Reconstruction Techniques and Associated Morbidity in Minimally Invasive Gastrectomy for Cancer - Insights from the GastroBenchmark and GASTRODATA databases.

OBJECTIVE/BACKGROUND: Various anastomotic and reconstruction techniques are used for minimally invasive total (miTG) and distal gastrectomy (miDG). Their effects on postoperative morbidity have not been extensively studied. METHODS: MiTG and miDG patients were selected from 9356 oncological gastrectomies performed 2017-2021 in 44 centers. Endpoints included anastomotic leakage (AL) rate and postoperative morbidity tested by multivariable analysis. RESULTS: Three major anastomotic techniques (circular stapled (CS); linear stapled (LS); hand sewn (HS)), and three major bowel reconstruction types (Roux (RX); Billroth I (BI); Billroth II (BII)) were identified in miTG (n=878) and miDG (n=3334). Postoperative complications including AL (5.2% vs. 1.1%), overall (28.7% vs. 16.3%) and major morbidity (15.7% vs. 8.2%), as well as 90-day mortality (1.6% vs. 0.5%) were higher after miTG compared with miDG. After miTG, AL rate was higher after CS (4.3%) and HS (7.9%) compared with LS (3.4%). Similarly, major complications (LS: 9.7%, CS: 16.2%, HS: 12.7%) were lowest after LS. Multivariate analysis confirmed anastomotic technique as predictive factor for AL, overall and major complications. In miDG, AL rate (BI: 1.4%, BII 0.8%, RX 1.2%), overall (BI: 14.5%, BII: 15.0%, RX: 18.7%,) and major morbidity (BI: 7.9%, BII: 9.1%, RX: 7.2%), and mortality (BI: 0%, BII: 0.1%, RY: 1.1%%) were not affected by bowel reconstruction. CONCLUSION: In oncologically suitable situations, miDG should be preferred to miTG, as postoperative morbidity is significantly lower. LS should be a preferred anastomotic technique for miTG in Western Centers. Conversely, bowel reconstruction in DG may be chosen according to surgeon's preference.

Long-term impact of weight loss in people with class II obesity on the overall burden of disease: Evidence from the National Health Screening Cohort in Korea.

BACKGROUND: Obesity is known to increase overall disease burden but does obesity management actually help reduce disease burden? OBJECTIVES: To investigate the effects of weight loss on disease burden in people with obesity using the National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) in Korea. SETTING: Pure longitudinal observational study using Nationwide cohort database. METHODS: Out of 514,866 NHIS-HEALS cohort, participants with class II obesity in Asia-Pacific region (30 ≤ body mass index [BMI] < 35) who underwent health check-up provided by NHIS during 2003-2004 (index date) were included. All final participants continued to receive a total of 5 biennial health check-ups over the next 10 years without missing. A group-based trajectory model (GBTM) was used to categorize subjects based on 10-year BMI change patterns. The changes of co-morbidities, healthcare resource utilization, and medical cost were analyzed. RESULTS: The final study subjects (9857) were categorized into 3 trajectory clusters based on the pattern of BMI (kg/m2) change: maintenance (57.35%) with an average change of -.02 ± .06, loss (38.65%) with -.04 ± .08, and substantial loss (4.0%) with -.10 ± .18. The annual increases in the number of co-morbidities per subject in each cluster were .18, .18, and .16 (all P < .001), respectively. The increase of healthcare resource utilization over time was lowest for the substantial loss compared to maintenance and loss. With each passing year, the average annual total healthcare cost increased by ₩21,200 ($16.48, P = .034) and ₩10,500 ($8.16, P = .498) in the maintenance and loss, respectively, but decreased by ₩62,500 ($48.59, P = .032) in the substantial loss. CONCLUSIONS: Weight loss in people with obesity was associated with a reduced burden of disease, as evidenced by lower co-morbidity, healthcare resource utilization rate, and decreased medical costs. This study highlights the potential positive long-term impact on Korean society when actively managing weight in individuals with obesity.

