To:
`
`Subject:
`
`Sent:
`Sent As:
`
`KIRA KHANH MCCARTHY(cxltrademarks@wolfgreenfield.com)
`U.S. Trademark Application Serial No. 88960633
`- NF-LIGHT
`Q00522001301
`January 18, 2022 03:24:33 PM EST
`tmng.notices@uspto.gov
`
`-
`
`Attachments
`
`United States Patent and Trademark Office (USPTO)
`Office Action (Official Letter) About Applicant’s Trademark Application
`
`
`
`U.S. Application Serial No.  88960633
`
`Mark:   NF-LIGHT
`
`Correspondence Address:  
`KIRA KHANH MCCARTHY
`WOLF GREENFIELD & SACKS PC
`600 ATLANTIC AVENUE
`BOSTON MA 02210 UNITED STATES
`
`Applicant:   Uman Diagnostics AB
`
`Reference/Docket No.  Q00522001301
`
`Correspondence Email Address:   cxltrademarks@wolfgreenfield.com
`
`
`
`
`
`
`REQUEST FOR RECONSIDERATION
`AFTER FINAL ACTION
`DENIED
`
`Issue date:   January 18, 2022
`
`STATUS OF THE APPLICATION
`
`The referenced application is currently the subject of an appeal with the Trademark Trial and Appeal
`Board (Board). However, the Board has suspended action on the appeal and has remanded the
`application to the trademark examining attorney to consider additional evidence pertaining to the
`refusal. See 37 C.F.R. §2.142(d), (f); TMEP §1209.04.
`
`This Office Action responds to applicant’s Request for Reconsideration dated December 20, 2021,
`where applicant:
`
`           
`

`

`
`
`1.
`2.
`
`Amended the identification and classification of goods; and
`Provided additional evidence and arguments against the  Sections 1, 2, & 45 Refusal, Section
`2(e)(1) Refusal in the alternative, and Section 2(f) Refusal
`
`
`The examining attorney has reviewed the applicant’s response and determined the following:
`
`
`1.
`
`2.
`
`Applicant’s amended identification and classification of goods is acceptable and made of record,
`therefore the Identification of Goods Requirement and the Clarification of Number of Classes to
`be Registered Requirement are  satisfied; and
`Applicant's additional evidence and arguments against the refusals are not persuasive,
`and  therefore the request for reconsideration is denied and the FINAL Sections 1, 2, & 45
`Refusal, Section 2(e)(1) Refusal in the alternative, and Section 2(f) Refusal, are  maintained and
`continued. See 37 C.F.R. §2.64(b); TMEP 715.03(a)(2)(B), (a)(2)(E), 715.04(a)
`
`
`APPLICANT'S REQUEST FOR RECONSIDERATION IS HEREBY DENIED
`
`Applicant’s request for reconsideration is denied.  See 37 C.F.R. §2.63(b)(3). The trademark
`examining attorney has carefully reviewed applicant’s request and determined the request did not: (1)
`raise a new issue, (2) resolve all the outstanding issue(s), (3) provide any new or compelling evidence
`with regard to the outstanding issue(s), or (4) present analysis and arguments that were persuasive or
`shed new light on the outstanding issue(s). TMEP §§715.03(a)(ii)(B), 715.04(a).  
`
`In the Request for Reconsideration, the applicant presented additional evidence and arguments against
`the Sections 1, 2, & 45 Refusal, Section 2(e)(1) Refusal in the alternative, and Section 2(f) Refusal.
`Applicant’s additional evidence and arguments are unpersuasive as explained below.
`
`First, the applicant argues that the sophistication of the relevant purchasers merits further
`consideration in determining whether the mark is generic. This is an incorrect interpretation of the
`relevant case law.  The fact that the relevant consumers are sophisticated or knowledgeable in a
`particular field does not necessarily mean that they are sophisticated or knowledgeable in the field of
`trademarks. TMEP §1207.01(d)(vii); see, e.g., Stone Lion Capital Partners, LP v. Lion Capital LLP,
`746 F.3d. 1317, 1325, 110 USPQ2d 1157, 1163-64 (Fed. Cir. 2014); Top Tobacco LP v. N. Atl.
`Operating Co., 101 USPQ2d 1163, 1170 (TTAB 2011).  Although the applicant's consumers may be
`sophisticated scientists and researchers, the relevant question is what do they understand about whether
`the applied-for mark is a generic term for the goods.  In re Cordua Rests., Inc., 823 F.3d 594, 599, 118
`USPQ2d 1632, 1634 (Fed. Cir. 2016) (citing H. Marvin Ginn Corp. v. Int’l Ass’n of Fire Chiefs, Inc.,
`782 F.2d 987, 990, 228 USPQ 528, 530 (Fed. Cir. 1986)); TMEP §1209.01(c)(i). Applicant's arguments
`that the sophistication of the relevant purchasers in the field of science and research somehow makes
`them immune to generic confusion is unsupported by any case law. A term that is generic for a specific
`good remains generic for that good regardless of the knowledge and sophistication of the consumers
`within the field of use. 
`
`Second, applicant submits numerous exhibits showing use of the applied-for mark NF-LIGHT being
`used as a source identifier. 
`
`As a preliminary matter, all exhibits except for Exhibits H, J, and W are objected to by the examining
`attorney.  As evidence against the refusal, applicant has provided screenshots or printouts of scientific
`articles from online webpages that do not specify the date it was downloaded or accessed and the
`
`

