Association studies of salinity tolerance in sunflower provide robust breeding and selection strategies under climate change.

Phytotoxic soil salinity is a global problem, and in the northern Great Plains and western Canada, salt accumulates on the surface of marine sediment soils with high water tables under annual crop cover, particularly near wetlands. Crop production can overcome saline-affected soils using crop species and cultivars with salinity tolerance along with changes in management practices. This research seeks to improve our understanding of sunflower (Helianthus annuus) genetic tolerance to high salinity soils. Genome-wide association was conducted using the Sunflower Association Mapping panel grown for two years in naturally occurring saline soils (2016 and 2017, near Indian Head, Saskatchewan, Canada), and six phenotypes were measured: days to bloom, height, leaf area, leaf mass, oil percentage, and yield. Plot level soil salinity was determined by grid sampling of soil followed by kriging. Three estimates of sunflower performance were calculated: (1) under low soil salinity (< 4 dS/m), (2) under high soil salinity (> 4 dS/m), and (3) plasticity (regression coefficient between phenotype and soil salinity). Fourteen loci were significant, with one instance of co-localization between a leaf area and a leaf mass locus. Some genomic regions identified as significant in this study were also significant in a recent greenhouse salinity experiment using the same panel. Also, some candidate genes underlying significant QTL have been identified in other plant species as having a role in salinity response. This research identifies alleles for cultivar improvement and for genetic studies to further elucidate salinity tolerance pathways.

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Characterization of Visual Pathway Abnormalities in Infants With Congenital Zika Syndrome Using Computed Tomography and Magnetic Resonance Imaging.

BACKGROUND: Severe visual impairment is present in nearly all infants with congenital Zika syndrome (CZS); however, ocular abnormalities are present only in a subset of these infants. The purpose of this study was to characterize the visual pathway abnormalities seen on computed tomography (CT) and MRI scans in infants with CZS. METHODS: Preliminary neuroimaging information was obtained from a referred sample of 105 infants with clinical and epidemiologic data consistent with CZS in the Pernambuco state of Brazil. Subjects were excluded if Zika virus infection was not confirmed by serologic or cerebrospinal fluid studies or if images were nondiagnostic. Of the 105 subjects initially screened, head CT images adequate for interpretation were available for 54, and brain MRI images adequate for interpretation were available for 20. Four patients had both CT and MRI images. Magnetic resonance imaging and CT scans from infants with CZS were systematically reviewed for globe malformations, optic nerve and chiasmal atrophy, occipital cortical volume loss, white matter abnormalities, ventriculomegaly, and calcifications. Neuroimaging findings were correlated with measures of visual function and with ocular examinations in these infants. RESULTS: Thirty-three males and 37 females were included in the analysis. The mean age of the infants at the time of neuroimaging was 16.0 weeks (range 0 days-15.5 months), and the mean gestational age at the time of birth was 38 weeks. All patients were from the Pernambuco state of Brazil. Overall, 70 of 74 (95%) scans showed occipital volume loss, whereas 9 (12%) showed optic nerve atrophy, 3 (4%) showed chiasmal atrophy, and 1 (1%) showed an ocular calcification. Sixty-two of the infants underwent ophthalmologic examinations. A total of 34 (55%) infants had at least one documented structural ocular abnormality, and 26 (42%) had at least one structural ocular abnormality documented in both eyes. Of those with available visual acuity data, all had visual impairment. Among those with visual impairment and normal eye examinations, 100% had visual pathway abnormalities on neuroimaging, including 100% with occipital cortical volume loss, 8% with optic nerve atrophy, and 8% with chiasmal atrophy. CONCLUSION: Our results suggest that cortical visual impairment related to structural abnormalities of the occipital cortex is likely an important cause of visual impairment in children with CZS with normal eye examinations.

Impact of a mobile-based (mHealth) tool to support community health nurses in early identification of depression and suicide risk in Pacific Island Countries.

