@article{chon_sakthikumar_tang_hamilton_vaughan_smith_sommer_robat_manley_mullin_et al._2023, title={Novel genomic prognostic biomarkers for dogs with cancer}, volume={10}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.16893}, abstractNote={AbstractBackgroundGrowing evidence from dogs and humans supports the abundance of mutation‐based biomarkers in tumors of dogs. Increasing the use of clinical genomic diagnostic testing now provides another powerful data source for biomarker discovery.HypothesisAnalyzed clinical outcomes in dogs with cancer profiled using SearchLight DNA, a cancer gene panel for dogs, to identify mutations with prognostic value.AnimalsA total of 127 cases of cancer in dogs were analyzed using SearchLight DNA and for which clinical outcome information was available.MethodsClinical data points were collected by medical record review. Variables including mutated genes, mutations, signalment, and treatment were fitted using Cox proportional hazard models to identify factors associated with progression‐free survival (PFS). The log‐rank test was used to compare PFS between patients receiving and not receiving targeted treatment before first progression.ResultsCombined genomic and outcomes analysis identified 336 unique mutations in 89 genes across 26 cancer types. Mutations in 6 genes (CCND1, CCND3, SMARCB1, FANCG, CDKN2A/B, and MSH6) were significantly associated with shorter PFS. Dogs that received targeted treatment before first progression (n = 45) experienced significantly longer PFS compared with those that did not (n = 82, P = .01). This significance held true for 29 dogs that received genomically informed targeted treatment compared with those that did not (P = .05).Conclusion and Clinical ImportanceWe identified novel mutations with prognostic value and demonstrate the benefit of targeted treatment across multiple cancer types. These results provide clinical evidence of the potential for genomics and precision medicine in dogs with cancer.}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Chon, Esther and Sakthikumar, Sharadha and Tang, Min and Hamilton, Matthew J. and Vaughan, Andrew and Smith, Ashley and Sommer, Breann and Robat, Cecilia and Manley, Christina and Mullin, Christine and et al.}, year={2023}, month={Oct} } @article{medland_marks_intile_2022, title={Discharge summaries provided to owners of pets newly diagnosed with cancer exceed recommended readability levels}, volume={260}, ISSN={["1943-569X"]}, DOI={10.2460/javma.21.09.0410}, abstractNote={Abstract OBJECTIVE To analyze the readability of discharge summaries distributed to owners of pets newly diagnosed with cancer. SAMPLE 118 discharge summaries provided to pet owners following initial consultation. PROCEDURES A database search identified records of new patients that had been presented to the North Carolina State Veterinary Hospital medical oncology service between June 2017 and January 2019. Owner-directed portions of the summaries provided at the time of discharge were copied and pasted into a document and stripped of all identifying information. Readability of summaries was assessed with the use of 2 previously established readability calculators: the Flesch-Kincaid Grade Level (FKGL) and Flesch Reading Ease (FRE) tests. RESULTS Mean ± SD FKGL was 11.9 ± 1.1 (median, 11.9; range, 8.6 to 15.5; target ≤ 6), and the mean ± SD FRE score was 43 ± 5.9 (median, 42.7; range, 25.5 to 58.1; target ≥ 60). There were no significant differences in FKGL or FRE scores among discharge summaries for patients with the 4 most common tumor types diagnosed or the described treatment options. Ninety-three percent (110/118) of summaries were scored as difficult or very difficult to read. CLINICAL RELEVANCE Owner-directed written information regarding a diagnosis of cancer at a single teaching hospital exceeded readability levels recommended by the American Medical Association and NIH and was above the average reading level of most US adults. Efforts to improve readability are an important component of promoting relationship-centered care and may improve owner compliance and patient outcomes. }, number={6}, journal={JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION}, author={Medland, Julia E. and Marks, Steven L. and Intile, Joanne L.