`

`complete URL. To properly introduce Internet evidence into the record, an applicant must provide (1)
`an image file or printout of the downloaded webpage, (2) the date the evidence was downloaded or
`accessed, and (3) the complete URL address of the webpage. See In re I-Coat Co., LLC, 126 USPQ2d
`1730, 1733 (TTAB 2018); TBMP §1208.03; see TMEP §710.01(b). Accordingly, these webpages
`cannot be considered.  These exhibits are clearly webpage articles as many of them include hyper-links
`and/or other indications that the articles come from online sources. For example: 1) Exhibit 1 contains a
`link entitled “OPEN” directly beneath the article title on Page 1; 2) Exhibit B does contain a URL at the
`bottom of each page, however there is no date of access; 3) Exhibit C contains a link that states “check
`for updates” at the top of the first page; 4) Exhibit D contains a link that states “check for updates” at
`the top of the second page; 5) Exhibit E contains a heading “Contents lists available at ScienceDirect”
`which the wording “ScienceDirect” in hyperlink form; 6) Exhibit F the final page contains numerous
`hyperlinks and several of the other pages contain the webpage URL in the footer, but lacks the date
`printed/accessed; 7) Exhibit G contains the URL in the header of the first page but not date
`printed/accessed; 8) Exhibit I contains a link that states “check for updates” at the top of the first page
`and contains a URL on the header line of most pages, but no date printed/accessed. Only exhibits H and
`J appear to contain both the relevant URL and the date printed. Exhibit W appears to be the only article
`without any indication that it was obtained online, however, to the extent the article was obtained
`online, the objection is extended to this exhibit as well.
`Although these exhibits are not properly submitted and therefore cannot be considered, in the event the
`Board overrules such objection, the exhibits fail to prove that the term NF-LIGHT is not generic.
`
`First, limited evidence that some sources may recognize the term NF-LIGHT as a source identifier does
`not overcome the previous evidence of generic use. There is no balancing test for a generic refusal that
`states that if there are more pieces of evidence showing source-identifier use than generic use then the
`refusal is obviated. Moreover, the Court of Appeals for the Federal Circuit and Trademark Trial and
`Appeal Board have long recognized that the USPTO has limited resources for obtaining evidence when
`examining applications for registration; the practicalities of these limited resources are routinely taken
`into account when reviewing a trademark examining attorney’s action. See In re Pacer Tech., 338 F.3d
`1348, 1352, 67 USPQ2d 1629, 1632 (Fed. Cir. 2003) (citing In re Loew’s Theatres, Inc., 769 F2d 764,
`768, 226 USPQ 865, 868 (Fed. Cir. 1985)); In re Mr. Recipe, LLC, 118 USPQ2d 1084, 1087 n.4
`(TTAB 2016) (quoting In re Budge Mfg., Inc., 857 F.2d 773, 775, 8 USPQ2d 1259, 1260-61 (Fed. Cir.
`1988)); TBMP §1208 nn.2 & 10.  Therefore, an applicant cannot overcome a refusal by overloading the
`record with evidence beneficial to their arguments and arguing more evidence on their side.
`Second, a close examination of some submitted pieces of evidence clearly show the authors of the
`articles are, at a minimum, confused whether the term NF-LIGHT is generic or a source identifier. In
`Exhibit B for example, the following section has been highlighted on page B under “Introduction”:
`
`
`Neurofilaments (NFs) are the main structural proteins of neurons and are members of the class
`IV intermediate filament protein family. NFs are selectively expressed in the nervous system and
`are found at the highest levels in long projection axons. They are composed of four subunits,
`namely NF light (NFL), NF medium (NFM), and NF heavy (NFH) chain subunits plus an
`unstable alpha‐internexin sub‐unit.
`
`
`[emphasis added]. In this paragraph, the authors are clearly using the term NF LIGHT as a generic
`term to refer to one of the four subunits of neurofilaments. There is no mention of the applicant nor of a
`testing kit of any type. Whether the authors later use the registration symbol in connection with the
`term NF-LIGHT when referring to the applicant's kits is irrelevant. The authors have already shown in
`their introduction paragraph that such term is generic for the name of a neurofilament subunit
`(particularly the one which the applicant's kit detects). The confusing usage of the term as both a
`
`