OBJECTIVE: To convert screening tools for depression and suicide risk into algorithmic decision support on smartphones for use by community health nurses (CHNs), and to evaluate the efficiency, effectiveness, and usability of the mHealth tool in providing mental health (MH) care. METHOD: Two scenarios of depression and suicide risk were developed and presented to 48 nurses using paper-based and mobile-based guidelines under laboratory (nonclinical) conditions. Participants read through the case scenarios to provide summaries, diagnoses, and management recommendations. Audiotapes were transcribed and analyzed for accuracy in scoring guidelines, therapy decisions, and time for tasks completion. The validated System Usability Scale (SUS) was used to measure mobile app usability. RESULTS: Using mHealth-based guidelines, nurses took significantly less time to complete their tasks, and generated no errors of addition, as compared to paper-based guidelines. Although coding errors were noted when using the mHealth app, it did not influence treatment recommendations. The system usability scores for both guidelines were over 84%. CONCLUSIONS: Usable mHealth technology can support task-sharing for CHNs in Fiji, for the efficient and accurate screening of patients for depression and suicide risks in a nonclinical setting. Studies on clinical implementation of the mHealth tool are needed and planned.

Dietary Intake and Diet Quality of Hematopoietic Stem Cell Transplantation Survivors.

Hematopoietic stem cell transplantation (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population. HCT survivors are susceptible to multiple complications that may result in chronic illness. Unfortunately, no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guidelines for Americans (DGA), which are designed specifically to provide guidance for making healthy food choices. The primary aim of this study was to evaluate diet quality and nutrient intake adequacy of HCT survivors. A secondary aim was to assess these survivors' willingness to take part in a future dietary intervention. The dietary intake of adults who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1 year post-transplantation was assessed using the Block 2014 food frequency questionnaire, and diet quality was estimated using the Healthy Eating Index 2015. Nutrient intake adequacies of the group were estimated by the estimated average requirement cutpoint method. Survivors' (n = 90) HEI-2015 scores averaged 61.6 ± 1.1. Adherence to a good-quality diet was reported by only 10% of survivors. Intakes of vitamins A, C, and D, as well as magnesium and calcium, suggested inadequacy. Fiber intake at 8.9 g per 1000 kcal/day fell below the recommended adequate intake. "Change in taste" was associated with lower quality of diet (P = .02). HCT survivors within 2 years post-transplantation were more receptive than survivors beyond 2 years to participating in a dietary intervention (95% versus 65%; P = .0013). Adult HCT survivors reported less-than-optimal adherence to the 2015-2020 DGA and had numerous shortfall nutrient intakes; however, their willingness to participate in a dietary intervention was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care.

Poor peripheral blood stem cell mobilization affects long-term outcomes in multiple myeloma patients undergoing autologous stem cell transplantation.

BACKGROUND: Peripheral blood stem cell (PBSC) mobilization is routinely undertaken prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A number of studies have identified risk factors for poor PBSC mobilization, however, little data exists to correlate mobilization with disease-specific outcomes in this patient population. Prospective work in MM has demonstrated similar outcomes in a homogenous patient population. METHODS: In this single institution analysis, we retrospectively studied the impact of poor PBSC mobilization on progression free survival (PFS) and OS in MM patients undergoing PBSC mobilization. Poor mobilizers are defined as patients that collected < 4 × 106 CD34+ cells/kg over maximum of 5 apheresis days, or those that required ≥2 mobilization cycles to achieve this target. RESULTS: We confirm that poor PBSC mobilization is significantly associated with a shortened PFS (P = .0012) and OS (P = .0005) compared with good mobilizers. Our univariate analysis also shows that independent risk factors for poor mobilization include male gender, higher ideal body weight, and a greater median number of lines of chemotherapy prior to PBSC mobilization. However, by multivariate analysis, only number of prior lines of chemotherapy remains significantly predictive of poor mobilization (Odds ratio 1.857, P = .0095). The use of high-dose G-CSF (> 10 mcg/kg/day) and/or plerixafor can significantly improve mobilization and ASCT chances in this population. DISCUSSION: These data indicate that poor mobilization can be predictable and is associated with more aggressive disease biology and worse outcomes, warranting intensive post-ASCT management.