}, year={2022}, month={Mar}, pages={657–661} } @article{berlato_bulman-fleming_clifford_garrett_intile_jones_kamstock_liptak_pavuk_powell_et al._2021, title={Value, Limitations, and Recommendations for Grading of Canine Cutaneous Mast Cell Tumors: A Consensus of the Oncology-Pathology Working Group}, volume={4}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211009785}, abstractNote={ One of the primary objectives of the Oncology Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects and provide guidelines for oncologic pathology. Consensus is established through review of relevant peer-reviewed literature relative to a subgroup’s particular focus. In this article, the authors provide a critical review of the current literature for grading of canine cutaneous mast cell tumors, suggest guidelines for reporting, and provide recommendations for its clinical interpretation. The article mainly focuses on histologic grading, but relevant information on mitotic count and cytological grading are also discussed. This document represents the opinions of the working group and the authors but does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society. }, journal={VETERINARY PATHOLOGY}, author={Berlato, Davide and Bulman-Fleming, Julie and Clifford, Craig A. and Garrett, Laura and Intile, Joanne and Jones, Pamela and Kamstock, Debra A. and Liptak, Julius M. and Pavuk, Alana and Powell, Roger and et al.}, year={2021}, month={Apr} } @article{fogle_intile_sheats_2021, title={Veterinary Clinical Ethics and Patient Care Dilemmas}, volume={51}, ISSN={["1878-1306"]}, DOI={10.1016/j.cvsm.2021.05.003}, abstractNote={Veterinary ethical dilemmas are common, complex, and unavoidable. Creating a transparent and deliberate approach to ethical issues empowers the entire veterinary team and reduces stress associated with these dilemmas. This article discusses ethical considerations and principles and propose use of the 4Es model and core communication skills to address ethical dilemmas in veterinary practice. It reviews literature defining ethical issues in practice and provides case examples to show the application of our proposed methods. The goal is to provide veterinary professionals with an approach they can use to frame and address their own ethical decisions.}, number={5}, journal={VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE}, author={Fogle, Callie and Intile, Joanne and Sheats, Mary Katherine}, year={2021}, month={Sep}, pages={1079–1097} } @inbook{intile_2019, edition={4th}, title={Anal Sac}, booktitle={Clinical Veterinary Advisor: Dogs and Cats}, publisher={Elsevier}, author={Intile, J.L.}, editor={Cote, E.Editor}, year={2019} } @article{intile_rassnick_al-sarraf_chretin_2019, title={Evaluation of the Tolerability of Combination Chemotherapy with Mitoxantrone and Dacarbazine in Dogs with Lymphoma}, volume={55}, ISSN={["1547-3317"]}, DOI={10.5326/JAAHA-MS-6878}, abstractNote={ABSTRACT Combination chemotherapy can be an effective option for treating resistant lymphoma in dogs. This retrospective study examined the tolerability and efficacy of the combination of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (dacarbazine) (DTIC) in a population of dogs with lymphoma resistant to a doxorubicin-containing chemotherapy protocol. Mitoxantrone was administered at 5 mg/m 2 IV over 10 min followed by DTIC at 600 mg/m 2 IV over 5 hr, every 3 wk. All dogs were treated with prophylactic trimethoprim–sulfadiazine and metoclopramide. The frequency of grade 4 neutropenia was 18%, and 5% of dogs were hospitalized from sepsis. Gastrointestinal toxicity was uncommon. The overall response rate was 34% (15 of 44; 95% confidence interval 20–48%) for a median duration of 97 days (range 24–636 days, 95% confidence interval 44–150 days). Fourteen of 15 dogs who received mitoxantrone and DTIC as first rescue responded to treatment. Dogs who achieved complete remission to their initial L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy protocol were more likely to respond to mitoxantrone and DTIC (23 versus 11%, P = .035). The combination of mitoxantrone and DTIC is a safe treatment option for resistant lymphoma in dogs.}, number={2}, journal={JOURNAL OF THE AMERICAN ANIMAL HOSPITAL ASSOCIATION}, author={Intile, Joanne L. and Rassnick, Kenneth M. and Al-Sarraf, Renee and Chretin, John D.