`

`generic term in the introduction and as an attempted source identifier in the same article is a prime
`example of why the applicant's mark must be refused, to both avoid a similar confusion and to allow
`others to use the generic term when referencing similar goods. 
`
`Similar confusing usage can be found in exhibit C which contains the following wording under
`“Introduction”:
`
`
`Neurofilaments (Nfs) are major structural elements of neurons that are specifically expressed in
`axons and dendrites. They are heteropolymers composed of four subunits: the triplet of the Nf
`light (NfL), medium (NfM) and heavy (NfH) chain, and either α-internexin in the central or
`peripherin in the peripheral nervous system
`[emphasis added]. Again in this article, the authors are clearly using the term NF LIGHT as a generic
`term to refer to one of the four subunits of neurofilaments. There is no mention of the applicant nor of a
`testing kit of any type.
`
`Third, several of the articles appear to be either written by individuals connected to the applicant and/or
`by individuals who received applicant's testing kits for free, almost certainly in exchange for
`referencing NF-LIGHT as a source identifier in their articles. For example, exhibit C states one of the
`authors is an employee of the applicant in the “Conflict of Interest” section of the article, and in exhibit
`D the “Acknowledgments” sections specifies that all the testing kits were donated by the applicant.
`Therefore, these articles do not show unbiased third-party use of the wording NF-LIGHT as a source
`identifier, but merely evidence that the applicant believes that the mark identifies source and has
`influenced certain articles as such. 
`Not every designation that appears on a product or its packaging functions as a trademark, even though
`it may have been adopted with the intent to do so. See In re Peace Love World Live, LLC, 127 USPQ2d
`1400, 1404 (TTAB 2018) (citing In re Pro-Line Corp., 28 USPQ2d 1141, 1142 (TTAB 1993)). A
`designation can only be registered when purchasers would be likely to regard it as a source-indicator
`for the goods. See In re Manco, Inc., 24 USPQ2d 1938, 1941 (TTAB 1992) (citing In re Remington
`Prods. Inc., 3 USPQ2d 1714, 1715 (TTAB 1987)); TMEP §1202.
`
`Finally, the applicant argued that the examining attorney failed to carry the burden of the evidence in
`light of the additional evidence submitted by the applicant and that doubt should be resolved in favor of
`the applicant. Again,  the Court of Appeals for the Federal Circuit and Trademark Trial and Appeal
`Board have long recognized that the USPTO has limited resources for obtaining evidence when
`examining applications for registration; the practicalities of these limited resources are routinely taken
`into account when reviewing a trademark examining attorney’s action. See In re Pacer Tech., 338 F.3d
`1348, 1352, 67 USPQ2d 1629, 1632 (Fed. Cir. 2003) (citing In re Loew’s Theatres, Inc., 769 F2d 764,
`768, 226 USPQ 865, 868 (Fed. Cir. 1985)); In re Mr. Recipe, LLC, 118 USPQ2d 1084, 1087 n.4
`(TTAB 2016) (quoting In re Budge Mfg., Inc., 857 F.2d 773, 775, 8 USPQ2d 1259, 1260-61 (Fed. Cir.
`1988)); TBMP §1208 nn.2 & 10.  Moreover, in the present case, the previous evidence of record leaves
`no doubt that the mark is generic.  However, the examining attorney has attached additional evidence of
`generic usage of the term NF-LIGHT to offset the applicant's arguments that a higher burden of
`evidence is necessary based on applicant's own additional evidence. See attached evidence.
`
`Therefore, the applicant’s additional evidence and arguments are not persuasive and the request for
`reconsideration is denied and the FINAL refusal is maintained and continued as to the  Sections 1, 2,
`& 45 Refusal, Section 2(e)(1) Refusal in the alternative, and Section 2(f) Refusal.
`
`RESPONSE GUIDELINES
`
`

