInvestigationReport_June2015.pdf (Accessed November 1, 2020).
67. Charlotte-Mecklenburg Historic Landmarks Commission. Dairy Farming in Mecklenburg County. 2017. Available online: http://landmarkscommission.org/author/historic/ (Accessed November 1, 2020).
68. Weidner A. Impact of Nitrogen Loading from Dairy Cattle on the Susquehanna River Basin. University of Texas. 2013. Available online: http://www.caee.utexas.edu/prof/maidment/giswr2013/Reports/Weidner.pdf (Accessed November 1, 2020).
69. Pierce ES. Ulcerative colitis and Crohn's disease: is Mycobacterium avium subspecies paratuberculosis the common villain? Gut Pathog 2010;2:21. [Crossref] [PubMed]
70. Pickup RW, Rhodes G, Arnott S, et al. Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the River Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn's disease cases in the city of Cardiff. Appl Environ Microbiol 2005;71:2130-9. [Crossref] [PubMed]
71. Nunes GC, Ahlquist RE Jr. Increasing incidence of Crohn's disease. Am J Surg 1983;145:578-81. [Crossref] [PubMed]
72. Scantland L, Svinth CA, Taves MJ. A square look at Spokane County. 1952. Available online: http://rex.libraries.wsu.edu/esploro/outputs/report/A-square-look-at-Spokane-County/99900502261601842 (Accessed November 1, 2020).
73. Tinsley J. Then and Now. Dairy dreams: Brothers led innovation, growth in regional industry. The Spokesman-Review, 2012.
74. Kramer B. Study tracks reasons for high rate of illness near Northport. The Spokesman-Review, 2011.
75. VanEenwyk J. Approaches to community concerns: applied public health. Public Health 1997;111:405-10. [PubMed]
76. Fowler SA, Nestor M, Cole EB, et al. Tu1289 An unusual cluster of IBD in a town downstream from a potential environmental risk factor. Gastroenterology 2012;5:S794. [Crossref]
77. Kramer B. Researcher seeking clues behind clusters of disease in tiny town: high number of Northport residents have colitis or Crohn's disease. The Spokesman-Review, 2012.
78. Pierce ES. Free-ranging Rocky Mountain bighorn sheep and an outbreak of inflammatory bowel disease along the Clark Fork River in Plains, Montana. Virulence 2012;3:546-50. [Crossref] [PubMed]
79. Pierce ES, Borowitz SM, Naser SA. The Broad Street pump revisited: dairy farms and an ongoing outbreak of inflammatory bowel disease in Forest, Virginia. Gut Pathog 2011;3:20. [Crossref] [PubMed]
80. The Eyecare Group. The curious case of an eye cancer cluster 2020. Available online: http://www.eyecaregroupnc.com/the-curious-case-of-an-eye-cancer-cluster/ (Accessed November 1, 2020).
81. Falkinham JO 3rd, Iseman MD, de Haas P, et al. Mycobacterium avium in a shower linked to pulmonary disease. J Water Health 2008;6:209-13. [Crossref] [PubMed]
82. Falkinham JO 3rd. Ecology of nontuberculous mycobacteria--where do human infections come from? Semin Respir Crit Care Med 2013;34:95-102. [Crossref] [PubMed]
83. Aisenberg J, Janowitz HD. Cluster of inflammatory bowel disease in three close college friends? J Clin Gastroenterol 1993;17:18-20. [Crossref] [PubMed]
84. Moss BR. Dairy Industry in Alabama. Encyclopedia of Alabama. 2017. Available online: http://encyclopediaofalabama.org/article/h-1393 (Accessed November 1, 2020).
85. Harvey B. Lee County cattle farms more than nostalgia. Opelika-Auburn News. 2013. Available online: http://oanow.com/news/lee-county-cattle-farms-more-than-nostalgia/article_81a4847e-f220-5a83-9857-2892ff1c9b9d.html (Accessed November 1, 2020).
86. Auburn University - Student Affairs - University Housing. The Hill. 2021. Available online: http://universityhousing.auburn.edu/communities/the-hill/ (Accessed Nov 1, 2022).