Long-Term Outcome of Proximal Gastrectomy for Upper-Third Advanced Gastric and Siewert Type II Esophagogastric Junction Cancer Compared With Total Gastrectomy: A Propensity Score-Matched Analysis.

BACKGROUND: This study aimed to investigate the oncologic long-term safety of proximal gastrectomy for upper-third advanced gastric cancer (AGC) and Siewert type II esophagogastric junction (EGJ) cancer. METHODS: The study enrolled patients who underwent proximal gastrectomy (PG) or total gastrectomy (TG) with standard lymph node (LN) dissection for pathologically proven upper-third AGC and EGJ cancers between January 2007 and December 2018. Propensity score-matching with a 1:1 ratio was performed to reduce the influence of confounding variables such as age, sex, tumor size, T stage, N stage, and tumor-node-metastasis (TNM) stage. Kaplan-Meier survival analysis was performed to analyze oncologic outcome. The prognostic factors of recurrence-free survival (RFS) were analyzed using the Cox proportional hazard analysis. RESULTS: Of the 713 enrolled patients in this study, 60 received PG and 653 received TG. Propensity score-matching yielded 60 patients for each group. The overall survival rates were 61.7 % in the PG group and 68.3 % in the TG group (p = 0.676). The RFS was 86.7 % in the PG group and 83.3 % in the TG group (p = 0.634). The PG group showed eight recurrences (1 anastomosis site, 1 paraaortic LN, 1 liver, 1 spleen, 1 lung, 1 splenic hilar LN, and 2 remnant stomachs). In the multivariate analysis, the operation method was not identified as a prognostic factor of tumor recurrence. CONCLUSION: The patients who underwent PG had a long-term oncologic outcome similar to that for the patients who underwent TG for upper-third AGC and EGJ cancer.

Can prospective monitoring improve complication rates after gastrectomy? Experience of Billroth I reconstruction at a high-volume tertiary center.

INTRODUCTION: Prospective database is imperative in surgical outcome monitoring and has shown success in providing a comprehensive complication index to monitor surgical quality. This study aims to review whether prospective monitoring has an effect on postoperative complication rates, especially leakage after Billroth I (BI) anastomosis and to identify risk factors of anastomosis leakage after BI anastomosis. MATERIALS AND METHODS: Patients who underwent distal gastrectomy with BI reconstruction at Seoul National University Hospital between January 2018 and April 2021 were enrolled. Clinicopathological characteristics and perioperative variables were retrieved. The risk factor that was statistically significant in univariate analysis was further analyzed by binomial logistic regression analysis. RESULTS: BI leakage rate in three years has declined by half on a yearly basis from 5.7% to 1.8%. The leakage group patients were predominantly male (100%) when compared to the non-leakage group (67.6%) (p = 0.04). The BMI (25.00 ± 1.42 vs. 24.16 ± 3.15, p = 0.048) and CRP measured on POD#2 (16.47 ± 5.64 vs. 9.99 ± 5.42, p < 0.001) showed significant differences between the two groups. POD#2 CRP greater than 12.7 mg/dL was able to predict risk of anastomosis leak with sensitivity 73.3% and specificity 73.1%. CONCLUSION: Understanding variations in outcomes is important for improvements in surgical care, and through prospective monitoring and intra-departmental feedback, it is possible to reduce complication rates after gastrectomy. This study shows that age, gender and BMI are risk factors to BI leakage and POD#2 CRP greater than 12.7 mg/dL can be used to suspect leakage after BI anastomosis.

Clinical Outcomes of Resectional Roux-en-Y Gastric Bypass, Compared to Sleeve Gastrectomy for Severe Obesity.