`

`
`If applicant has already filed an appeal with the Trademark Trial and Appeal Board, the Board will
`be notified to resume the appeal.  See TMEP §715.04(a).  
`
`If applicant has not filed an appeal and time remains in the six-month response period, applicant has
`the remainder of that time to (1) file another request for reconsideration that complies with and/or
`overcomes any outstanding final requirement(s) and/or refusal(s), and/or (2) file a notice of appeal to
`the Board. TMEP §715.03(a)(ii)(B). Filing a request for reconsideration does not stay or extend the
`time for filing an appeal.  37 C.F.R. §2.63(b)(3); See TMEP §715.03(c).
`
`
`/Lyal Fox/
`Lyal Fox
`Trademark Examining Attorney
`Law Office 113
`(571) 270-7884
`lyal.fox@uspto.gov
`
`
`
`

`

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`Home » NF-L » NF-L ELISA Kits » Mouse NF-L ELISA Kit (Colorimetric)
`Mouse NF-L ELISA Kit (Colorimetric)
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`ELISA: Mouse NF-L ELISA Kit
`(Colorimetric) [NBP2-80299] -
`Standard Reference Curve
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`Mu Species Glossary
`ELISA
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`0,156-10 ng/mL
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`0.094 ng/mL
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`Mouse NF-L ELISAKit (Colorimetric) Summary
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`Standard Curve Range
`0156-10 ng/mL
`Sensitivity
`0,094 ng/mL
`Assay Type
`Sandwich-ELISA
`Inter-Assay
`CV% < 4.95%
`Intra-Assay
`CV% < 4.85%
`Spike Recovery
`B8-105%
`Sample Volume
`100 ul
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`ELISAKit (Colorimetric)
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`No significant cross-reactivity or interference between Mouse NF-L and analogues
`was observed.
`
` Storage
`Storage of componentsvaries. See protocol for specific
`instructions,
`
`Components
`
`1, Biotinylated Detection Ab Diluent
`2. Certificate of Analysis
`3, Concentrated Biotinylated Detection Ab (100X)
`4, Concentrated HRP Conjugate (100%)
`5. Concentrated Wash Buffer (25X)
`6. HRP Conjugate Diluent
`7. Micro ELISA Plate(Dismountable)
`8. Plate Sealer
`9, Product Description
`10, Reference Standard and Sample Diluent
`11, Reference Standard
`12, Stop Solution
`13. Substrate Reagent
`
`
`
`= 68 kDa neurofilament protein
`* CMT2E
`« NEFL
`* neurofilamentprotein,light chain
`* neurofilament subunit NF-L
`= Neurofilamenttriplet L protein
`= neurofilament, light polypeptide
`* neurofilament-light
`= NF6S
`+ NF6SFLIS3642
`* NFL
`» NF-L
`NFLlight polypeptide 68kDa
`
`Neurofilaments are 10nm intermediate filamentproteins located in vertebrate
`neurons, which regulate axonal diameter. They are composed predominantly of the
`three major neurofilamentproteins:
`NF-Medium and NF-Heavy. NF-L is the
`light or low molecular weight polypeptide, and it runs on SDS-PAGE gels at about
`68kDa, with some size variation in across species.
`Antibodies to NF-L maybe used to identify NF-L in neurons andto study neuronal
`processes in tissue sections and/or culture. NF-L antibodies canalso be usedto
`study microfilament accumulations seen in many neurological diseases, such as Lou
`Geri's disease or Alzheimer's disease.
`
` This product is for research use only and is not approved for use in humans or in
`clinical diagnosis. ELISA Kits are guaranteed for 6 months from dateof receipt.
`
`NRAAN-12
`
`NBANA-13S
`
`