87. Vågerö D, Swerdlow AJ, Beral V. Occupation and malignant melanoma: a study based on cancer registration data in England and Wales and in Sweden. Br J Ind Med 1990;47:317-24. [Crossref] [PubMed]
88. Pierce ES. Mycobacterium avium subspecies paratuberculosis as a soil bacteria and ALS clusters in outdoor sports players. Science Trends. 2019. Available online: http://sciencetrends.com/mycobacterium-avium-subspecies-paratuberculosis-as-a-soil-bacteria-and-als-clusters-in-outdoor-sports-players/ (Accessed November 1, 2020).
89. Guénel P, Laforest L, Cyr D, et al. Occupational risk factors, ultraviolet radiation, and ocular melanoma: a case-control study in France. Cancer Causes Control 2001;12:451-9. [Crossref] [PubMed]
90. Holly EA, Aston DA, Ahn DK, et al. Intraocular melanoma linked to occupations and chemical exposures. Epidemiology 1996;7:55-61. [Crossref] [PubMed]
91. Dixon AJ, Dixon BF. Ultraviolet radiation from welding and possible risk of skin and ocular malignancy. Med J Aust 2004;181:155-7. [Crossref] [PubMed]
92. Guha N, Loomis D, Guyton KZ, et al. Carcinogenicity of welding, molybdenum trioxide, and indium tin oxide. Lancet Oncol 2017;18:581-2. [Crossref] [PubMed]
93. Shah CP, Weis E, Lajous M, et al. Intermittent and chronic ultraviolet light exposure and uveal melanoma: a meta-analysis. Ophthalmology 2005;112:1599-607. [Crossref] [PubMed]
94. Schwartz LH, Ferrand R, Boelle PY, et al. Lack of correlation between the location of choroidal melanoma and ultraviolet-radiation dose distribution. Radiat Res 1997;147:451-6. [Crossref] [PubMed]
95. Gilbert Y, Veillette M, Duchaine C. Metalworking fluids biodiversity characterization. J Appl Microbiol 2010;108:437-49. [Crossref] [PubMed]
96. Respiratory illness in workers exposed to metalworking fluid contaminated with nontuberculous mycobacteria--Ohio 2001. MMWR 2002;349-52. [PubMed]
97. Veillette M, Thorne PS, Gordon T, et al. Six month tracking of microbial growth in a metalworking fluid after system cleaning and recharging. Ann Occup Hyg 2004;48:541-6. [PubMed]
98. Thorne PS, Adamcakova-Dodd A, Kelly KM, et al. Metalworking fluid with mycobacteria and endotoxin induces hypersensitivity pneumonitis in mice. Am J Respir Crit Care Med 2006;173:759-68. [Crossref] [PubMed]
99. Burge PS. Hypersensitivity Pneumonitis Due to Metalworking Fluid Aerosols. Curr Allergy Asthma Rep 2016;16:59. [Crossref] [PubMed]
100. Blanchard DC, Syzdek L. Mechanism for the water-to-air transfer and concentration of bacteria. Science 1970;170:626-8. [Crossref] [PubMed]
101. Blanchard DC, Syzdek LD. Water-to-Air Transfer and Enrichment of Bacteria in Drops from Bursting Bubbles. Appl Environ Microbiol 1982;43:1001-5. [Crossref] [PubMed]
102. Falkinham JO 3rd. Mycobacterial aerosols and respiratory disease. Emerg Infect Dis 2003;9:763-7. [Crossref] [PubMed]
103. Ge YR, Tian N, Lu Y, et al. Occupational cooking and risk of uveal melanoma: a meta-analysis. Asian Pac J Cancer Prev 2012;13:4927-30. [Crossref] [PubMed]
104. Nayman T, Bostan C, Logan P, et al. Uveal Melanoma Risk Factors: A Systematic Review of Meta-Analyses. Curr Eye Res 2017;42:1085-93. [Crossref] [PubMed]
105. Behrens T, Lynge E, Cree I, et al. Occupational exposure to endocrine-disrupting chemicals and the risk of uveal melanoma. Scand J Work Environ Health 2012;38:476-83. [Crossref] [PubMed]
106. Louria DB, Coumbis RJ, Lavenhar MA, et al. An apparent small cluster of choroidal melanoma cases. Am J Ophthalmol 1982;94:172-80. [Crossref] [PubMed]
107. Savi R, Ricchi M, Cammi G, et al. Survey on the presence of Mycobacterium avium subsp. paratuberculosis in ground beef from an industrial meat plant. Vet Microbiol 2015;177:403-8. [Crossref] [PubMed]
108. Alonso-Hearn M, Molina E, Geijo M, et al. Isolation of Mycobacterium avium subsp. paratuberculosis from muscle tissue of naturally infected cattle. Foodborne Pathog Dis 2009;6:513-8. [Crossref] [PubMed]
109. Bower KL, Begg DJ, Whittington RJ. Culture of Mycobacterium avium subspecies paratuberculosis (MAP) from blood and extra-intestinal tissues in experimentally infected sheep. Vet Microbiol 2011;147:127-32. [Crossref] [PubMed]
110. Vidyarthi S, Vaddella V, Cao N, et al. Pathogens in animal carcasses and the efficacy of rendering for pathogen inactivation in rendered products: a review. Future Foods 2020:100010.
