rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice.

Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus-specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome.

Mucinous neoplasm of the appendix: A case report and review of literature.

BACKGROUND: Appendiceal mucinous neoplasms (AMNs), although not classified as rare, are relatively uncommon tumors most often discovered incidentally during colorectal surgery. Accurate identification of AMNs is difficult due to non-specific symptoms, overlapping tumor markers with other conditions, and the potential for misdiagnosis. This underscores the urgent need for precision in diagnosis to prevent severe complications. CASE SUMMARY: This case report describes the unexpected discovery and treatment of a low-grade AMN (LAMN) in a 74-year-old man undergoing laparoscopic hemicolectomy for transverse colon adenocarcinoma (AC). Preoperatively, non-specific gastrointestinal symptoms and elevated tumor markers masked the presence of AMN. The tumor, presumed to be an AMN peritoneal cyst intraoperatively, was confirmed as LAMN through histopathological examination. The neoplasm exhibited mucin accumulation and a distinct immunohistochemical profile: Positive for Homeobox protein CDX-2, Cytokeratin 20, special AT-rich sequence-binding protein 2, and Mucin 2 but negative for cytokeratin 7 and Paired box gene 8. This profile aids in distinguishing appendiceal and ovarian mucinous tumors. Postoperative recovery was uncomplicated, and the patient initiated adjuvant chemotherapy for the colon AC. CONCLUSION: This case highlights the diagnostic complexity of AMNs, emphasizing the need for vigilant identification to avert potential complications, such as pseudomyxoma peritonei.

Diffuse large B-cell lymphoma-induced intussusception: A case report and literature review.

Adult intussusception necessitates early surgical intervention. We emphasis the significance of considering diffuse large B-Cell lymphoma in differential diagnoses for adult intussusception, particularly in the colon, to ensure precise diagnosis and optimal management.

Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys.

Retinoic acid-induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith-Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS. Here, we performed comparative analyses to uncover the evolutionarily convergent and divergent expression profiles of RAI1 in major cell types during prefrontal cortex maturation in common marmoset monkeys (Callithrix jacchus) and mice (Mus musculus). We found that while RAI1 in both species is enriched in neurons, the percentage of excitatory neurons that express RAI1 is higher in newborn mice than in newborn marmosets. By contrast, RAI1 shows similar neural distribution in adult marmosets and adult mice. In marmosets, RAI1 is expressed in several primate-specific cell types, including intralaminar astrocytes and MEIS2-expressing prefrontal GABAergic neurons. At the molecular level, we discovered that RAI1 forms a protein complex with transcription factor 20 (TCF20), PHD finger protein 14 (PHF14), and high mobility group 20A (HMG20A) in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance. This work demonstrates that RAI1 expression and protein interactions are largely conserved but with some unique expression in primate-specific cells. The results also suggest that altered RAI1 abundance could contribute to disease features in disorders caused by TCF20 dosage imbalance.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Clinicopathological analysis of ß-catenin and Axin-1 in solid pseudopapillary neoplasms of the pancreas.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) is a distinct pancreatic neoplasm and has characteristic, aberrant nuclear expression of ß-catenin in most cases. However, alterations in components of the Wnt pathway, other than the ß-catenin (CTNNB1) gene mutation, have not been identified. In this study, we investigated the status of Axin-1, the spectrum of mutations in the CTNNB1 gene, and the clinicopathological features of SPNs. MATERIALS AND METHODS: We collected 27 SPNs from 25 patients. A tissue microarray was constructed to perform immunohistochemistry for ß-catenin, E-cadherin, and Axin-1. The CTNNB1 and AXIN1 gene mutations were analyzed by DNA sequencing. Finally, the clinicopathological features of SPNs were analyzed for association with the CTNNB1 mutations and the Axin-1 alterations. RESULTS: All 27 SPNs expressed nuclear immunoreactivity of ß-catenin and exhibited a lack of membranous decoration of E-cadherin. All SPNs harbored CTNNB1 gene mutations. No alterations were present in the AXIN1 gene, and the immunohistochemical analysis revealed weak or absent reactivity of Axin-1 in the cytosol. All cases with a codon-37 CTNNB1 mutation had weak Axin-1 immunoreactivity in the cytoplasm (P = 0.018). No other significant correlation was found between clinicopathological parameters, CTNNB1 mutations, and Axin-1 alterations. CONCLUSIONS: Nuclear ß-catenin immunoexpression is characteristic for SPNs and corresponds to the CTNNB1 mutation. The Wnt pathway is involved in the tumorigenesis of SPNs, primarily through the alteration of ß-catenin. Despite the absence of any identifiable genetic mutation, a low level of Axin-1 in the cytoplasm might contribute to the aberrant distribution of ß-catenin in SPNs.

Risk factors for lymph node metastasis in pT1 and pT2 rectal cancer: a single-institute experience in 943 patients and literature review.

BACKGROUND: Local excision has become an alternative for radical resection in rectal cancer for selected patients. The purpose of this study was to assess the clinicopathologic factors determining lymph node metastasis (LNM) in patients with T1-2 rectal cancer. METHODS: Between January 1995 and December 2009, a total of 943 patients with pT1 or pT2 rectal adenocarcinoma received radical resection at a single institution. Clinicopathologic factors were evaluated by univariate and multivariate analyses to identify risk factors for LNM. RESULTS: A total of 943 patients (544 men and 399 women) treated for T1-2 rectal cancer were included in this study. LNM was found in 188 patients (19.9%). In multivariate analysis, lymphovascular invasion (LVI; P < 0.001, hazard ratio 11.472), poor differentiation (PD; P = 0.007, hazard ratio 3.218), and depth of invasion (presence of pT2; P = 0.032, hazard ratio 1.694) were significantly related to nodal involvement. The incidence for LNM lesions in the presence of LVI, PD, and pT2 was 68.8, 50.0, and 23.1%, respectively, while that for pT1 carcinomas with no LVI or PD was 7.5%. CONCLUSIONS: LVI, PD, and pT2 are independent risk factors predicting LNM in pT1-2 rectal carcinoma.