}, year={2019}, pages={101–109} } @inbook{intile_2019, edition={4th}, title={Lymphoma, Rescue Therapy}, booktitle={Clinical Veterinary Advisor: Dogs and Cats}, publisher={Elsevier}, author={Intile, J.L.}, editor={Cote, E.Editor}, year={2019} } @inbook{intile_2019, edition={4th}, title={Perianal}, booktitle={Clinical Veterinary Advisor: Dogs and Cats}, author={Intile, J.L.}, editor={Cote, E.Editor}, year={2019} } @misc{thamm_avery_berlato_bulman-fleming_clifford_hershey_intile_jones_kamstock_liptak_et al._2019, title={Prognostic and predictive significance of KIT protein expression and c-kit gene mutation in canine cutaneous mast cell tumours: A consensus of the Oncology-Pathology Working Group}, volume={17}, ISSN={["1476-5829"]}, DOI={10.1111/vco.12518}, abstractNote={AbstractOne of the primary objectives of the Oncology‐Pathology Working Group (OPWG), a joint initiative of the Veterinary Cancer Society and the American College of Veterinary Pathologists, is for oncologists and pathologists to collaboratively generate consensus documents to standardize aspects of and provide guidelines for oncologic pathology. Consensus is established through critical review of peer‐reviewed literature relevant to a subgroup's particular focus. Subsequent acceptance and approval of the document by the OPWG membership at large establishes consensus. The intent of this publication is to help educate practitioners and pathologists on the value of diagnostics related to the KIT receptor tyrosine kinase for canine cutaneous mast cell tumours and to provide a guide for the use of these tests in veterinary medicine. This document represents the opinions of the OPWG and the authors and does not constitute a formal endorsement by the American College of Veterinary Pathologists or the Veterinary Cancer Society.}, number={4}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Thamm, Douglas H. and Avery, Anne C. and Berlato, Davide and Bulman-Fleming, Julie and Clifford, Craig A. and Hershey, A. Elizabeth and Intile, Joanne L. and Jones, Pamela D. and Kamstock, Debra A. and Liptak, Julius M. and et al.}, year={2019}, month={Dec}, pages={451–455} } @article{epperly_hume_moirano_stokol_intile_erb_scrivani_2018, title={Dogs with acute myeloid leukemia or lymphoid neoplasms (large cell lymphoma or acute lymphoblastic leukemia) may have indistinguishable mediastinal masses on radiographs}, volume={59}, ISSN={["1740-8261"]}, DOI={10.1111/vru.12622}, abstractNote={AbstractAcute myeloid leukemia is an uncommon hematopoietic neoplasm of dogs that should be differentiated from lymphoid neoplasms, such as lymphoma, because of different treatment protocols and a worse prognosis. Thoracic radiography is performed frequently in dogs with suspected hematopoietic neoplasia, and detecting a mediastinal mass often prioritizes lymphoma as the most likely diagnosis. However, we have observed a mediastinal mass in several dogs with acute myeloid leukemia and hypothesized that (1) the frequency of a mediastinal mass was higher and (2) the size of the mass was larger in dogs with acute myeloid leukemia compared to dogs with lymphoid neoplasms. In this analytical study (observational, retrospective, and cross‐sectional), the sample population included 238 dogs with hematopoietic neoplasia. These dogs were divided into lymphoid (large cell lymphoma, acute lymphoblastic leukemia) and myeloid groups based on standard phenotyping tests. A mediastinal mass was detected during thoracic radiography in 73/218 (33%) and nine of 20 (45%) dogs in the lymphoid and myeloid groups (P = 0.21), respectively. The median size ratio of mediastinal mass to cardiac silhouette was 0.20 and 0.23 in the lymphoid and myeloid groups (P = 0.96), respectively. Additionally, we observed normal thoracic radiographs in 111/218 (51%) dogs in the lymphoid group and nine of 20 (45%) dogs in the myeloid group. In conclusion, acute myeloid leukemia should be considered when a mediastinal mass is detected during radiography in dogs with suspected hematopoietic neoplasia—but the presence or size of a mediastinal mass does not differentiate between myeloid and lymphoid neoplasms.}, number={5}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={Epperly, Erin and Hume, Kelly R. and Moirano, Steven and Stokol, Tracy and Intile, Joanne and Erb, Hollis N. and Scrivani, Peter V.