111. Franke-Whittle IH, Insam H. Treatment alternatives of slaughterhouse wastes, and their effect on the inactivation of different pathogens: a review. Crit Rev Microbiol 2013;39:139-51. [Crossref] [PubMed]
112. Kubala A, Perehinec TM, Evans C, et al. Development of a Method to Detect Mycobacterium paratuberculosis in the Blood of Farmed Deer Using Actiphage(R) Rapid. Front Vet Sci 2021;8:665697. [Crossref] [PubMed]
113. Greenstein RJ, Su L, Grant IR, et al. Comparison of a mycobacterial phage assay to detect viable Mycobacterium avium subspecies paratuberculosis with standard diagnostic modalities in cattle with naturally infected Johne disease. Gut Pathog 2021;13:30. [Crossref] [PubMed]
114. Pribylova R, Slana I, Kralik P, et al. Correlation of Mycobacterium avium subsp. paratuberculosis counts in gastrointestinal tract, muscles of the diaphragm and the masseter of dairy cattle and potential risk for consumers. Int J Food Microbiol 2011;151:314-8. [Crossref] [PubMed]
115. Hu DN, Yu GP, McCormick SA, et al. Population-based incidence of uveal melanoma in various races and ethnic groups. Am J Ophthalmol 2005;140:612-7. [Crossref] [PubMed]
116. Mackintosh JA. The antimicrobial properties of melanocytes, melanosomes and melanin and the evolution of black skin. J Theor Biol 2001;211:101-13. [Crossref] [PubMed]
117. Hurbain I, Romao M, Sextius P, et al. Melanosome Distribution in Keratinocytes in Different Skin Types: Melanosome Clusters Are Not Degradative Organelles. J Invest Dermatol 2018;138:647-56. [Crossref] [PubMed]
118. MASSARO D. KATZ S, SACHS M. CHOROIDAL TUBERCLES. A CLUE TO HEMATOGENOUS TUBERCULOSIS. Ann Intern Med 1964;60:231-41. [Crossref] [PubMed]
119. Prout S, Benatar SR. Disseminated tuberculosis. A study of 62 cases. S Afr Med J 1980;58:835-42. [PubMed]
120. Furashova O, Engelmann K, Joussen AM, et al. Unusual initial manifestation of choroidal melanoma in a 46-year-old adult with rapid growth over 9 months. Am J Ophthalmol Case Rep 2022;26:101518. [Crossref] [PubMed]
121. Girgis DO, Karp CL, Miller D. Ocular infections caused by non-tuberculous mycobacteria: update on epidemiology and management. Clin Exp Ophthalmol 2012;40:467-75. [Crossref] [PubMed]
122. Weiter JJ, Delori FC, Wing GL, et al. Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci 1986;27:145-52. [PubMed]
123. Robertson S. Genetics of Eye Color. 2019. Available online: http://www.news-medical.net/health/Genetics-of-Eye-Color.aspx (Accessed November 1, 2020).
124. VIB (the Flanders Institute for Biotechnology). Scientists pinpoint surprising origin of melanoma. Science Daily. 2017. Available online: www.sciencedaily.com/releases/2017/10/171012143402.htm (Accessed November 1, 2020).
