Guofeng Xie

Background: High‐resolution esophageal manometry (HREM) is the gold standard test for esophageal motility disorders. Nasopharyngeal airway‐assisted insertion of the HREM catheter is a suggested salvage technique for failure from the inability to pass the catheter through the upper esophageal sphincter (UES). It has not been demonstrated that the nasopharyngeal airway improves procedural success rate.Methods: Patients undergoing HREM between March 2019 and March 2023 were evaluated. Chart review was conducted for patient factors and procedural success rates before and after use of nasopharyngeal airway. Patients from March 2019 to May 2021 did not have nasopharyngeal airway available and were compared to patients from May 2021 to March 2023 who had the nasopharyngeal airway available.Key Results: In total, 523 HREM studies were conducted; 234 occurred prior to nasopharyngeal airway availability, and 289 occurred with nasopharyngeal airway availability. There was no difference in HREM catheter UES intubation rates between periods when a nasopharyngeal airway attempt was considered procedural failure (85% vs. 85%, p = 0.9). Nasopharyngeal airway use after UES intubation failure lead to improved UES intubation rates (94% vs. 85%, p < 0.01). Thirty‐six patients that failed HREM catheter UES intubation had the procedure reattempted with a nasopharyngeal airway, 30 (83%) of which were successful. The nasopharyngeal airway assisted catheter UES intubation for failures attributed to nasal pain and hypersensitivity, gagging, coughing, and pharyngeal coiling.Conclusions & Inferences: Utilization of the nasopharyngeal airway increased rates of UES intubation. When HREM catheter placement through the UES fails, placement of a nasopharyngeal airway can be trialed to overcome patient procedural intolerance.

Background: Hypercontractile esophagus (HE) is a disorder of increased esophageal body contractile strength on high‐resolution esophageal manometry (HREM). Compartmentalized pressurization (CP) is a pattern with an isobaric contour of >30 mmHg extending from the contractile front to the lower esophageal sphincter on HREM. The relevance of CP to HE has yet to be explored.Methods: A retrospective review was performed on 830 HREM studies of patients to identify HE. HE patients' CP status and symptoms by Eckardt score (ES) were reviewed. Diagnoses were made using Chicago Classification (CC) v4.0.Key Results: Forty‐seven patients (5.6%) were identified as having HE by CCv3, 30 (3.6%) of which had HE by CCv4. 11/30 HE patients had CP, and 19/30 did not. CP was associated with chronic opioid use (36.4% vs. 5.3% p = 0.047). Presenting ES was greater for HE patients with CP (7 vs. 4). Seven HE patients with CP and 11 without CP were managed medically. ES after medical therapy was higher in HE patients with CP compared to those without CP (9 vs. 0). No HE patients with CP responded to medical therapy. Kaplan–Meier analysis demonstrated significance of this association over time. 83% of all HE patients had all‐cause symptom remission.Conclusions & Inferences: HE patients with CP are associated with a higher presenting ES. HE patients with CP do not respond to medical therapy, while HE patients without CP frequently do respond. CP in HE may have prognostic value in determination of treatment strategy for patients with HE.

M₃ muscarinic receptors (M₃R) modulate β-catenin signaling and colon neoplasia. CDC42/RAC guanine nucleotide exchange factor, βPix, binds to β-catenin in colon cancer cells, augmenting β-catenin transcriptional activity. Using in silico, in vitro, and in vivo approaches, we explored whether these actions are regulated by M₃R. At the invasive fronts of murine and human colon cancers, we detected co-localized nuclear expression of βPix and β-catenin in stem cells overexpressing M₃R. Using immunohistochemistry, immunoprecipitation, proximity ligand, and fluorescent cell sorting assays in human tissues and established and primary human colon cancer cell cultures, we detected time-dependent M₃R agonist-induced cytoplasmic and nuclear association of βPix with β-catenin. βPix knockdown attenuated M₃R agonist-induced human colon cancer cell proliferation, migration, invasion, and expression of PTGS2, the gene encoding cyclooxygenase-2, a key player in colon neoplasia. Overexpressing βPix dose-dependently augmented β-catenin binding to the transcription factor TCF4. In a murine model of sporadic colon cancer, advanced neoplasia was attenuated in conditional knockout mice with intestinal epithelial cell deficiency of βPix. Expression levels of β-catenin target genes and proteins relevant to colon neoplasia, including c-Myc and Ptgs2, were reduced in colon tumors from βPix-deficient conditional knockout mice. Targeting the M₃R/βPix/β-catenin axis may have therapeutic potential.

