Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC

Abstract Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by peripheral cytopenias and risk of progression to leukemia. MDS patients (pts) are often anemic, resulting in increased red blood cell transfusions (tfns) and fatigue. Previous studies have shown that 150mcg/week (wk) or 300mcg/wk of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in low-risk MDS pts (Patton et al. J Support Oncol.2005;3:419–426). We present data from a phase 2, single-arm, open-label study on the efficacy of 500mcg DA administered every three wks (Q3W) for treating anemia in low-risk MDS pts. Eligibility criteria included ≥18 years, anemia (Hb ≤11g/dL), and low- or intermediate-1-risk MDS (IPSS definition). If pts did not respond by wk 7, the dosing frequency was escalated to Q2W. After the last DA dose on wk 52, the end of study (EOS) was wk 53 (Q2W dosing) or wk 55 (Q3W dosing). The primary endpoint was the percentage of pts with an erythroid response (International Working Group criteria) by wk 13. Secondary 53/55-wk endpoints included incidence of erythroid responses, incidence of tfns, and the change in Hb levels and FACT-F score from baseline (BL). Results were stratified by whether pts had prior ESA therapy: ESA-naive (ESA-N) vs prior ESA-treated (ESA-T). A previous interim analysis showed that low-risk MDS pts could achieve an erythroid response after 13 wks of DA 500mcg Q3W (Gabrilove et al. Blood.2005;106:abstract2541). This is the first reported summary after 53/55 wks (n=148). Of 98 ESA-N pts, 47% were men, 85% were white, and the mean (SD) age was 74 (10) years; the 50 ESA-T pts had similar demographics. Both ESA-N and ESA-T pts had similar BL Hb (Table). By wk 53/55, the percentage (95% CL) of pts with a major erythroid response (≥2g/dL Hb rise from BL or tfn independence) was 56% (46, 66) in ESA-N pts and 30% (17, 43) in ESA-T pts. Both ESA-N and ESA-T pts had a clinically meaningful rise (≥3 points) in FACT-F score from BL. Of the 148 pts, 89% reported adverse events (AEs) with the most common AE being fatigue, 7% had AEs considered related to DA treatment, and 1.4% had thromboembolic events. These results suggested that DA 500mcg Q3W was well tolerated and increased Hb levels in the MDS pts in this study. ESA-N, N=98 ESA-T, N=50 KM%= Kaplan-Meier percentage Crude % (95% CL) pts with a major erythroid response 56% (46, 66) 30% (17, 43) Crude % (95% CL) pts with a minor erythroid response 15% (8, 22) 20% (9, 31) Mean (SD) BL Hb, g/dL 9.8 (1.0) [n=84] 10.0 (1.2) [n=41] Mean (SD) Hb change (BL to wk 53/55) (last value carried forward) 1.1 (1.6) [n=84] 0.2 (1.7) [n=41] Crude % (95% CL) pts achieved target Hb (11g/dL) 68% (58, 78) [n=87] 46% (31, 60) [n=46] Mean (SD) Hb after reached Hb target, g/dL 11.7 (0.8) [n=68] 11.6 (0.9) [n=25] KM% (95% CL) pts with tfns (wk 1 to EOS) 29% (19, 39) 43% (27, 59) KM% (95% CL) pts with tfns (wk 5 to EOS) 28% (19, 38) [n=96] 43% (26, 60) [n=45] Mean (SD) change in FACT-F score (BL to wk 53/55) 5.8 (8.6) [n=45] 7.2 (9.3) [n=15]

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Molecular Features and Methylation Status in Early Onset (≤40 Years) Colorectal Cancer: A Population Based, Case-Control Study

Gastroenterology Research and Practice ◽

10.1155/2015/132190 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Giulia Magnani ◽

Daniela Furlan ◽

Nora Sahnane ◽

Luca Reggiani Bonetti ◽

Federica Domati ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Early Onset ◽