125. Köhler C, Nittner D, Rambow F, et al. Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes. Cell Stem Cell 2017;21:679-693.e6. [Crossref] [PubMed]
126. Motiwala AS, Janagama HK, Paustian ML, et al. Comparative transcriptional analysis of human macrophages exposed to animal and human isolates of Mycobacterium avium subspecies paratuberculosis with diverse genotypes. Infect Immun 2006;74:6046-56. [Crossref] [PubMed]
127. Bach H, Ko HH, Raizman EA, et al. Immunogenicity of Mycobacterium avium subsp. paratuberculosis proteins in Crohn's disease patients. Scand J Gastroenterol 2011;46:30-9. [Crossref] [PubMed]
128. Rees WD, Lorenzo-Leal AC, Steiner TS, et al. Mycobacterium avium Subspecies paratuberculosis Infects and Replicates within Human Monocyte-Derived Dendritic Cells. Microorganisms 2020; [Crossref] [PubMed]
129. Bannantine JP, Bermudez LE. No holes barred: invasion of the intestinal mucosa by Mycobacterium avium subsp. paratuberculosis. Infect Immun 2013;81:3960-5. [Crossref] [PubMed]
130. Golan L, Livneh-Kol A, Gonen E, et al. Mycobacterium avium paratuberculosis invades human small-intestinal goblet cells and elicits inflammation. J Infect Dis 2009;199:350-4. [Crossref] [PubMed]
131. Toyoda H, Fukui K, Okabe H, et al. A case of malignant melanoma with orbital metastasis which caused the first symptoms. No To Shinkei 1992;44:929-33. [PubMed]
132. Ullah T, Gurwood AS, Myers MD. Ocular metastasis of cutaneous malignant melanoma. Optometry 2009;80:572-8. [Crossref] [PubMed]
133. Fishman ML, Tomaszewski MM, Kuabara T. Malignant melanoma of the skin metastatic to the eye. Frequency in autopsy series. Arch Ophthalmol 1976;94:1309-11. [Crossref] [PubMed]
134. Conforti C, Zalaudek I. Epidemiology and Risk Factors of Melanoma: A Review. Dermatol Pract Concept 2021;11:e2021161S. [Crossref] [PubMed]
135. Drummond SR, Fenton S, Pantilidis EP, et al. A case of cutaneous melanoma metastatic to the right eye and left orbit. Eye (Lond) 2003;17:420-2. [Crossref] [PubMed]
136. Hirst LW, Reich J, Galbraith JE. Primary cutaneous malignant melanoma metastatic to the iris. Br J Ophthalmol 1979;63:165-8. [Crossref] [PubMed]
137. Bacin F, Rozan R, Chollet P. Unilateral iris metastasis of cutaneous malignant melanoma. J Fr Ophtalmol 1992;15:611-3. [PubMed]