`

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`[i (o Pubiications)
`BB (20 Pubtications)
`Species: By, Ch, Eq, Hu, Mu, Po,
`Species: Bv, 9, Hu, Mu, Po, Rt
`Rt
`Applications: ELISA, ICC/IF, IHC-
`Applications: ICC/IF, IHC, IHC-Fr,
`WhMt, IHC, IHC-Fr,
`IHC-P, Invitro,
`IHC-P, KO, WB
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` \ ScienceDirect
`
`Journals & Books ao
`
`USPatent & Trademark Office-
`
`STIC
`
`Neurofilament Protein
`
`Related terms:
`
`Naee To
`
`Addto Mendeley
`
`BTeCore RhaBy
`
`NYcar ota
`
`Immunohistology of Neoplasms of Soft
`Tissue and Bone
`
`David J. Dabbs MD,in Diagnostic Immunohistochemistry, 2019
`Neurofilament Proteins
`NFPs are composedofthree basic subunits with molecular weights
`of 68, 150, and 200 kD; hence,they are largerthan all other IFPs.
`Each NFP appears to be a separate gene product, rather than a
`derivative of the other two.?? Expression ofthis family ofIFPs is
`correlated with differentiation of neurogenicblastcells into
`committed neurons in the developing embryo orin neoplasia, and
`eachisoformis differentially expressed in different types of
`neurons.?4?5 Another peculiarity of NFPs that is shared only by GFAP,
`another intermediatefilament,is that each of the three
`neurofilament isoforms maybe either phosphorylated or
`nonphosphorylatedin vivo.?° Therefore antibodies to the NFPs may
`be specific for only one of those two configurations.?”8
`MIRE CSbus 2 mUSEee eee ee
`
`Immunohistology of Soft Tissue and
`Osseous Neoplasms
`Mark R. Wick, Jason L. Hornick, in Diagnostic
`Immunohistochemistry (Third Edition), 2011
`NEUROFILAMENT PROTEINS
`Neurofilament proteins are composed of three basic subunits with
`molecular weights of 68 kD, 150 kD, and 200 kD,°°° hence they are
`clearly larger thanall other IFPs, Each NFP appears to be a separate
`gene product, rather thanderivatives of the other two.*” Expression
`ofthis family of IFPs is correlated with the differentiation of
`neurogenicblast cells into committed neuronsin the developing
`embryo or in neoplasia.*®°? Another peculiarity of NFPsthat is not
`shared by other intermediate filament classes, except for GFAP,is
`that each of the three neurofilament isoforms may beeither
`phosphorylated or nonphosphorylated in vivo.© Correspondingly,
`antibodies to the NFPs maybespecific for only one of those two
`configurations.°}6?
`
`
`
`