PURPOSE: Resectional Roux-en-Y gastric bypass (RRYGB) is considered an alternative bariatric surgery in countries with a high incidence of stomach cancer because there is no excluded stomach after RRYGB. This study aimed to evaluate the efficacy and safety of RRYGB. MATERIALS AND METHODS: This study included patients who underwent RRYGB and sleeve gastrectomy (SG) between 2011 and 2021. Surgical complications and metabolic and nutritional profiles were compared between the patients preoperatively and at 1, 6, and 12 months after surgery. RESULTS: Twenty and seventy-six patients underwent RRYGB and SG, respectively; 7 in the SG group were lost to follow-up within 1 year. Surgical complications and baseline characteristics were comparable between two groups, except for diabetes (90.0% vs. 44.7%, p < 0.001). The decrease of HbA1c levels and incidence of reflux esophagitis were lower in the RRYGB group compared to that of SG at 1-year postoperative (-3.0% vs. -1.8%, p = 0.014; 0% vs. 26.7%, p = 0.027). The percentage of total weight loss at 1- year postoperative and incidence of dumping syndrome were comparable between the two groups. The RRYGB group had significantly lower total cholesterol level (161.9 mg/dl vs. 196.4 mg/dl, p < 0.001), but higher incidence of vitamin B12 deficiency (30.0% vs. 3.6%, p = 0.003) at 1 year postoperative compared to those of the SG group. CONCLUSIONS: The RRYGB group had better postoperative outcomes for diabetes and dyslipidemia without increasing surgical complications compared to that of the SG group. Thus, RRYGB can be considered a safe and effective alternative in areas where gastric cancer is prevalent.

Clinical outcomes of gastric cancer surgery after liver transplantation.

Purpose: De novo malignancy is common after liver transplantation (LT); however, there are limited reports on the clinical outcomes of gastric cancer surgery after LT. Our study aimed to investigate the feasibility and safety of gastric cancer surgery after LT. Methods: Seventeen patients underwent gastric cancer surgery after LT at a single institution between January 2013 and June 2021. We retrospectively collected data on surgical complications, survival, and recurrence status of these cases. Results: Fifteen patients (88.2%) underwent curative gastrectomy, with 10 open distal (66.7%) and 5 laparoscopic distal (33.3%) gastrectomies. Surgical and severe complication rates were 3 of 15 (20.0%) and 1 of 15 (6.7%), respectively. There were no significant differences between laparoscopic (33.3%) and open surgery (66.7%) in terms of operation time and complication rate. No surgery-related mortalities occurred. Immunosuppressants could be maintained without difficulty, and no suspicious acute rejection was identified during the perioperative period. There was 1 recurrence after curative surgery (recurrence rate, 6.7%), and the 5-year cancer-specific survival rate after curative surgery was 93.3%. Conclusion: Laparoscopic gastrectomy can be safely done even after LT in terms of postoperative complications and graft safety.

Outcomes and Adverse Events After Bariatric Surgery: An Updated Systematic Review and Meta-analysis, 2013-2023.

Purpose: Bariatric surgery is an increasingly common treatment for obesity and related comorbidities. This meta-analysis aimed to compare the outcomes of bariatric surgery and medical treatment (MT). Materials and Methods: A systematic search of articles published from January 2013 to May 2023 identified 20 studies. The treatment arms included Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), gastric banding, and MT. The assessed outcomes included body weight loss, diabetes mellitus (DM) remission, changes in dyslipidemia and hypertension markers, and adverse events. Results: Bariatric surgery resulted in significantly better short- and long-term weight loss than MT, with RYGB and SG showing the most substantial reduction. The DM remission rates were notably higher in the surgery group, with marked improvements in hemoglobin A1c and fasting glucose levels. Improvements in dyslipidemia were inconclusive, whereas hypertension showed modest improvements, particularly with RYGB. Complication rates varied, with RYGB reporting higher rates of early complications, and SG reporting increased rates of late complications. The perioperative reoperation rates were low across all surgical treatments. Specific adverse events, such as intestinal obstruction and anastomosis site problems, were more common in the RYGB group, whereas reflux symptoms were more common in the SG group. Conclusion: Bariatric surgery, especially RYGB and SG, provided superior weight loss and DM remission outcomes compared to MT, although with varied complication profiles. These findings underscore the need for careful patient selection and postoperative management in bariatric surgery. Future studies should aim to refine these processes to improve patient outcomes.