138. Houlston RS, Damato BE. Genetic predisposition to ocular melanoma. Eye (Lond) 1999;13:43-6. [Crossref] [PubMed]
139. Prouteau A, André C. Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison. Genes (Basel) 2019.
140. Aitken JM, Phan K, Bodman SE, et al. A Mycobacterium species for Crohn's disease? Pathology 2021;53:818-23. [Crossref] [PubMed]
141. Kuenstner JT, Potula R, Bull TJ, et al. Presence of Infection by Mycobacterium avium subsp. paratuberculosis in the Blood of Patients with Crohn's Disease and Control Subjects Shown by Multiple Laboratory Culture and Antibody Methods. Microorganisms 2020; [Crossref] [PubMed]
142. Tuci A, Tonon F, Castellani L, et al. Fecal detection of Mycobacterium avium paratuberculosis using the IS900 DNA sequence in Crohn's disease and ulcerative colitis patients and healthy subjects. Dig Dis Sci 2011;56:2957-62. [Crossref] [PubMed]
143. Singh SV, Kuenstner JT, Davis WC, et al. Concurrent Resolution of Chronic Diarrhea Likely Due to Crohn's Disease and Infection with Mycobacterium avium paratuberculosis. Front Med (Lausanne) 2016;3:49. [Crossref] [PubMed]
144. Honap S, Johnston E, Agrawal G, et al. Anti-Mycobacterium paratuberculosis (MAP) therapy for Crohn’s disease: An overview and update. Frontline Gastroenterol 2020;12:397-403. [Crossref] [PubMed]
145. Agrawal G, Clancy A, Sharma R, et al. Targeted Combination Antibiotic Therapy Induces Remission in Treatment-Naive Crohn's Disease: A Case Series. Microorganisms 2020;8. [Crossref] [PubMed]
146. Savarino E, Bertani L, Ceccarelli L, et al. Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for Mycobacterium avium subspecies paratuberculosis in Crohn's disease: pharmacological and clinical implications. Expert Opin Biol Ther 2019;19:79-88. [Crossref] [PubMed]
147. Agrawal G, Hamblin H, Clancy A, et al. Anti-Mycobacterial Antibiotic Therapy Induces Remission in Active Paediatric Crohn's Disease. Microorganisms 2020; [Crossref] [PubMed]
148. Collyer R, Clancy A, Agrawal G, et al. Crohn's strictures open with anti-mycobacterial antibiotic therapy: A retrospective review. World J Gastrointest Endosc 2020;12:542-54. [Crossref] [PubMed]
149. Agrawal G, Clancy A, Huynh R, et al. Profound remission in Crohn's disease requiring no further treatment for 3-23 years: a case series. Gut Pathog 2020;12:16. [Crossref] [PubMed]
150. Qasem A, Elkamel E, Naser SA. Anti-MAP Triple Therapy Supports Immunomodulatory Therapeutic Response in Crohn's Disease through Downregulation of NF-κB Activation in the Absence of MAP Detection. Biomedicines 2020; [Crossref] [PubMed]
151. Parsonnet J. Bacterial infection as a cause of cancer. Environ Health Perspect 1995;103:263-8. [PubMed]
152. Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clin Microbiol Rev 2010;23:837-57. [Crossref] [PubMed]
153. Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 2013;13:800-12. [Crossref] [PubMed]
154. Xavier JB, Young VB, Skufca J, et al. The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View. Trends Cancer 2020;6:192-204. [Crossref] [PubMed]
155. Bronkhorst IH, Jager MJ. Inflammation in uveal melanoma. Eye (Lond) 2013;27:217-23. [Crossref] [PubMed]
156. Gamblin T, Alexander H, Edwards R, et al. Concepts of regional therapies for advanced malignancy. Ann Surg Oncol 2012;19:1371-2. [Crossref] [PubMed]
157. Pierce ES. Where are all the Mycobacterium avium subspecies paratuberculosis in patients with Crohn's disease? PLoS Pathog 2009;5:e1000234. [Crossref] [PubMed]
158. Shoenfeld Y, Agmon-Levin N, Rose NR. Infection and Autoimmunity. Academic Press, 2015.
159. McNees AL, Markesich D, Zayyani NR, et al. Mycobacterium paratuberculosis as a cause of Crohn's disease. Expert Rev Gastroenterol Hepatol 2015;9:1523-34. [Crossref] [PubMed]
160. Dow CT, Sechi LA. Cows Get Crohn's Disease and They're Giving Us Diabetes. Microorganisms 2019; [Crossref] [PubMed]
161. Biemans F, Tratalos J, Arnoux S, et al. Modelling transmission of Mycobacterium avium subspecies paratuberculosis between Irish dairy cattle herds. Vet Res 2022;53:45. [Crossref] [PubMed]
162. Dow CT, Alvarez BL. Mycobacterium paratuberculosis zoonosis is a One Health emergency. Ecohealth 2022;19:164-74. [Crossref] [PubMed]
163. Naser SA, Schwartz D, Shafran I. Isolation of Mycobacterium avium subsp paratuberculosis from breast milk of Crohn's disease patients. Am J Gastroenterol 2000;95:1094-5. [Crossref] [PubMed]
164. Lewandowska AM, Rudzki M, Rudzki S, et al. Environmental risk factors for cancer - review paper. Ann Agric Environ Med 2019;26:1-7. [Crossref] [PubMed]
165. Lax AJ. Opinion: Bacterial toxins and cancer--a case to answer? Nat Rev Microbiol 2005;3:343-9. [Crossref] [PubMed]
166. Lax AJ, Thomas W. How bacteria could cause cancer: one step at a time. Trends Microbiol 2002;10:293-9. [Crossref] [PubMed]