`

`INPRS 1UfTT a frajor COMpONeNt OF Une CYLOSKeIELOT! OF neUrUnS anu
`their axons. Expression is not seen in normal epithelium. Practically
`speaking, NFPs are generally not well detected in FFPE tissue, even
`with modern IHC methods and commercial antibodies. Among
`these, the Sternberger Monoclonal, Inc. (SMI) series of monoclonal
`antibodies*® and clone 2F11 are probably the most consistently active
`against routinely processed surgical pathology specimens. Among
`soft tissue neoplasms, NFP staining demonstrates axons in
`neurofibroma and ganglioneuroma; in the latter tumor, ganglion
`cells will also be positive for NFP. Neuroblastomaandits variants also
`express NFP, as do paragangliomas/pheochromocytomas and a
`subset of neuroendocrine tumors; the presence of a perinuclear dot-
`like pattern of staining is characteristically found in Merkel cell
`carcinoma,in which it may be a helpful diagnostic feature.?°-?3 NFP
`expression in other sarcomasis very limited.
`
`
`Practically speaking, NFPs are generally not well detected in formalin-
`fixed, paraffin-embeddedtissue, even with modern
`immunohistochemical methods and commercial antibodies. Among
`these, our experience has beenthat the SMI series of monoclonal
`antibodies® is most consistentlyactive against routinely processed
`surgical pathology specimens.It is known that among softtissue
`neoplasms, neuroblastomavariants, ganglioneuromas,
`
`paragangliomas, and metastatic neuroendocrine carcinomas are the
`onlylesions that are potentially labeled for NFPs.°*©”
`Purchase book
`
`‘The Primate Nervous System,Part II
`J.H. Morrison, ... G.W. Huntley, in Handbook of Chemical
`Neuroanatomy, 1998
`
`Immunohistology of the Mediastinum
`David J. Dabbs MD, in Diagnostic Immunchistochemistry, 2019
`Neuroectodermal Tumorsof the Mediastinum
`Although the majority of neuroectodermal-derived neoplasms occur
`in the posterior mediastinum,rarely these tumors mayarise in
`association with the thymus orin other compartments of the
`mediastinum, Neural tumors of the mediastinum derived from
`Schwann cells include neurofibroma, schwannoma(Fig. 11.12A), and
`their malignant counterpart, malignantperipheral nerve sheath
`8.2.2.6 The prefrontal cortex (areas FEF, SEF, 45 and 46)
`tumor (MPNST). Both neurofibromas and schwannomasexpress
`In neurofilament protein-stained sections, the frontal eye field (FEF)
`
`$100 protein, although schwannomasdo so morediffusely and
`is a distinct cortical area in the anterior wall of the posterior portion
`of the prearcuate gyrus,at the level ofthe spur of the arcuate sulcus.
`consistently than neurofibromas(seeFig, 11.12B).”° In addition,
`
`neurofibromas can show reactivity for neurofilament protein (NFP)
`The supplementary eye field (SEF) represents a transition zone
`
`and also CD34in a characteristic “fingerprint” pattern, and a subset
`between areas 6 and 9 on the superior aspectofthe frontalcortex,
`of schwannomascan also show immunoreactivity for glial fibrillary
`dorsal to the ascending branch ofthe arcuate sulcus. The FEF and
`acidic protein (GFAP), podoplanin,calretinin, SOX10, and,very rarely,
`SEF showdistinct neurofilament protein immunoreactivity patterns
`in both layerIll and V, compared to premotor area 6 and prefrontal
`CK.7°-173 MPNST shows a very similar IHC phenotype, however,
`expression of $100 protein is usually more focal, and this is true also
`areas 9, 45 and 46. The FEFis characterized by a diffuse population of
`labeled pyramidal neurons in layers V and VI that outnumberthose in
`for NFP, podoplanin, and SOX10.”° A rare tumor commonly
`
`layerIII. Layer V contains somelarge isolated neurofilament protein- associated with neurofibromatosis type1(NF1) is an MPNST with
`immunoreactive cells, however smaller and less numerous than those
`heterologousdifferentiation in the form ofskeletal muscle, the so-
`observedin area 6. Thestaining pattern oflayerIll is comparable to
`called malignant Triton tumor. The rhabdomyosarcomatous elements
`
`that in area 6. The border between the FEF and areas 46 and 45is
`in this tumor can beidentified by using desmin, MyoD1, MSA, and
`well visible due to much lower numbers of neurofilament protein-
`myogenin in keeping with skeletal muscle differentiation7*
`
`