Gastric Cancer After Bariatric Surgeries.

Bariatric surgery has been covered by medical insurance in Korea, since January 2019; and its number is steadily increasing. Representative bariatric surgeries include adjustable gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass. Each surgical method can be applied according to the patient's condition; however, there are other issues to consider in Korea. Because of the high incidence of gastric cancer in Korea, gastroscopy is recommended every two years after the age of 40. Therefore, it is difficult to perform conventional gastroscopy after Roux-en-Y gastric bypass. In this review, the incidence of gastric cancer after representative bariatric surgery was investigated through a literature review, so that it could be used as a reference for the selection of bariatric surgery in Korea.

Demarcating the Exact Midplane of the Liver Using Indocyanine Green Near-Infrared Fluorescence Imaging During Laparoscopic Donor Hepatectomy.

Indocyanine green (ICG) near-infrared fluoroscopy has been recently implemented in pure laparoscopic donor hepatectomy (PLDH). This study aims to quantitatively evaluate the effectiveness of ICG fluoroscopy during liver midplane dissection in PLDH and to demonstrate that a single injection of ICG is adequate for both midplane dissection and bile duct division. Retrospective analysis was done with images acquired from recordings of PLDH performed without ICG (pre-ICG group) from November 2015 to May 2016 and with ICG (post-ICG group) from June 2016 to May 2017. 30 donors from the pre-ICG group were compared with 46 donors from the post-ICG group. The operation time was shorter (P = 0.002) and postoperative peak aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were lower (P = 0.031 and P = 0.019, respectively) in the post-ICG group than the pre-ICG group. Within the post-ICG group, the color intensity differences between the clamped versus nonclamped regions in the natural, black-and-white, and fluorescent modes were 39.7 ± 36.2, 89.6 ± 46.9, and 19.1 ± 36.8 (mean ± SD, P < 0.001), respectively. The luminosity differences were 37.2 ± 34.5, 93.8 ± 32.1, and 26.7 ± 25.7 (P < 0.001), respectively. Meanwhile, the time from when ICG was injected to when the near-infrared camera was turned on for bile duct visualization was 85.6 ± 25.8 minutes. All grafts received from the 46 donors were successfully transplanted. In conclusion, ICG fluoroscopy helps to reduce operation time and lower postoperative AST/ALT levels. ICG injection visualized with black-and-white imaging is most effective for demarcating the liver midplane during PLDH. A single intravenous injection of ICG is sufficient for midplane dissection as well as bile duct division.

Retroperitoneal sarcomas: Outcomes of repeated resections.

Purpose: Retroperitoneal sarcomas (RPS) are rare malignant tumors arising from mesenchymal cells. The objective of this study was to review the treatment experiences and to identify prognostic factors for overall survival (OS) after primary resection and subsequent reoperations for recurrences. Methods: The medical records of patients who underwent resection for RPS at our institution between June 2002 and December 2016 were retrospectively reviewed. Univariate and multivariable Cox proportional hazards modeling was used to assess the prognostic factors for OS. Results: A total of 48 patients were enrolled. On multivariable analysis in primary resection group, the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) grade was a significant prognostic factor for OS (P=0.006). The patients who received chemotherapy after primary resection were significantly associated with poor prognosis (P=0.009). The 5-year OS rate after primary resection (n=48) were 58.1% and the 5-year cumulative reoperation rate after primary resection was 62.5%. After second resection for recurrence after primary resection (n=23), the 5-year OS rate was 64.3%. There was a tendency towards decreased surgery-free survival rate as the number of repeated resections for recurrent RPS increased. In the subset of patients (n=16) who underwent more than 3 repeated resections at our institute, the 5-year OS rate was 75.0%, indicating that repeated resections are not associated with worse outcome. Conclusion: Only low tumor grade was an independent favorable prognostic factor for OS. Although the prognosis for RPS remains poor, repeated resections for recurrence are not associated with poor prognosis. Aggressive surgical strategies for recurred RPS patients are warranted.

PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch.

PRMT5 is the primary enzyme responsible for the deposition of the symmetric dimethylarginine in mammalian cells. In an effort to understand how PRMT5 is regulated, we identified a threonine phosphorylation site within a C-terminal tail motif, which is targeted by the Akt/serum- and glucocorticoid-inducible kinases. While investigating the function of this posttranslational modification, we serendipitously discovered that its free C-terminal tail binds PDZ domains (when unphosphorylated) and 14-3-3 proteins (when phosphorylated). In essence, a phosphorylation event within the last few residues of the C-terminal tail generates a posttranslational modification-dependent PDZ/14-3-3 interaction "switch." The C-terminal motif of PRMT5 is required for plasma membrane association, and loss of this switching capacity is not compatible with life. This signaling phenomenon was recently reported for the HPV E6 oncoprotein but has not yet been observed for mammalian proteins. To investigate the prevalence of PDZ/14-3-3 switching in signal transduction, we built a protein domain microarray that harbors PDZ domains and 14-3-3 proteins. We have used this microarray to interrogate the C-terminal tails of a small group of candidate proteins and identified ERBB4, PGHS2, and IRK1 (as well as E6 and PRMT5) as conforming to this signaling mode, suggesting that PDZ/14-3-3 switching may be a broad biological paradigm.

Assessing angiogenic responses induced by primary human prostate stromal cells in a three-dimensional fibrin matrix assay.

Accurate modeling of angiogenesis in vitro is essential for guiding the preclinical development of novel anti-angiogenic agents and treatment strategies. The formation of new blood vessels is a multifactorial and multi-stage process dependent upon paracrine factors produced by stromal cells in the local microenvironment. Mesenchymal stem cells (MSCs) are multipotent cells in adults that can be recruited to sites of inflammation and tissue damage where they aid in wound healing through regenerative, trophic, and immunomodulatory properties. Primary stromal cultures derived from human bone marrow, normal prostate, or prostate cancer tissue are highly enriched in MSCs and stromal progenitors. Using conditioned media from these primary cultures, a robust pro-angiogenic response was observed in a physiologically-relevant three-dimensional fibrin matrix assay. To evaluate the utility of this assay, the allosteric HDAC4 inhibitor tasquinimod and the anti-VEGF monoclonal antibody bevacizumab were used as model compounds with distinct mechanisms of action. While both agents had a profound inhibitory effect on endothelial sprouting, only bevacizumab induced significant regression of established vessels. Additionally, the pro-angiogenic properties of MSCs derived from prostate cancer patients provides further evidence that selective targeting of this population may be of therapeutic benefit.

Targeting p38 mitogen-activated protein kinase signaling restores subventricular zone neural stem cells and corrects neuromotor deficits in Atm knockout mouse.