}, year={2018}, pages={507–515} } @article{rassnick_bailey_malone_flory_kiselow_intile_2014, title={Tolerability of Lomustine in Combination with Cyclophosphamide in Dogs with Lymphoma}, volume={50}, ISSN={0587-2871 1547-3317}, url={http://dx.doi.org/10.5326/jaaha-ms-6020}, DOI={10.5326/jaaha-ms-6020}, abstractNote={This retrospective study describes toxicity associated with a protocol of lomustine (CCNU) and cyclophosphamide (CTX) in dogs with lymphoma. CCNU was administered per os (PO) at a targeted dosage of 60 mg/m2 body surface area on day 0, CTX was administered PO at a targeted dosage of 250 mg/m2 divided over days 0 through 4, and all dogs received prophylactic antibiotics. Ninety treatments were given to the 57 dogs included in the study. Neutropenia was the principal toxic effect, and the overall frequency of grade 4 neutropenia after the first treatment of CCNU/CTX was 30% (95% confidence interval, 19–43%). The mean body weight of dogs with grade 4 neutropenia (19.7 kg ± 13.4 kg) was significantly less than the mean body weight of dogs that did not develop grade 4 neutropenia (31.7 kg ± 12.4 kg; P = .005). One dog (3%) developed hematologic changes suggestive of hepatotoxicity. No dogs had evidence of either renal toxicity or hemorrhagic cystitis. Adverse gastrointestinal effects were uncommon. On the basis of the findings reported herein, a dose of 60 mg/m2 of CCNU combined with 250 mg/m2 of CTX (divided over 5 days) q 4 wk is tolerable in tumor-bearing dogs.}, number={3}, journal={Journal of the American Animal Hospital Association}, publisher={American Animal Hospital Association}, author={Rassnick, Kenneth M. and Bailey, Dennis B. and Malone, Erin K. and Flory, Andrea B. and Kiselow, Michael A. and Intile, Joanne L.}, year={2014}, month={May}, pages={167–173} } @article{rassnick_bailey_russell_flory_kiselow_intile_malone_balkman_barnard_2010, title={A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high-dose vinblastine and prednisone (CVP) for treatment of dogs with high-grade, metastatic or nonresectable mast cell tumours}, volume={8}, ISSN={1476-5810 1476-5829}, url={http://dx.doi.org/10.1111/j.1476-5829.2010.00217.x}, DOI={10.1111/j.1476-5829.2010.00217.x}, abstractNote={Safety and efficacy of a protocol of alternating 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU; 70 mg m(-2)) and vinblastine (3.5 mg m(-2)), and prednisone (1-2 mg kg(-1); CVP) in dogs with mast cell tumours (MCT) were evaluated. A total of 17 dogs had nonresectable MCTs and 35 received CVP as adjunctive treatment to locoregional control of metastatic MCTs or grade III MCTs. Neutropenia with fever occurred in 8% of dogs after treatment with vinblastine and in 2% after treatment with CCNU. Persistent elevation of serum alanine transaminase, suggestive of hepatotoxicity, occurred in 9% of the dogs. Response rate in dogs with nonresectable MCTs was 65%; five achieved a complete response (median, 141 days) and six achieved a partial response (median, 66 days). Overall median progression-free survival (PFS) time in dogs treated in the adjuvant setting was 489 days. Dogs with grade III MCTs had shorter PFS compared with dogs with metastatic grade II MCTs (190 days versus 954 days; P < 0.001). Phase III studies are needed to provide reliable information about the comparative efficacy of this protocol.}, number={2}, journal={Veterinary and Comparative Oncology}, publisher={Wiley}, author={Rassnick, K. M. and Bailey, D. B. and Russell, D. S. and Flory, A. B. and Kiselow, M. A. and Intile, J. L. and Malone, E. K. and Balkman, C. E. and Barnard, S. M.}, year={2010}, month={Jun}, pages={138–152} } @article{rassnick_bailey_malone_intile_kiselow_flory_barlow_balkman_barnard_waite_et al._2010, title={Comparison between l-CHOP and an l-CHOP protocol with interposed treatments of CCNU and MOPP (l-CHOP-CCNU-MOPP) for lymphoma in dogs}, volume={8}, ISSN={1476-5810}, url={http://dx.doi.org/10.1111/j.1476-5829.2010.00224.x}, DOI={10.1111/j.1476-5829.2010.00224.x}, abstractNote={An L-CHOP protocol with interposed treatments of CCNU and MOPP (L-CHOP-CCNU-MOPP) was evaluated in 66 dogs with stages III-V lymphoma. Results were compared with a historical group of 71 dogs treated with an L-CHOP protocol. Complete remission (CR) rates (85 and 80%, respectively) did not differ significantly between protocols (P = 0.48). First CR duration for dogs treated