M₃ muscarinic receptor (M₃R) activation stimulates colon cancer cell proliferation, migration, and invasion; M₃R expression is augmented in colon cancer and ablating M₃R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M₃R, M₁R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M₁R versus M₃R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M₁R agonists. We detected divergent expression of M₁R and M₃R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M₁R agonists, we found that in contrast to the effects of M₃R activation, selective activation of M₁R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M₁R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M₁R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M₁R agonist-induced attenuated cell proliferation. Lastly, adding M₁R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M₁R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.

Despite colorectal cancer remaining a leading worldwide cause of cancer-related death, there remains a paucity of effective treatments for advanced disease. The molecular mechanisms underlying the development of colorectal cancer include altered cell signaling and cell cycle regulation that may result from epigenetic modifications of gene expression and function. Acting as important transcriptional regulators of normal biological processes, zinc finger proteins also play key roles in regulating the cellular mechanisms underlying colorectal neoplasia. These actions impact cell differentiation and proliferation, epithelial–mesenchymal transition, apoptosis, homeostasis, senescence, and maintenance of stemness. With the goal of highlighting promising points of therapeutic intervention, we review the oncogenic and tumor suppressor roles of zinc finger proteins with respect to colorectal cancer tumorigenesis and progression.

Background: Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility disorder characterized by a lack of relaxation of the esophagogastric junction (EGJ), with preserved esophageal body peristalsis. We propose new terminology for the coexistence of EGJOO with hypercontractile esophagus and distal esophageal spasm as a major mixed motility disorder (MMMD), and normal peristalsis or a minor disorder of peristalsis such as ineffective esophageal motility with EGJOO as isolated or ineffective EGJOO (IEGJOO).Methods: We reviewed prior diagnoses of EGJOO, stratified diagnoses as IEGJOO or MMMD, and compared their symptomatic presentations, high‐resolution manometry (HRM) and endoluminal functional lumen imaging probe (EndoFLIP) metrics, and treatment responses at 2–6 months of follow‐up.Results: Out of a total of 821 patients, 142 met CCv3 criteria for EGJOO. Twenty‐two were confirmed by CCv4 and EndoFLIP as having EGJOO and were clinically managed. Thirteen had MMMD, and nine had IEGJOO. Groups had no difference in demographic data or presenting symptoms by Eckardt score (ES). HRM showed MMMD had greater distal contractile integral, frequency of hypercontractile swallows, and frequency of spastic swallows, and greater DI by EndoFLIP. Patients with MMMD showed greater reduction in symptoms after LES‐directed intervention when measured by ES compared with IEGJOO (7.2 vs. 4.0).Conclusion: Patients with MMMD and IEGJOO present similarly. Detectable differences in HRM portend different responses to endoscopic therapy. Because patients with MMMD have greater short‐term prognosis, they should be considered a different diagnostic classification to guide therapy.

Gastric pneumatosis, an uncommon radiologic finding characterized by the presence of gas within the gastric wall, presents a diagnostic challenge due to its association with both benign gastric emphysema and more severe emphysematous gastritis. The contrasting outcomes and management approaches for these conditions underscore the necessity for accurate diagnosis and appropriate intervention. We present a case of a 29-year-old female with a medical history significant for type 1 diabetes mellitus who presented with abdominal pain, nausea, and vomiting. Initial evaluation revealed elevated blood glucose levels, an anion gap metabolic acidosis, and evidence of gastric pneumatosis on imaging. The patient was managed with aggressive fluid resuscitation and intravenous insulin therapy per diabetic ketoacidosis protocol. General surgery evaluation ruled out the need for acute surgical intervention and attributed the gastric pneumatosis to increased intragastric pressures from prolonged vomiting. The patient was managed with conservative measures, including nasogastric tube decompression and antibiotics. Over the course of a few days, the patient showed signs of clinical and radiologic improvement, with a resolution of symptoms. This case highlights the importance of accurate diagnosis and appropriate management strategies tailored to the underlying pathology to optimize patient outcomes in cases of gastric pneumatosis.

Click on the article title to read more.

Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 ( ZNF277 ; murine Zfp277 ), a transcription factor regulating cellular senescence, is overexpressed in colon cancer, but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and Apc ^Min/+ mice with dysregulated β -catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF 2 77/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF 2 77/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the Apc ^Min/+ mouse colon, implicating ZNF 2 77/Zfp277 as a transcriptional target of β -catenin signaling. We confirmed this by showing β -catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 β -catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and it strikingly prolonged Apc ^Min/+ mouse survival. RNA-Seq and PCR analyses revealed that Zfp277 modulates expression of genes in key cancer pathways, including β -catenin signaling, the HOXD family that regulates development, and p21 ^WAF1 , a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF 2 77/Zfp277 deficiency induced p21 ^WAF1 expression and promoted senescence. Our findings identify ZNF 2 77/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21 ^WAF1 expression.

The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.