Litter decay controlled by temperature, not soil properties, affecting future soil carbon.

Widespread global changes, including rising atmospheric CO2 concentrations, climate warming and loss of biodiversity, are predicted for this century; all of these will affect terrestrial ecosystem processes like plant litter decomposition. Conversely, increased plant litter decomposition can have potential carbon-cycle feedbacks on atmospheric CO2 levels, climate warming and biodiversity. But predicting litter decomposition is difficult because of many interacting factors related to the chemical, physical and biological properties of soil, as well as to climate and agricultural management practices. We applied 13 C-labelled plant litter to soil at ten sites spanning a 3500-km transect across the agricultural regions of Canada and measured its decomposition over five years. Despite large differences in soil type and climatic conditions, we found that the kinetics of litter decomposition were similar once the effect of temperature had been removed, indicating no measurable effect of soil properties. A two-pool exponential decay model expressing undecomposed carbon simply as a function of thermal time accurately described kinetics of decomposition. (R2  = 0.94; RMSE = 0.0508). Soil properties such as texture, cation exchange capacity, pH and moisture, although very different among sites, had minimal discernible influence on decomposition kinetics. Using this kinetic model under different climate change scenarios, we projected that the time required to decompose 50% of the litter (i.e. the labile fractions) would be reduced by 1-4 months, whereas time required to decompose 90% of the litter (including recalcitrant fractions) would be reduced by 1 year in cooler sites to as much as 2 years in warmer sites. These findings confirm quantitatively the sensitivity of litter decomposition to temperature increases and demonstrate how climate change may constrain future soil carbon storage, an effect apparently not influenced by soil properties.

A new captorhinid reptile from the Lower Permian of Oklahoma showing remarkable dental and mandibular convergence with microsaurian tetrapods.

The Lower Permian fossiliferous infills of the Dolese Brothers Limestone Quarry, near Richards Spur, Oklahoma, have preserved the most diverse assemblage of Paleozoic terrestrial vertebrates, including small-bodied reptiles and lepospondyl anamniotes. Many of these taxa were previously known only from fragmentary remains, predominantly dentigerous jaw elements and numerous isolated skeletal elements. The recent discovery of articulated skulls and skeletons of small reptiles permits the recognition that dentigerous elements, previously assigned at this locality to the anamniote lepospondyl Euryodus primus, belong to a new captorhinid eureptile, Opisthodontosaurus carrolli gen. et sp. nov. This mistaken identity points to a dramatic level of convergence in mandibular and dental anatomy in two distantly related and disparate clades of terrestrial tetrapods and sheds light on the earliest instance of durophagy in eureptiles.

Quality of life and adherence to antiretroviral therapy in Southern Brazil.

The absence of or limited adherence to treatment is the main cause for the failure of Highly Active Antiretroviral Therapy (HAART). In Brazil, adherence to antiretroviral therapy has been lower than the recommended levels. Although HAART may produce adverse reactions, failure to comply with it may aggravate patients' health status and impair Quality of Life (QoL). The QoL of individuals living chronically with HIV and AIDS has been considered one of the main treatment outcomes. This study is part of a 225-day prospective trial in which participants were enrolled in two different modalities of follow-up: the usual model medical follow-up or an intervention based on the Medication Adherence Training Instrument (MATI). The WHOQOL-HIV BREF questionnaire was used to evaluate QoL of research participants in both groups on the 15th and 225th days of follow-up after the baseline assessment. The result of this study revealed no significant differences of WHOQOL-HIV BREF scores between participants allocated to MATI and non-MATI groups in the first assessment. However, there was a significant difference between the scores obtained on the 15th and 225th days in the domain related to spirituality and personal beliefs irrespective of the modality of follow-up. Other domains of the WHOQOL-HOV BREF remained unchanged. These results indicate that, in this sample, personal beliefs and spirituality may be relevant subjects to explain sustained levels of adherence to HAART.

Simultaneous colonic adenocarcinoma and medulloblastoma in a 12-year-old with biallelic deletions in PMS2.