with L-CHOP-CCNU-MOPP was significantly longer: median, 317 days; 2-year CR rate, 35% versus median, 298 days; 2-year CR rate, 13%, P = 0.05). For the L-CHOP-CCNU-MOPP protocol, dogs in substage-b had a 4.3 times greater hazard of having a relapse than dogs in substage-a (P = 0.002). Frequency of adverse chemotherapy-associated gastrointestinal effects did not differ between protocols (P = 0.77). Neutropenia (primarily after CCNU) occurred more frequently in dogs treated with L-CHOP-CCNU-MOPP (P < 0.001). In summary, the L-CHOP-CCNU-MOPP protocol showed an improved duration of first CR as compared with an L-CHOP protocol, but the relevance of this finding might be subject to clinical judgement.}, number={4}, journal={Veterinary and Comparative Oncology}, publisher={Wiley}, author={Rassnick, K. M. and Bailey, D. B. and Malone, E. K. and Intile, J. L. and Kiselow, M. A. and Flory, A. B. and Barlow, L. L. and Balkman, C. E. and Barnard, S. M. and Waite, A. H. and et al.}, year={2010}, month={Nov}, pages={243–253} } @article{rassnick_moore_russell_northrup_kristal_bailey_flory_kiselow_intile_2010, title={Phase II, Open-Label Trial of Single-Agent CCNU in Dogs with Previously Untreated Histiocytic Sarcoma}, volume={24}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/j.1939-1676.2010.0588.x}, DOI={10.1111/j.1939-1676.2010.0588.x}, abstractNote={BACKGROUND Histiocytic sarcoma (HS) is an aggressive neoplasm in dogs, and in most instances, the disease is localized, but not amenable to surgical removal, or is disseminated. Affected patients usually die within 6 months. There have been no prospective studies to determine efficacy of single-agent chemotherapy in dogs with HS. HYPOTHESIS Single-agent CCNU [1-(2-chloroethyl)3-cyclohexyl-1-nitrosourea; lomustine] has antitumor activity against HS in dogs. ANIMALS Twenty-one dogs with histologically confirmed, nonresectable localized or disseminated HS. METHODS Prospective, open-label phase II clinical trial in which dogs with previously untreated HS were uniformly treated with CCNU as a single oral dosage of 90 mg/m2 every 4 weeks. The primary outcome measure was reduction in tumor size. RESULTS Fourteen dogs with disseminated HS and 7 with localized HS were enrolled between 1999 and 2008. Overall response rate was 29% (95% confidence interval [CI], 14–50%) for a median of 96 days (95% CI, 55–137 days). Three dogs (1 disseminated, 2 localized) had complete responses lasting for 54–269 days and 3 dogs (2 disseminated, 1 localized) had partial responses lasting for 78–112 days. CONCLUSIONS AND CLINICAL IMPORTANCE CCNU, when used as a single agent, has activity against HS in dogs. Evaluation of CCNU postoperatively for dogs with resectable localized HS and as part of combination therapy for tumors that are nonresectable or disseminated should be considered.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Rassnick, K.M. and Moore, A.S. and Russell, D.S. and Northrup, N.C. and Kristal, O. and Bailey, D.B. and Flory, A.B. and Kiselow, M.A. and Intile, J.L.}, year={2010}, month={Sep}, pages={1528–1531} } @article{intile_rassnick_bailey_al-sarraf_chretin_balkman_flory_kiselow_wakshlag_2009, title={Evaluation of dexamethasone as a chemoprotectant for CCNU-induced bone marrow suppression in dogs}, volume={7}, ISSN={1476-5810 1476-5829}, url={http://dx.doi.org/10.1111/j.1476-5829.2008.00175.x}, DOI={10.1111/j.1476-5829.2008.00175.x}, abstractNote={AbstractIn mice and people, administering corticosteroids before chemotherapy can reduce the severity of myelosuppression without reducing antitumour effects. This study investigated whether pretreatment with dexamethasone would reduce the incidence of grade 4 neutropenia in dogs receiving CCNU. Twenty‐five dogs received dexamethasone [0.1 mg kg−1 per os (PO) every 12 h] for 5 days and on the sixth day received CCNU (90 mg m−2 PO). Historical dogs (n = 67) received CCNU alone (90 mg m−2 PO). Forty‐five percent of historical dogs had grade 4 neutropenia, while 64% of dogs pretreated with dexamethasone had grade 4 neutropenia (P = 0.16). Dexamethasone plasma levels were quantified by enzyme‐linked immunosorbent assay in three healthy dogs. Peak plasma concentrations after a single oral 0.1‐mg kg−1 dose were <80 ng mL−1, the minimum level associated with chemoprotective effects of dexamethasone in people. Pretreatment with dexamethasone did not reduce the incidence of grade 4 neutropenia in dogs receiving CCNU.