167. Eye Cancer (Ocular Melanoma). American Cancer Society. 2022. Accessed Nov 1, 2022.
168. Foretová L, Navrátilová M, Svoboda M, et al. BAP1 Syndrome - Predisposition to Malignant Mesothelioma, Skin and Uveal Melanoma, Renal and Other Cancers. Klin Onkol 2019;32:118-22. [Crossref] [PubMed]
169. Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology 2013;45:116-26. [Crossref] [PubMed]
170. Walpole S, Pritchard AL, Cebulla CM, et al. Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. J Natl Cancer Inst 2018;110:1328-41. [Crossref] [PubMed]
171. Gupta MP, Lane AM, DeAngelis MM, et al. Clinical Characteristics of Uveal Melanoma in Patients With Germline BAP1 Mutations. JAMA Ophthalmol 2015;133:881-7. [Crossref] [PubMed]
172. Chen Y, Wen Y, Song J, et al. The correlation between family food handling behaviors and foodborne acute gastroenteritis: a community-oriented, population-based survey in Anhui, China. BMC Public Health 2018;18:1290. [Crossref] [PubMed]
173. See TR, Stålhammar G, Phillips S, et al. BAP1 Immunoreactivity Correlates with Gene Expression Class in Uveal Melanoma. Ocul Oncol Pathol 2020;6:129-37. [Crossref] [PubMed]
174. Scholz SL, Möller I, Reis H, et al. Frequent GNAQ, GNA11, and EIF1AX Mutations in Iris Melanoma. Invest Ophthalmol Vis Sci 2017;58:3464-70. [Crossref] [PubMed]
175. Xiong S, Liang H, Liang P, et al. The Predilection Site and Risk Factor of Second Primary Cancer: A Pan-Cancer Analysis Based on the SEER Database. Social Science Research Network 2021.
176. Wang WL, Chang IW, Chen CC, et al. The Spatial Predilection for Early Esophageal Squamous Cell Neoplasia: A "Hot Zone" for Endoscopic Screening and Surveillance. Medicine (Baltimore) 2016;95:e3311. [Crossref] [PubMed]
177. Byers TE, Vena JE, Rzepka TF. Predilection of lung cancer for the upper lobes: an epidemiologic inquiry. J Natl Cancer Inst 1984;72:1271-5. [PubMed]
178. Magi L, Rinzivillo M, Panzuto F. Tumor Heterogenity in Gastro-Entero-Pancreatic Neuroendocrine Neoplasia. Endocrines 2021;2:28-36. [Crossref]
179. Types of Eye Cancer. Ocular melanoma foundation. Available online: http://www.ocularmelanoma.org/types-of-eye-cancer.htm (Accessed Nov 1, 2022).
180. Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009;457:599-602. [Crossref] [PubMed]
181. Peng J, Liu H, Liu C. MiR-155 Promotes Uveal Melanoma Cell Proliferation and Invasion by Regulating NDFIP1 Expression. Technol Cancer Res Treat 2017;16:1160-7. [Crossref] [PubMed]
182. Singh M, Durairaj P, Yeung J. Uveal Melanoma: A Review of the Literature. Oncol Ther 2018;6:87-104. [Crossref] [PubMed]
183. Arisi M, Zane C, Caravello S, et al. Sun Exposure and Melanoma, Certainties and Weaknesses of the Present Knowledge. Front Med (Lausanne) 2018;5:235. [Crossref] [PubMed]
184. Mellotte GS, Sabu D, O'Reilly M, et al. The challenge of primary gastric melanoma: a systematic review. Melanoma Manag 2020;7:MMT51. [Crossref] [PubMed]
185. Rebecca VW, Sondak VK, Smalley KS. A brief history of melanoma: from mummies to mutations. Melanoma Res 2012;22:114-22. [Crossref] [PubMed]
186. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-47. [Crossref] [PubMed]