We describe a 12-year-old girl, simultaneously presenting with colonic adenocarcinoma and medulloblastoma from bialleic deletions in the mismatch repair gene PMS2. Her distinctive physical and clinical findings are characteristic of constitutional mismatch repair deficiency syndrome. Earlier recognition of such findings may permit better screening and more effective treatment.

Pilot study of nurse-led rheumatic heart disease echocardiography screening in Fiji--a novel approach in a resource-poor setting.

We designed a pilot study of a training module for nurses to perform rheumatic heart disease echocardiography screening in a resource-poor setting. The aim was to determine whether nurses given brief, focused, basic training in echocardiography could follow an algorithm to potentially identify cases of rheumatic heart disease requiring clinical referral, by undertaking basic two-dimensional and colour Doppler scans. Training consisted of a week-long workshop, followed by 2 weeks of supervised field experience. The nurses' skills were tested on a blinded cohort of 50 children, and the results were compared for sensitivity and specificity against echocardiography undertaken by an expert, using standardised echocardiography definitions for definite and probable rheumatic heart disease. Analysis of the two nurses' results revealed that when a mitral regurgitant jet length of 1.5 cm was used as the trigger for rheumatic heart disease identification, they had a sensitivity of 100% and 83%, respectively, and a specificity of 67.4% and 79%, respectively. This pilot supports the principle that nurses, given brief focused training and supervised field experience, can follow an algorithm to undertake rheumatic heart disease echocardiography in a developing country setting to facilitate clinical referral with reasonable accuracy. These results warrant further research, with a view to developing a module to guide rheumatic heart disease echocardiographic screening by nurses within the existing public health infrastructure in high-prevalence, resource-poor regions.

Effects of nitrogen fertilization and a commercial arbuscular mycorrhizal fungal inoculant on root rot and agronomic production of pea and lentil crops.

In the Canadian prairies, pulse crops such as field pea (Pisum sativum L.) and lentil (Lens culinaris L.) are economically important and widely grown. However, in recent years, root rot, caused by a variety of fungal and oomycete pathogens, including Aphanomyces euteiches, has become a limiting factor on yield. In this study, we examined the impacts of nitrogen (N) fertilization and a commercial arbuscular mycorrhizal fungal (AMF) inoculant on pea and lentil plant health and agronomic production at three locations in Saskatchewan: Swift Current, Indian Head and Melfort. The AMF inoculation had no impact on root rot severity, and therefore is not considered a reliable method to manage root rot in pea and lentil. In contrast, N fertilization led to reductions in root rot in Swift Current, but not the other two sites. However, N fertilization did reduce nodulation. When both pea and lentil are considered, the abundance of A. euteiches in soil increased from pre-seeding to mid-bloom. A negative correlation between soil pH and disease severity was also observed. The high between-site variability highlights the importance of testing root rot mitigation strategies under multiple soil conditions to develop site-specific recommendations. Use of N fertilizer as a root rot management strategy merits further exploration, including investigation into its interactions with other management strategies, soil properties, and costs and benefits.

Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas.

Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

Effects of seeding rate, nitrogen rate and cultivar on barley malt quality.

BACKGROUND: Crop management tools have been shown to affect barley kernel size and grain protein content, but the direct effect on malt quality is not well understood. The present study investigated the effect of seeding rate, nitrogen fertilisation and cultivar on malt quality. RESULTS: Higher seeding rates produced barley with less grain protein and smaller, more uniformly sized kernels. The small, uniformly sized kernels modified more completely, leading to malt with higher extract and lower wort ß-glucan than malt from low-seeding-rate barley. Increasing rates of nitrogen fertilisation caused grain protein levels to increase, which limited endosperm modification and reduced malt extract levels. AC Metcalfe showed better modification and higher malt extract than CDC Copeland, but CDC Copeland had better protein modification at higher fertilisation rates, which resulted in less reduction of malt extract as nitrogen rate increased. CONCLUSION: Higher seeding rates reduced kernel size and grain protein levels without compromising malt extract owing to better endosperm modification of the more uniformly sized kernels. Negative effects of higher nitrogen rates on malt quality can be reduced through development of cultivars with improved ability to modify protein during malting.