Methylation Status ◽

The Elderly ◽

Population Based ◽

Repair System ◽

Molecular Features ◽

A Minor ◽

Early Onset Colorectal Cancer

Colorectal cancer is usually considered a disease of the elderly. However, a small fraction of patients develops colorectal cancer earlier. The aim of our study was to define the frequency of known hereditary colorectal syndromes and to characterise genetic and epigenetic features of early nonhereditary tumors. Thirty-three patients ≤40 years with diagnosis of colorectal cancer and 41 patients with disease at >60 years of age were investigated for MSI, Mismatch Repair proteins expression,KRASandBRAFmutations, hypermethylation, and LINE-1 hypomethylation. Detection of germline mutations was performed in Mismatch Repair,APCandMUTYHgenes. Early onset colorectal cancer showed a high incidence of hereditary forms (18%).KRASmutations were detected in 36% of early nonhereditary tumors. Early onset colorectal cancer disclosed an average number of methylated genes significantly lower when compared to the controls (p=0.02). Finally both of the two groups were highly methylated inESR1,GATA5, andWT1genes and were similar for LINE-1 hypomethylation. The genetic make-up of carcinomas differs from young to elderly patients. Early onset tumors showed more frequently a constitutional defective of Mismatch Repair System and a minor number of methylated genes. Hypermethylation ofESR1,GATA5, andWT1genes suggests possible markers in the earlier diagnosis of colorectal tumorigenesis.

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Diurnal feeding strategies of the Ferruginous Duck (Aythya nyroca) in Lake Tonga (Northeastern Algeria)

Ornis Hungarica ◽

10.2478/orhu-2019-0005 ◽

2019 ◽

Vol 27 (1) ◽

pp. 85-98 ◽

Cited By ~ 1

Author(s):

Khalil Draidi ◽

Badis Bakhouche ◽

Naouel Lahlah ◽

Imed Djemadi ◽

Mourad Bensouilah

Keyword(s):

Feeding Behaviour ◽

Foraging Behaviour ◽

Time Budget ◽

Search Time ◽

Environmental Parameters ◽

Feeding Strategies ◽

A Minor ◽

Northeastern Algeria ◽

Foraging Time ◽

Minor Activity

Abstract Although the Ferruginous Duck (Aythya nyroca) has thoroughly been studied, the foraging behaviour of this species is still not completely known. In the present paper we studied the diurnal feeding behaviour of ducks. We monitored the annual cycle of birds through two fieldtrips per month. The instantaneous behaviour of birds was recorded in regular 30-minute intervals from 7 a.m. to 4:30 p.m., amounting a total of 456 observation hours. Food searching activity corresponds to a quarter of the total diurnal time budget of the Ferruginous Duck. Foraging behaviour was classified into five categories dominated by the “diving”, which is almost 45.61% of the total search time. Foraging activities at the water surface considered to be secondary activities, including feeding by “bill”, “neck and head”, and “beak and head” in a rate of 19.86%, 14.53%, and 13.98%, respectively. The “toggle” remains a minor activity and represents only 5.99% of foraging time. The feeding behaviour of this species correlated to several environmental parameters (rainfall, temperature and wind velocity), and linked to the group size of ducks visiting the lake. Regarding the food intensity, our results show the highest values for “bill and head” behaviour. “Diving” has the longest feeding interval (16.16±14.1 minutes), while foraging by “bill” has the shortest (0.69 ± 0.48 minutes).

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MLH3, a minor player in mismatch repair, is a major force in GAA•TTC repeat expansion (736.9)

The FASEB Journal ◽

10.1096/fasebj.28.1_supplement.736.9 ◽

2014 ◽

Vol 28 (S1) ◽

Author(s):

Kayla Fuselier ◽

Ed Grabczyk

Keyword(s):

Mismatch Repair ◽

Repeat Expansion ◽

A Minor

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Factor XII-Dependent Fibrinolysis: A Double Function of Plasma Kallikrein and the Occurrence of a Previously Undescribed Factor XII- and Kallikrein-Dependent Plasminogen Proactivator

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646835 ◽

1979 ◽

Vol 41 (04) ◽

pp. 756-773 ◽

Cited By ~ 32

Author(s):

C Kluft ◽

M M Trumpi-Kalshoven ◽

A F H Jie ◽

E C Veldhuyzen-Stolk

Keyword(s):