Management of lung metastases from colorectal cancer: video-assisted thoracoscopic surgery versus thoracotomy--a case-matched study.

OBJECTIVES: The benefits of video-assisted thoracoscopic surgery (VATS) for performing pulmonary metastasectomy are considered controversial. This case-matched study aimed to compare long-term outcomes after surgical resection of pulmonary metastases from colorectal cancer using different approaches (VATS vs. thoracotomy). METHODS: Between 1997 and 2008, 143 patients with colorectal cancer who had received their first pulmonary metastasectomy were selected. Fifty-three patients underwent a surgical procedure that utilized a thoracotomy approach (Group 1), and 90 patients underwent a surgical procedure that used a VATS-based approach (Group 2). After being matched for tumor number, diameter (measured by computed tomography), and surgical procedure (wedge resection or lobectomy), 35 pairs of patients were finally enrolled. Study endpoints included tumor recurrence and survival. RESULTS: There was no hospital mortality in both groups. Within the mean follow-up period of 50 months, 47.1% patients developed a recurrence (52% at the pulmonary level and 48% at systemic level), and 52.9% of the patients were alive at the time of analysis. There was no difference between Groups 1 and 2 in terms of overall recurrences (54 vs. 40%, p = 0.23), all pulmonary recurrences (25.7 vs. 22.9%, p = 0.78), and same side lung recurrences (14.3 vs. 20%, p = 0.75). The 5-year overall survival (OS) after lung resection was 43 and 51% in Groups 1 and 2, respectively (p = 0.21). CONCLUSIONS: Our case-matched study showed that survival outcome of pulmonary metastasectomy using VATS is not inferior to that of open thoracotomy in selected cases.

Neuro-Inspired Reinforcement Learning to Improve Trajectory Prediction in Reward-Guided Behavior.

Hippocampal pyramidal cells and interneurons play a key role in spatial navigation. In goal-directed behavior associated with rewards, the spatial firing pattern of pyramidal cells is modulated by the animal's moving direction toward a reward, with a dependence on auditory, olfactory, and somatosensory stimuli for head orientation. Additionally, interneurons in the CA1 region of the hippocampus monosynaptically connected to CA1 pyramidal cells are modulated by a complex set of interacting brain regions related to reward and recall. The computational method of reinforcement learning (RL) has been widely used to investigate spatial navigation, which in turn has been increasingly used to study rodent learning associated with the reward. The rewards in RL are used for discovering a desired behavior through the integration of two streams of neural activity: trial-and-error interactions with the external environment to achieve a goal, and the intrinsic motivation primarily driven by brain reward system to accelerate learning. Recognizing the potential benefit of the neural representation of this reward design for novel RL architectures, we propose a RL algorithm based on [Formula: see text]-learning with a perspective on biomimetics (neuro-inspired RL) to decode rodent movement trajectories. The reward function, inspired by the neuronal information processing uncovered in the hippocampus, combines the preferred direction of pyramidal cell firing as the extrinsic reward signal with the coupling between pyramidal cell-interneuron pairs as the intrinsic reward signal. Our experimental results demonstrate that the neuro-inspired RL, with a combined use of extrinsic and intrinsic rewards, outperforms other spatial decoding algorithms, including RL methods that use a single reward function. The new RL algorithm could help accelerate learning convergence rates and improve the prediction accuracy for moving trajectories.

Hepatoid microcarcinoma of the pancreas: a case report and review of the literature.

Hepatoid differentiation in pancreatic carcinoma is a rare phenomenon. It occurs either as a pure form or as a component with other subtypes. Herein, we report a 52-year-old man with an ampullary large cell neuroendocrine carcinoma presenting with obstructive jaundice for 2 months. A 0.5-cm nodule was found in the pancreatic head. Morphologically, the nodule was composed of exclusively hepatocytic tumor cells and sinusoids with dysplastic cytology and capsular invasion. The patient did not have a hepatic mass or ectopic normal liver tissue. This is the first reported case of ampullary large cell neuroendocrine carcinoma coinciding with a pancreatic hepatoid microcarcinoma. The clinicopathological features of pancreatic hepatoid carcinomas and their histogenesis are discussed.

Duodenal duplication cyst: a rare cause of geriatric gastrointestinal bleeding.

Duodenal duplication cysts are rare congenital anomalies usually found in children, but rare cases, often presenting with pancreatitis, have been reported in adults. We report the case of a duodenal duplication cyst in an 81-year-old man who presented with gastrointestinal bleeding. Despite endoscopy and endoscopic ultrasonography, duodenal duplication was not diagnosed until exploratory laparotomy was performed to remove the lesion. To the best of our knowledge, this was the first case of a duodenal duplication cyst that presented with gastrointestinal bleeding in an elderly adult. The patient's recovery was uneventful. A high index of suspicion is required to diagnose duodenal duplication cysts, particularly in elderly patients with an atypical presentation.

Y-shaped colonic duplication: report of a case and literature review.

Colonic duplication is a very rare congenital anomaly that is usually detected in infancy and early childhood. In the English literature, 6 cases of Y-shaped colonic duplication have been reported since 1953. We conducted a review of the reported cases, and we present a new case of a Y-shaped duplication of the sigmoid colon manifesting as long-term abdominal pain and constipation.