Ataxia-telangiectasia (A-T) is a progressive degenerative disorder that results in major neurological disability. In A-T patients, necropsy has revealed atrophy of cerebellar cortical layers along with Purkinje and granular cell loss. We have previously identified an oxidative stress-mediated increase in phospho-p38 mitogen-activated protein kinase (MAPK) and the resultant downregulation of Bmi-1 and upregulation of p21 as key components of the mechanism causing defective proliferation of neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm(-/-) mice. However, the in vivo aspect of alteration in SVZ tissue and the functional significance of p38MAPK activation in NSCs for neuropathogenesis of ATM deficiency remain unknown. Here we show that the NSC population was abnormally decreased in the SVZ of 3-month-old Atm(-/-) mice; this decrease was accompanied by p38MAPK activation. However, after a 2-month treatment with the p38MAPK inhibitor SB203580, starting at 1 month old, Atm(-/-) mice showed restoration of normal levels of Bmi-1 and p21 with the rescue of NSC population in the SVZ. In addition, treated Atm(-/-) mice exhibited more Purkinje cells in the cerebellum. Most importantly, motor coordination of Atm(-/-) mice was significantly improved in the treatment group. Our results show for the first time in vivo evidence of depleted NSCs in the SVZ of Atm(-/-) mice and also demonstrate that pharmacologic inhibition of p38MAPK signaling has the potential to treat neurological defects of A-T. This study provides a promising approach targeting the oxidative stress-dependent p38 signaling pathway not only for A-T but also for other neurodegenerative disorders.

p38 MAPK-Mediated Bmi-1 down-regulation and defective proliferation in ATM-deficient neural stem cells can be restored by Akt activation.

A-T (ataxia telangiectasia) is a genetic disease caused by a mutation in the Atm (A-T mutated) gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm(-/-) mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK) and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm(-/-) NSCs remained unclear. Here, we show that over-expression of Bmi-1 increases self-renewal and proliferation of Atm(-/-) NSCs to normal, indicating that defective proliferation in Atm(-/-) NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF)-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm(-/-) NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm(-/-) NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm(-/-) NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway.

Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling.

Ataxia-telangiectasia (A-T) is a genetic disorder caused by a mutation of the Atm gene, which controls DNA repair, cell cycling, and redox homeostasis. Even though oxidative stress has been implicated in the neurological anomalies in A-T, the effects of ATM loss on neural stem cell (NSC) survival has remained elusive. In this study, we investigated the effects of oxidative stress on NSC proliferation in an animal model for A-T neurodegeneration. We found that cultured subventricular zone neurosphere cells from Atm(-/-) mice show impaired proliferation, as well as intrinsic elevation of reactive oxygen species (ROS) levels, compared with those from Atm(+/+) mice. We also show that increasing the levels of ROS by H(2)O(2) treatment significantly reduces Atm(+/+) neurosphere formation and proliferation. In Atm(-/-) neurosphere cells, the Akt and Erk1/2 pathways are disrupted, together with enhanced activity of the p38 mitogen-activated protein kinase (MAPK). Treatment of these cells with the antioxidant N-acetyl-L-cysteine (NAC) or with a p38 MAPK inhibitor restores normal proliferation and reduced expression of p21(cip1) and p27(kip1) in the Atm(-/-) NSCs. These observations indicate that ATM plays a crucial role in NSC proliferation, by activating Akt and Erk1/2 pathways and by suppressing ROS-p38 MAPK signaling. Together, our results suggest that p38 MAPK signaling acts as a negative regulator of NSC proliferation in response to oxidative stress. These findings suggest a potential mechanism for neuronal cell loss as a result of oxidative stress in NSCs in progressive neurodegenerative diseases such as A-T.

Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes.

The gene that encodes the ATM protein kinase is mutated in ataxia-telangiectasia (A-T). One of the prominent features of A-T is progressive neurodegeneration. We have previously reported that primary astrocytes isolated from Atm(-/-) mice grow slowly and die earlier than control cells in culture. However, the mechanisms for this remain unclear. We show here that intrinsic elevated intracellular levels of reactive oxygen species (ROS) are associated with the senescence-like growth defect of Atm(-/-) astrocytes. This condition is accompanied by constitutively higher levels of ERK1/2 phosphorylation and p16(Ink4a) in Atm(-/-) astrocytes. We also observe that ROS-induced up-regulation of p16(Ink4a) occurs correlatively with ERK1/2-dependent down-regulation and subsequent dissociation from chromatin of Bmi-1. Furthermore, both mitogen-activated protein kinase (MAPK)/ERK inhibitor PD98059 and antioxidant N-acetyl-l-cysteine restored normal proliferation of Atm(-/-) astrocytes. These results suggest that ATM is required for normal astrocyte growth through its ability to stabilize intracellular redox status and that the inability to control ROS is the molecular basis of limited cell growth of Atm(-/-) astrocytes. This defect may be mediated by a mechanism involving ERK1/2 activation and Bmi-1 derepression of p16(Ink4a). These data identify new potential targets for therapeutic intervention in A-T neurodegeneration.