Plasminogen Activator ◽

Low Molecular Weight ◽

Plasma Kallikrein ◽

Factor Xii ◽

Normal Plasma ◽

Double Function ◽

Plasma Fractions ◽

A Minor ◽

Molecular Weight Form ◽

Minor Activity

SummaryFibrinolytic studies in euglobulin fractions of Fletcher trait plasma (deficient in prekallikrein) revealed reduced activities as compared to normal plasma. A quantitative assay for total plasminogen activator plus proactivator in plasma showed that the amount in Fletcher trait patients is about half of normal (normal = ± 100 blood activator units [BAU]/ ml). Plasma kallikrein partially purified in a high and low molecular weight form exerted plasminogen activator activity amounting to 10–15 BAU/ml plasma. So, the absence of kallikrein in the deficient plasma can not fully account for the reduction in activator activity. Additions of kallikrein preparations or normal plasma fractions resulted in additional activator activity in Fletcher trait plasma which was assessed at 30–40 BAU/ml. This activity was assumed to originate from a previously undescribed plasminogen proactivator whose activation is kallikrein- and factor XH-dependent.Fractionation experiments demonstrated the presence of two major activities and a minor activity caused by kallikrein in normal plasma.It is concluded that plasma kallikrein has two functions in the generation of factor XII- dependent fibrinolytic activity: one as a direct plasminogen activator and another as a factor in the activation of a major factor XH-dependent plasminogen proactivator.

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Defective mismatch-repair as a minor tumorigenic pathway in Barrett esophagus-associated adenocarcinoma

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2004.08.003 ◽

2005 ◽

Vol 157 (1) ◽

pp. 82-86 ◽

Cited By ~ 13

Author(s):

Dan Falkenback ◽

Jan Johansson ◽

Britta Halvarsson ◽

Mef Nilbert

Keyword(s):

Mismatch Repair ◽

Barrett Esophagus ◽

A Minor ◽

Defective Mismatch Repair

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Silvicultural contracting in British Columbia

The Forestry Chronicle ◽

10.5558/tfc74899-6 ◽

1998 ◽

Vol 74 (6) ◽

pp. 899-910 ◽

Cited By ~ 1

Author(s):

Sen Wang ◽

Bill Wilson ◽

G. C. van Kooten

Keyword(s):

Timber Harvesting ◽

The Past ◽

Public Expectations ◽

Contractual Relationships ◽

Payment Schemes ◽

Long Time ◽

Three Stages ◽

Forest Nurseries ◽

A Minor ◽

Minor Activity

Over the past eight decades, British Columbia's silvicultural programs have gone through three stages: initiation, establishment and development. For a long time, silviculture was a minor activity associated with timber harvesting, and the formation of silviculture as a distinct sector did not take place until the late 1960s. Shifts in societal values and changes in public expectations concerning forest management contributed to changes in B.C.'s forestry institutions that, in turn, altered the structure of silviculture programs. Especially since the 1980s, expansion in the scope and scale of silvicultural activities transformed contractual relationships. This paper profiles the contractual structure of B.C.'s silviculture sector. Results of a survey of contractors indicate that seed orchards, forest nurseries and companies holding timber tenures on public land economize on transaction costs by choosing appropriate organizational and contractual forms in accordance with identifiable attributes of silvicultural activities and firms' characteristics. Key words: silviculture, contractual forms, transaction cost, payment schemes

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THE RELATION OF THE SPLEEN TO BLOOD DESTRUCTION AND REGENERATION AND TO HEMOLYTIC JAUNDICE

Journal of Experimental Medicine ◽

10.1084/jem.16.6.780 ◽

1912 ◽

Vol 16 (6) ◽

pp. 780-788 ◽

Cited By ~ 7

Author(s):

Richard M. Pearce ◽

J. H. Austin

Keyword(s):