}, number={1}, journal={Veterinary and Comparative Oncology}, publisher={Wiley}, author={Intile, J. L. and Rassnick, K. M. and Bailey, D. B. and Al-Sarraf, R. and Chretin, J. D. and Balkman, C. E. and Flory, A. B. and Kiselow, M. A. and Wakshlag, J. J.}, year={2009}, month={Mar}, pages={69–77} } @article{rassnick_bailey_flory_balkman_kiselow_intile_autio_2008, title={Efficacy of Vinblastine for Treatment of Canine Mast Cell Tumors}, volume={22}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2008.0195.x}, DOI={10.1111/j.1939-1676.2008.0195.x}, abstractNote={Background: The optimal dosage and clinical efficacy of vinblastine (VBL) for treatment of mast cell tumors (MCTs) in dogs has not been established.Hypothesis: Single‐agent VBL has antitumor activity against MCTs in dogs.Animals: Fifty‐one dogs with nonresectable grade II or III cutaneous MCTs.Methods: Prospective, open clinical trial. Dogs were systematically allocated (by hospital record number) to receive IV treatment with VBL at a dosage of 2.0 mg/m2 (weekly for 4 treatments then biweekly for 4 treatments; VBL 2.0) or treatment with VBL at a dosage of 3.5 mg/m2 (biweekly for 5 treatments; VBL 3.5). The primary outcome measure was reduction in tumor size.Results: Twenty‐five dogs were allocated to the VBL 2.0 group and 26 were allocated to the VBL 3.5 group. In the VBL 2.0 group, 3 (12%) had a partial response (PR) for a median of 77 days (range, 48–229 days). Overall response rate in the VBL 3.5 group was 27%. One dog (4%) had a complete response for 63 days and 6 dogs (23%) had a PR for a median of 28 days (range, 28–78 days). Toxicoses were uncommon in the VBL 2.0 group. Twelve (46%) dogs in the VBL 3.5 group had <500 neutrophils/μL 7 days after treatment; 2 dogs with neutropenia developed concurrent fevers.Conclusions and Clinical Importance: VBL, when used as a single‐agent, has activity against MCTs in dogs although the response rate is lower than those reported for VBL‐containing combination protocols. Further, findings suggest VBL at a dosage of 3.5 mg/m2 should be considered for use in future phase II/III trials.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Rassnick, K.M. and Bailey, D.B. and Flory, A.B. and Balkman, C.E. and Kiselow, M.A. and Intile, J.L. and Autio, K.}, year={2008}, month={Nov}, pages={1390–1396} } @article{nitabach_llamas_araneda_intile_thompson_zhou_holmes_2001, title={A mechanism for combinatorial regulation of electrical activity: Potassium channel subunits capable of functioning as Src homology 3-dependent adaptors}, volume={98}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/pnas.98.2.705}, DOI={10.1073/pnas.031446198}, abstractNote={It is an open question how ion channel subunits that lack proteinprotein binding motifs become targeted and covalently modified by cellular signaling enzymes.Here, we show that Src-family protein tyrosine kinases (PTKs) bind to heteromultimeric Shakerfamily voltage-gated potassium (Kv) channels by interactions between the Src homology 3 (SH3) domain and the proline-rich SH3 domain ligand sequence in the Shaker-family subunit Kv1.5.Once bound to Kv1.5, Src-family PTKs phosphorylate adjacent subunits in the Kv channel heteromultimer that lack proline-rich SH3 domain ligand sequences.This SH3-dependent tyrosine phosphorylation contributes to significant suppression of voltage-evoked currents flowing through the heteromultimeric channel.These results demonstrate that Kv1.5 subunits function as SH3-dependent adaptor proteins that marshal Src-family kinases to heteromultimeric potassium channel signaling complexes, and thereby confer functional sensitivity upon coassembled channel subunits that are themselves not bound directly to Src-family kinases by allowing their phosphorylation.This is a mechanism for information transfer between subunits in heteromultimeric ion channels that is likely to underlie the generation of combinatorial signaling diversity in the control of cellular electrical excitability.}, number={2}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Nitabach, M. N. and Llamas, D. A. and Araneda, R. C. and Intile, J. L. and Thompson, I. J. and Zhou, Y. I. and Holmes, T. C.}, year={2001}, month={Jan}, pages={705–710} }