Patients' Perception of Factors Influencing Noncompliance with Medication among Cardiac Patients in Fiji: A Qualitative Study.

BACKGROUND: Noncompliance with prescribed medication leads to disease progression, which often leads to premature deaths. It often leads to worsening symptoms of cardiac conditions and hospitalization. Due to the lack of previous research, this study aimed to explore the factors contributing to noncompliance with medication in cardiac patients in Fiji. METHODS: This qualitative study was conducted among 25 cardiac patients with congestive heart failure and coronary heart disease who attended special outpatient department (SOPD) clinics at Sigatoka Subdivisional Hospital in Fiji. Purposive sampling was used to select the study sample, and in-depth face-to-face interviews were conducted using a semistructured, open-ended questionnaire. Data were analyzed using thematic analysis, whereby the data collected were grouped in subthemes and then common themes related to the topic. RESULTS: A total of 25 patients were interviewed, with a majority (n=14) being men and 15 Fijian of Indian descent. A greater number (n=17) of participants were above the age of 60 years, 19 had had primary education, while 12 were unemployed. Eight themes were identified as factors affecting noncompliance with medication: scarcity of knowledge, patients' negative attitudes, poor family support, financial constraints, forgetfulness, irregular clinic attendance, heavy alcohol use, and alternative treatment vs pharmaceutical medication. CONCLUSION: Noncompliance with medication in cardiac patients contributes to worsening cardiac disease and premature deaths. For factors related to noncompliance, awareness can be raised in SOPD clinics for patients to realize the effects of noncompliance and provide ways to improve compliance. Providing professional counseling services for all SOPD patients would greatly help in increasing compliance with medication in Fiji.

Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: A case report and review of literature.

Despite improvements in first-line treatment of T-cell acute lymphoblastic leukemia (T-ALL), the outcome of relapsed T-ALL remains dismal with less than 7% achieving a long-term survival. Thus, there is an unmet need for new treatment strategies to improve outcomes in this setting. Suppression of apoptosis is one of the hallmarks of anticancer drug resistance. Hence, over the past few years, antiapoptotic proteins have become an attractive target for therapeutic intervention in several hematologic malignancies. Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor of B-cell lymphoma 2 (BCL-2), a key regulator of the intrinsic apoptotic pathway. Recent preclinical studies have suggested that inhibition of BCL-2 may be a novel therapeutic strategy for patients with T-ALL. Herein, we report a case of clinical response to venetoclax in combination with a hypomethylating agent in a patient with relapsed T-ALL after allogeneic stem cell transplant and review the existing literature.

The Perception of Undergraduate Dental Students Toward a Clinical Learning Environment at School of Dentistry and Oral Health, Fiji National University, Fiji.

BACKGROUND: The clinical learning environment is one of the key factors for undergraduate dental students to excel in their academic career. There has been no previous study in Fiji regarding dental students' perception of their learning environment. AIM: This study aimed at investigating the perception of undergraduate dental students toward the clinical learning environment at the School of Dentistry and Oral Health (SDOH), Fiji. MATERIALS AND METHODS: This is a cross-sectional prospective study conducted among 157 undergraduate dental students, all of whom were selected from three undergraduate dental programs. The modified 24-item Dental Clinical Learning Environment Inventory (DECLEI) was used to assess students' perceptions. The mean DECLEI score was interpreted as follows: ≤19.9 is very poor perception, 20-39.9 is poor perception, 40-59.9 is moderate perception, 60-79.9 is good perception, and >80 is excellent perception toward the clinical learning environment. A correlation test was used to examine the relationship between independent variables and DECLEI scores. P < 0.05 was considered as level of significance. RESULTS: The response rate was 82.8%. Majority of the participants (76.9%) were in the age range of 20-29 years, were females (72.3%), and were Fijians of Indian descent (75.4%). The mean DECLEI score was 70.83 ± 9.11 which could be interpreted as a good perception toward the clinical learning environment. Age and gender had a statistically significant negative correlation with DECLEI scores (P < 0.05). CONCLUSION: The dental clinical learning environment at SDOH can be perceived as "good"; however, issues related to patients' missing appointment were highlighted.