`

`immunoreactive neurons in layers V-VI ofthelatter regions. Areas 45
`and 46 display comparable populations of intermediate-to-large
`neurofilament protein-immunoreactive pyramidal neurons in both
`layers Ill and V-VI, with area 46 having higher neuron countsin layer
`Ill than area 45. The SEF is characterized by very high numbersof
`neurofilament protein-immunoreactive neurons in layerIll, and cell
`counts in layers V-VI comparable to those in the FEF. Thestaining
`pattern in area 9 is comparable to that in the SEF, with intermediate
`size pyramidal neuronsin supra- and infragranular layers. However,
`the SEF has much higher neurofilament protein-immunoreactive
`neuron counts than areas 9 and 6.
`
`The FEF and the SEFare involved in smooth eye movements and
`target selection during saccadic eye movements, and are
`characterized by distinct cytoarchitecture (Huerta et al. 1987; Stanton
`et al. 1989; Gottlieb et al. 1993; Schall and Hanes 1993), and both
`fields have quite similar connectivity patterns with cortical areas and
`subcortical structures (Parthasarathyet al. 1992; Schlag and Schlag-
`Rey 1992; Schall et al. 1993a,b; Stanton etal. 1993). Interestingly,
`these two visuomotorregions exhibit a very similar staining pattern
`with neurofilament protein, with a much higher density of labeled
`neuronsin the infragranular layers than observed in the othervisual
`areas. A comparably high density of neurofilament protein-
`immunoreactive neurons in the deeplayers is also present in the
`ventrally located area 45. The inferior convexity of the frontal cortex
`part of area 45 may,in fact, include the lateralmost aspect of the FEF.
`It is interesting to note that the laminar density of neurofilament
`protein-containing cells is much lower in area 45 than in FEF,
`permitting the definition of the boundary between thesefields. Areas
`46 and 45 are strongly connected to the frontal eye fields (Huerta et
`al. 1987; Huerta and Kaas 1990; Stantonet al. 1993), and may
`represent the frontal extension of the occipitoparietal and
`occipitotemporal pathways (Bachevalier and Mishkin 1986; Funahashi
`et al. 1990, 1991, 1993; Wilson et al. 1993).
`
`Purchase book
`
`Amyotrophic Lateral Sclerosis: Idiopathic
`
`Ganglioneuroma, ganglioneuroblastoma, and neuroblastomaare
`anotherset of neoplasmsthat can arise in the mediastinum,
`primarily in the posterior compartment. These tumors mainlyaffect
`children and young adults but have also been described in older
`patients.!75-1”8 Whereas ganglioneuromarepresents the benign
`matureendofthis spectrum of tumors, neuroblastoma formsthe
`malignant immature one. Ganglioneuromas are composed oftwo
`cell types, spindle cells and ganglioncells. The spindle cell
`componentofthese tumorsusually stains with NFP and $100
`protein.!7%180 NeuN,synaptophysin, and to a lesser extent
`chromogranin A are helpful determinants for the labeling of ganglion
`cells, which may be focal or widely scattered in
`ganglioneuromas.'®°!8! On the other hand, neuroblastomasare
`high-grade tumors composed ofsheets of small round cells and
`
`varying amounts of neuropil that can easily mimic other small round
`cell neoplasms such as rhabdomyosarcoma,primitive
`neuroectodermal tumor (PNET), or lymphoma.The small roundcells
`in neuroblastoma show variable reactivity for NSE, NFP,
`
`chromogranin A, synaptophysin, CD57, and CD56.178:182-184 |,
`addition, NB84 is a monoclonal antibodyraised specifically against
`neuroblastoma;althoughit is not specific for that neoplasm,this
`marker is positive in the great majority of neuroblastic tumors.18518
`Neuroblastomasare universally devoid of markers of myogenous
`differentiation (desmin, MyoD1, and myogenin), hematolymphoid
`lineage (CD45), and epithelial differentiation (CK, EMA, or CD99).
`hapter on Clin
`
`Immunohistology of Skin Tumors
`David J. Dabbs MD, in Diagnostic Immunohistochemistry, 2019
`Endocrine Tumors
`Primary cutaneous neuroendocrine carcinoma wasoriginally referred
`to astrabecular carcinomaofthe skin orTokercell carcinoma, butit is
`mostly known asMerkelcell carcinoma. Some authors have postulated
`that MCC displays neurotactile differentiation that emulates Merkel
`cells of the normalskin and oral mucosa. Nonneoplastic Merkelcells
`
`

