Relevance, Pathogenesis, and Testing Algorithm for Mismatch Repair–Defective Colorectal Carcinomas

Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder

Relevance, Pathogenesis, and Testing Algorithm for Mismatch Repair–Defective Colorectal Carcinomas A Report of the Association for Molecular Pathology

Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder

A gaming app developed for vestibular rehabilitation improves the accuracy of performance and engagement with exercises

IntroductionVestibular hypofunction is associated with dizziness, imbalance, and blurred vision with head movement. Vestibular rehabilitation is the gold standard recommendation to decrease symptoms and improve postural stability. The Clinical Practice Guidelines for vestibular hypofunction suggest home exercises 3–5 times daily, but patient adherence is a problem, with compliance rates often below 50%.MethodsAn app was developed to increase engagement with home exercises by providing exercises as games. This study compared the accuracy of exercise performance in a one-time session using the app versus no-app and gathered participant feedback on using the app for vestibulo-ocular reflex (VOR) and balance exercises. The app was tested with 40 adults (20 women), mean age of 67 ± 5.7 years, with symptomatic unilateral or bilateral vestibular hypofunction. Participants completed VOR exercises in pitch and yaw planes, weight-shift, and single-leg balance exercises using an inertial motion unit to move the character on the tablet screen. Participants were randomly assigned to begin the exercises with or without the app.ResultsResults show that during VOR exercises, participants achieved the prescribed frequency of head motion for the yaw plane (p ≤ 0.001) and reduced variability of head movement frequency in both the yaw (p ≤ 0.001) and pitch plane (p ≤ 0.001) in the app compared to the no-app condition. During weight-shifting exercises, a larger range of body motion was noted in the anteroposterior and mediolateral directions in the app compared to the no-app condition (p < 0.05). During single-leg balance exercises, pelvic motion was lower in the app versus no-app condition (p = 0.02). Participants modified their exercise performance and corrected their mistakes to a greater extent when they used the app during the VOR exercises. Participants agreed that they felt motivated while playing the games (97%) and felt motivated by the trophies (92%). They agreed that the app would help them perform the exercises at home (95%), improve their rehab performance (95%) and that it was fun to do the exercises using the app (93%).DiscussionThe results of this study show that technology that is interactive and provides feedback can be used to increase accuracy and engagement with exercises

Opposing effects of DNA on proteolysis of a replication initiator

DNA replication initiation proteins (Reps) are subjected to degradation by cellular proteases. We investigated how the formation of nucleoprotein complex, involving Rep and a protease, affects Rep degradation. All known Escherichia coli AAA+ cytosolic proteases and the replication initiation protein TrfA of the broad-host-range plasmid RK2 were used. Our results revealed that DNA influences the degradation process and that the observed effects are opposite and protease specific. In the case of ClpXP and ClpYQ proteases, DNA abolishes proteolysis, while in the case of ClpAP and Lon proteases it stimulates the process. ClpX and ClpY cannot interact with DNA-bound TrfA, while the ClpAP and Lon activities are enhanced by the formation of nucleoprotein complexes involving both the protease and TrfA. Lon has to interact with TrfA before contacting DNA, or this interaction can occur with TrfA already bound to DNA. The TrfA degradation by Lon can be carried out only on DNA. The absence of Lon results with higher stability of TrfA in the cell

Evidence That Two ATP-Dependent (Lon) Proteases in Borrelia burgdorferi Serve Different Functions

The canonical ATP-dependent protease Lon participates in an assortment of biological processes in bacteria, including the catalysis of damaged or senescent proteins and short-lived regulatory proteins. Borrelia spirochetes are unusual in that they code for two putative ATP-dependent Lon homologs, Lon-1 and Lon-2. Borrelia burgdorferi, the etiologic agent of Lyme disease, is transmitted through the blood feeding of Ixodes ticks. Previous work in our laboratory reported that B. burgdorferi lon-1 is upregulated transcriptionally by exposure to blood in vitro, while lon-2 is not. Because blood induction of Lon-1 may be of importance in the regulation of virulence factors critical for spirochete transmission, the clarification of functional roles for these two proteases in B. burgdorferi was the object of this study. On the chromosome, lon-2 is immediately downstream of ATP-dependent proteases clpP and clpX, an arrangement identical to that of lon of Escherichia coli. Phylogenetic analysis revealed that Lon-1 and Lon-2 cluster separately due to differences in the NH2-terminal substrate binding domains that may reflect differences in substrate specificity. Recombinant Lon-1 manifested properties of an ATP-dependent chaperone-protease in vitro but did not complement an E. coli Lon mutant, while Lon-2 corrected two characteristic Lon-mutant phenotypes. We conclude that B. burgdorferi Lons -1 and -2 have distinct functional roles. Lon-2 functions in a manner consistent with canonical Lon, engaged in cellular homeostasis. Lon-1, by virtue of its blood induction, and as a unique feature of the Borreliae, may be important in host adaptation from the arthropod to a warm-blooded host

"Places for children": Pluralization of forms of child care - raising institutional barriers

Grundlage für diesen Beitrag sind die Erfahrungen und Ergebnisse aus dem Projekt "Orte für Kinder", einem handlungsorientierten Modellprojekt des Deutschen Jugendinstituts, bei dem exemplarisch an ausgewählten Standorten Lösungen für bedarfsgerechte Angebote der Kinderbetreuung gesucht und erprobt wurden. Das Anliegen des Projekts war, in den bestehenden Strukturen von Tageseinrichtungen für Kinder und von Jugendhilfeplanung Handlungsspielräume ausfindig zu machen und Wege aufzuzeigen, wie Bedarf eruiert werden und wie sich das Angebot flexibler an die jeweilige Bedarfssituation vor Ort anpassen kann. Anschließend werden verschiedene Möglichkeiten zur Umstrukturierung des Betreuungsangebots beschrieben, die mehr Individualität im Rahmen von institutioneller Bedeutung zulassen sowie eine größere Vielfalt in der Kinderbetreuung durch Öffnung von institutionellen Schranken sowie durch Verknüpfung verschiedener Angebotsarten herstellen. (DIPF/Orig.)The article is based on the experiences and results of the "Places for Children" project run by the Deutsches Jugendinstitut, - an actionoriented model project in which, in selected locations, solutions were sought and tested aimed at meeting local requirements of child care. The central concern of the project was to discover where freedom of action is possible within the existing structures of day care arrangements and youth assistance planning and to show how local requirements can be determined and how care arrangements can be adapted more flexibly to local needs. Various possibilities are then described regarding a restructuring of care arrangements in order to allow for more individuality within the framework of institutional care and to introduce new qualities. Using selected examples from the range of innovative approaches in the "Places for [Children]" project, it is shown how the child\u27s experiential world can be broadened in day care institutions and how greater variety in child care can be achieved by raising institutional barriers and creating links between different types of care arrangements. (DIPF/Orig.