Information processing by community health nurses using mobile health (mHealth) tools for early identification of suicide and depression risks in Fiji Islands.

OBJECTIVES: High rates of depression and suicide and a lack of trained psychiatrists have emerged as significant concerns in the low-income and middle-income countries (LMICs) such as the Pacific Island Countries (PICs). Readily available smartphones were leveraged with community health nurses (CHNs) in task-sharing for early identification of suicide and depression risks in Fiji Islands, the largest of PICs. This investigation examines how CHNs can efficiently and effectively process patient information about depression and suicide risk for making diagnostic and management decisions without compromising safety. The research is driven by the theoretical framework of text comprehension (knowledge representation and interpretation) and decision-making. METHODS: Mobile health (mHealth) Application for Suicide Risk and Depression Assessment (ASRaDA) was designed to include culturally useful clinical guidelines for these disorders. A representative sample of 48 CHNs was recruited and presented with two clinical cases (depression and suicide) in a simulated setting under three conditions: No support, paper-based and mobile-based culturally valid guideline support. Data were collected as the nurses read through the scenarios, 'thinking aloud', before summarising, diagnoses and follow-up recommendations. Transcribed audiotapes were analysed using formal qualitative discourse analysis methods for diagnostic accuracy, comprehension of clinical problems and reasoning patterns. RESULTS: Using guidelines on ASRaDA, the CHNs took less time to process patient information with more accurate diagnostic and therapeutic decisions for depression and suicide risk than with paper-based or no guideline conditions. A change in reasoning pattern for nurses' information processing was observed with decision support.DiscussionAlthough these results are shown in a mental health setting in Fiji, there are reasons to believe they are generalisable beyond mental health and other lower-to-middle income countries. CONCLUSIONS: Culturally appropriate clinical guidelines on mHealth supports efficient information processing for quick and accurate decisions and a positive shift in reasoning behaviour by the nurses. However, translating complex qualitative patient information into quantitative scores could generate conceptual errors. These results are valid in simulated conditions.

Tnk1/Kos1: a novel tumor suppressor.

Tnk1/Kos1 is a non-receptor protein tyrosine kinase implicated in negative regulation of cell growth by a mechanism involving inhibition of Ras activation and requiring Tnk1/Kos1's intrinsic catalytic activity. Tnk1/Kos1 null mice were created by homologous recombination by deleting the catalytic domain. Upon aging, both Tnk1+/- and Tnk1-/- mice develop spontaneous tumors, including lymphomas and carcinomas at high rates (i.e. 27%, and 43%, respectively), indicating that Tnk1/Kos1 is a tumor suppressor. Tissues from Tnk1/Kos1-null mice exhibit proportionally higher levels of basal and growth factor-stimulated Ras activation. Mechanistically, Tnk1/Kos1 requires either or both Y277 and Y287 sites to be intact for enzymatic activity and phosphorylation of its substrate, growth factor receptor binding protein 2 (Grb2). Data indicate that following tyrosine phosphorylation of Grb2 by Tnk1/Kos1, the Grb2-Sos1 guanine exchange factor (GEF) complex that mediates growth factor stimulated Ras activation becomes disrupted, resulting in the reversal of Ras activation. Conversely, the loss of Tnk1/Kos1 activity results in constitutive activation of Ras due to prolonged stabilization/activation of the Grb2-Sos1 GEF activity. Tnk1/Kos1 is the first tyrosine kinase discovered to have tumor suppressor activity, and the mechanism of spontaneous tumor formation involves constitutive, indirect activation of Ras. Thus, Ras may display "oncogenic activity" without undergoing "oncogenic" mutation. We now find that a cohort of patients with diffuse large B-cell lymphoma (DLBCL) display downregulation of Tnk1/Kos1 that may account for tumorigenesis in humans.