`

`and Inherited
`
`Nicholas J. Maragakis MD,Jeffrey D. Rothstein MD, PhD,in
`Neurobiology of Disease, 2007
`C. Intermediate Filaments and ALS
`Neurofilament (NF) proteins represent the majority of cytoskeletal
`proteins that are present in motor neurons. These proteins play a
`significant role in determining the shapeofcells, caliber of axonal
`projections, and maintenanceof axonaltransport. Threedistinct
`
`neurofilament protein subunits exist, differing in molecular weight:
`NF-heavy, NF-medium, and NUFSU@HE. Structurally the NFelight
`subunit forms the core of the neurofilament around which the two
`larger subunits associate and contribute to the side arm projections
`radiating from the filament. Assembly ofthefilaments occurs in the
`motor neuron cell body, where they are then transported downthe
`axon [51]. Abnormal synthesis offilament units and the accumulation
`of these proteins in the cell body and proximal axons of motor
`neuronsis a hallmark pathological feature of the disease, observed in
`both familial and sporadic cases of ALS in patients as well as in SOD1
`mutant mice. Currently,it is unclear whether accumulation of
`neurofilaments occurs as a result of axonal transport blockade or
`whether(conversely) the build-up of protein leads to secondary
`impairmentof axonal transport. Excessive phosphorylation of
`neurofilaments [52-54] has been suggested as a factor affecting
`axonal transport, with some studies demonstrating an increase in
`perikaryal expression of phosphorylated filaments in ALS cases, but
`this finding has been refuted and remains inconclusive [55].
`Immunoreactivity of antibodies to neurofilament epitopes has also
`been shownin ubiquitinated inclusions with compact or Lewy body-
`like morphology in residual motor neurons in ALS cases[56]. Under
`normal physiological conditions, the covalent addition of ubiquitin to
`cellular proteins usually marks them for degradation by an ATP-
`dependent, non-lysosomalproteolytic system. In several cases of
`SOD1-related FALS, the detection of both nonphosphorylated and
`phosphorylated neurofilaments in dramatic hyaline conglomerate
`inclusions has beenrevealed within the perikarya and axons of motor
`neurons [56,57].
`In a mannersimilar to SOD1,the identification of genetic mutations
`
`and the use of transgenic animals have provided evidence that
`malielwelrs icakelimnanlarennn Poalahenmatananncmwt
`
`are reactive for CK20, CG, MOC-31, neurofilament protein (NFP),
`
`CD56, met-enkephalin, vasoactive intestinal polypeptide (VIP), and
`bloodgroupantigen Pr(h), but in general, they appear to lack the
`ability to synthesize other endocrine determinants consistently.
`
`Malignant Merkelcells may express keratins (with pankeratin
`
`cocktails), CK20, NFP, CD15, CD56, CD57, EMA, MOC-31 antigen,
`
`BerEP4 antigen, chromogranin A,calcitonin, somatostatin,
`adrenocorticotropic hormone (ACTH), VIP, pancreatic polypeptide,
`and substance P.’®*°|t has also been suggested that MCCis closely
`related to sweat gland carcinomas, because rare MCClesions show
`glandular or squamousdifferentiation.
`Duetoits capacity for diffuse or medullary patterns of growth andits
`uniform, occasional dyshesive small cell constituency, MCC is
`potentially mistaken for lymphoma and leukemia cutis. Although
`leukemia/lymphoma and MCC may express PAXS and terminal
`deoxynucleotidyltransferase (TdT),°!*? lymphomais reactive for
`
`CD45, whereas MCCis not. Moreover, keratin filaments in MCCs are
`often clustered in the perinuclear cytoplasm and yield a characteristic
`“dot” of chromogenic precipitate (Fig. 13.13), also seen in other
`markers(e.g., synaptophysin and chromogranin). Such an imageis
`simultaneously diagnostic of epithelial and neuroendocrine
`differentiation in a small cell cutaneous neoplasm.
`Histologi