Endothelial Cells ◽

Lymph Nodes ◽

Great Increase ◽

Stellate Cells ◽

Immune Serum ◽

Pathological Conditions ◽

Large Numbers ◽

A Minor ◽

Minor Activity

In a large proportion of dogs that have been splenectomized for periods of two weeks or more, one finds a great increase in the number of endothelial cells of the lymph nodes. In most splenectomized dogs that succumb to an injection of hemolytic immune serum within forty-eight hours, the sinuses of the lymph nodes contain large numbers of endothelial cells, phagocytic for red cells. This is not seen in normal dogs receiving hemolytic serum. Likewise a similar power of phagocytosis is seen frequently in the stellate cells of the capillaries of the liver. Both in the lymph nodes and the liver these cells appear to be formed in situ; we find no evidence that they have been transported to these organs. Such findings suggest the development of a compensatory function on the part of the lymph nodes and possibly of the liver. Normally the spleen contains cells which have the power to engulf and presumably to destroy the red blood corpuscles. In certain pathological conditions this function is frequently greatly augmented and may sometimes be shared by the lymph nodes, for example, in typhoid fever, as was first clearly shown by Mallory. Our observations suggest that in the absence of the spleen, this function of forming red blood corpuscle-phagocyting cells, normally a minor activity of the lymph nodes, becomes highly developed in the latter organs, and that these cells, and the stellate cells of the liver, thus assume, in part at least, the function of destroying red blood corpuscles by phagocytosis. In view of the somewhat limited material at our disposal, we offer this, not as definitely conclusive, but as evidence which, in connection with the work of others, is highly suggestive of the possibility of the lymph nodes assuming some of the function of the spleen. Whether this activity of the endothelial cells of the lymph nodes and the liver has any bearing on the anemia that follows splenectomy and on the occurrence of spontaneous jaundice in the late periods after splenectomy, is not yet clear.

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Does mismatch repair (MMR) deficiency have prognostic significance in low-risk endometrioid endometrial cancers?

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17122 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17122-e17122

Author(s):

Soyoun Rachel Kim ◽

Annick Pina ◽

Arianne Albert ◽

Jessica N. McAlpine ◽

Robert Wolber ◽

...

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Prognostic Significance ◽

Cox Proportional Hazards Model ◽

Low Risk ◽

Recurrence Rates ◽

Significant Difference ◽

Stage Ia ◽

Endometrial Cancers ◽

Mmr Deficiency

e17122 Background: Mismatch repair (MMR) deficiency is observed in 25-30% of all endometrial cancers. This can be detected by the absence of MMR protein staining on immunohistochemistry (IHC), and is used in many jurisdictions as a screen for an inherited mutation in one of the MMR genes (Lynch Syndrome). Only 10% of women with MMR deficiency (MMRd) have Lynch syndrome, but MMRd may still have prognostic significance. The objective of this study was to compare clinical outcomes between MMR deficient and proficient low-risk endometrioid endometrial cancers (stage IA, grade 1/2). Methods: This was a retrospective population-based cohort study of all low-risk endometrial cancers from Vancouver Coastal Health authority region from 2011 to 2016 that were assessed for MMR deficiency (MMRd). Primary outcome measures were recurrence rates expressed per person-years (py), progression free survival (PFS) and overall survival (OS) calculated using Kaplan-Meier method and log-rank tests. Cox proportional hazards model estimated the association between MMRd and recurrence and death after adjustment for covariates, expressed as hazard ratios (HR). Results: There were 475 low-risk patients, including 131 MMRd (27.6%) and 345 MMRp (proficient) patients. Women with MMRd tumors had higher recurrence rates (3.53p100py vs 1.21p100py) and worse PFS (p = 0.0082) compared to women with MMRp tumors. After adjustment for age, LVSI status, adjuvant therapy, and post-operative grade, MMRd status remained associated with a higher risk of recurrence (HR 2.99, 95% CI 1.27-7.04). There was no significant difference in OS between MMR groups (HR 1.38, 95% CI 0.57-3.33). Conclusions: In low-risk stage IA grade 1 or 2 endometrioid endometrial cancers, MMR deficiency is associated with a higher recurrence rate than in MMR proficient cases, after adjustment for covariates, implying that MMR deficiency reflects a different biology in endometrial cancer.

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