The effect of viewing speech on auditory speech processing is different in the left and right hemispheres.

We used whole-head magnetoencephalograpy (MEG) to record changes in neuromagnetic N100m responses generated in the left and right auditory cortex as a function of the match between visual and auditory speech signals. Stimuli were auditory-only (AO) and auditory-visual (AV) presentations of /pi/, /ti/ and /vi/. Three types of intensity matched auditory stimuli were used: intact speech (Normal), frequency band filtered speech (Band) and speech-shaped white noise (Noise). The behavioural task was to detect the /vi/ syllables which comprised 12% of stimuli. N100m responses were measured to averaged /pi/ and /ti/ stimuli. Behavioural data showed that identification of the stimuli was faster and more accurate for Normal than for Band stimuli, and for Band than for Noise stimuli. Reaction times were faster for AV than AO stimuli. MEG data showed that in the left hemisphere, N100m to both AO and AV stimuli was largest for the Normal, smaller for Band and smallest for Noise stimuli. In the right hemisphere, Normal and Band AO stimuli elicited N100m responses of quite similar amplitudes, but N100m amplitude to Noise was about half of that. There was a reduction in N100m for the AV compared to the AO conditions. The size of this reduction for each stimulus type was same in the left hemisphere but graded in the right (being largest to the Normal, smaller to the Band and smallest to the Noise stimuli). The N100m decrease for the Normal stimuli was significantly larger in the right than in the left hemisphere. We suggest that the effect of processing visual speech seen in the right hemisphere likely reflects suppression of the auditory response based on AV cues for place of articulation.

Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development.

The coactivator-associated arginine methyltransferase, CARM1, is a positive regulator of transcription. Using high density protein arrays, we have previously identified in vitro substrates for CARM1. One of these substrates, TARPP (thymocyte cyclic AMP-regulated phosphoprotein), is expressed specifically in immature thymocytes. Here, we have demonstrated that TARPP is arginine-methylated at a single residue, Arg(650), both in vitro and in vivo. In addition, recombinant TARPP is not methylated by extracts from Carm1(-/-) cells, indicating that there is no redundancy in this pathway. We show that thymi from Carm1(-/-) embryos (E18.5) have a 5-10-fold reduction in cellularity compared with wild type littermates. Flow cytometric analysis of thymocytes revealed a decrease in the relative proportion of double negative thymocytes in Carm1(-/-) embryos because of a partial developmental arrest in the earliest thymocyte progenitor subset. These results demonstrate that CARM1 plays a significant role in promoting the differentiation of early thymocyte progenitors, possibly through its direct action on TARPP.

Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice.

Arginine methylation has been implicated in the regulation of gene expression. The coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) binds the p160 family of steroid receptor coactivators (SRCs). This association enhances transcriptional activation by nuclear receptors. Here, we show that embryos with a targeted disruption of CARM1 are small in size and die perinatally. The methylation of two known CARM1 substrates, poly(A)-binding protein (PABP1) and the transcriptional cofactor p300, was abolished in knockout embryos and cells. However, CARM1-dependent methylation of histone H3 was not observed. Furthermore, estrogen-responsive gene expression was aberrant in Carm1-/- fibroblasts and embryos, thus emphasizing the role of arginine methylation as a transcription activation tag. These findings provide genetic evidence for the essential role of CARM1 in estrogen-mediated transcriptional activation.