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Cell Communication and Signaling : CCS Jun 2024Liver Kinase B1 (LKB1), encoded by Serine-Threonine Kinase 11 (STK11), is a master kinase that regulates cell migration, polarity, proliferation, and metabolism through... (Review)
Review
Liver Kinase B1 (LKB1), encoded by Serine-Threonine Kinase 11 (STK11), is a master kinase that regulates cell migration, polarity, proliferation, and metabolism through downstream adenosine monophosphate-activated protein kinase (AMPK) and AMPK-related kinase signalling. Since genetic screens identified STK11 mutations in Peutz-Jeghers Syndrome, STK11 mutants have been implicated in tumourigenesis labelling it as a tumour suppressor. In support of this, several compounds reduce tumour burden through upregulating LKB1 signalling, and LKB1-AMPK agonists are cytotoxic to tumour cells. However, in certain contexts, its role in cancer is paradoxical as LKB1 promotes tumour cell survival by mediating resistance against metabolic and oxidative stressors. LKB1 deficiency has also enhanced the selectivity and cytotoxicity of several cancer therapies. Taken together, there is a need to develop LKB1-specific pharmacological compounds, but prior to developing LKB1 inhibitors, further work is needed to understand LKB1 activity and regulation. However, investigating LKB1 activity is strenuous as cell/tissue type, mutations to the LKB1 signalling pathway, STE-20-related kinase adaptor protein (STRAD) binding, Mouse protein 25-STRAD binding, splicing variants, nucleocytoplasmic shuttling, post-translational modifications, and kinase conformation impact the functional status of LKB1. For these reasons, guidelines to standardize experimental strategies to study LKB1 activity, associate proteins, spliced isoforms, post-translational modifications, and regulation are of upmost importance to the development of LKB1-specific therapies. Therefore, to assess the therapeutic relevancy of LKB1 inhibitors, this review summarizes the importance of LKB1 in cell physiology, highlights contributors to LKB1 activation, and outlines the benefits and risks associated with targeting LKB1.
Topics: Humans; Protein Serine-Threonine Kinases; Animals; AMP-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Neoplasms; Signal Transduction
PubMed: 38844908
DOI: 10.1186/s12964-024-01689-5 -
Journal of Surgical Case Reports May 2024Peutz-Jeghers syndrome (PJS) is a rare genetic disorder causing gastrointestinal polyps and skin pigmentation. Our case report highlights a unique instance of...
Peutz-Jeghers syndrome (PJS) is a rare genetic disorder causing gastrointestinal polyps and skin pigmentation. Our case report highlights a unique instance of jejuno-jejunal intussusception associated with PJS in a 28-year-old female patient who presented to the emergency department with colicky abdominal pain, tachycardia, and gastrointestinal symptoms. Physical examination revealed mucocutaneous hyperpigmentation. Imaging studies showed a U-shaped distension in the jejunum with thickening and pneumatosis. Laparotomy revealed a jejuno-jejunal volvulus with intussusception. Surgical resection successfully addressed gangrenous jejunal tissue and ileal polyps. Histopathology confirmed PJS polyps. Postoperatively, the patient recovered well and was discharged. Family history revealed similar skin lesions in her uncle. Our case highlights the need for prompt surgical intervention to address complications associated with PJS and elucidates a unique presentation of PJS involving jejuno-jejunal intussusception and volvulus leading to complete small bowel obstruction. We aim to deepen understanding and prompt discussions on optimal therapeutic strategies.
PubMed: 38812577
DOI: 10.1093/jscr/rjae335 -
Cureus Apr 2024A relatively rare inherited condition known as Peutz-Jeghers syndrome (PJS) causes mucocutaneous pigmentation and gastrointestinal hamartomatous polyps. These polyps are... (Review)
Review
A relatively rare inherited condition known as Peutz-Jeghers syndrome (PJS) causes mucocutaneous pigmentation and gastrointestinal hamartomatous polyps. These polyps are non-cancerous, but the presence of PJS significantly increases the chances of developing various types of cancers, such as colorectal, pancreatic, gastric, and breast cancer. The purpose of this review article is to give an abbreviated summary of what is currently known about this syndrome, covering its clinical symptoms, pathophysiology, genetics, and management. PJS also raises the risk of getting many malignancies, especially gastrointestinal and pelvic cancers. Symptoms of the gastrointestinal tract brought on by hamartomatous polyps are frequent and include stool blockage, bleeding, and stomach pain. The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes. Small macules and large regions of lentiginous pigmentation are both possible. Numerous areas, including the perioral area, buccal mucosa, fingers, and lips, exhibit pigmentation. Bowel obstruction and intussusception risk can be decreased by early identification and routine surveillance of gastrointestinal polyps. The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation. Genetic counseling is recommended for the affected individuals and their families. This can help assess the risk of passing on the condition to future generations and provide information about available reproductive options. Regular surveillance is crucial for managing the syndrome and reducing the risk of cancer development. Other syndromes and extra-gastrointestinal characteristics, such as somatic tumor polyps outside the gastrointestinal tract, are also linked to this syndrome.
PubMed: 38800180
DOI: 10.7759/cureus.58887 -
Asian Journal of Surgery May 2024
PubMed: 38760211
DOI: 10.1016/j.asjsur.2024.04.115 -
JPGN Reports May 2024Mucosal prolapse syndrome (MPS) is a rare group of benign conditions characterized by a set of unifying histologic findings thought to be the result of repeated mucosal...
Mucosal prolapse syndrome (MPS) is a rare group of benign conditions characterized by a set of unifying histologic findings thought to be the result of repeated mucosal shearing and submucosal vascular congestion caused by straining. This set of conditions is often misdiagnosed as other polyposis syndromes, inflammatory bowel disease, or malignancy due to its clinical presentation, appearance, and rarity. We report a case of a 15-year-old male who presented with painless rectal bleeding. He was found to have four rectal polyps thought to be due to Peutz-Jeghers syndrome. A repeat colonoscopy with biopsies a year later revealed a diagnosis of MPS. Our case highlights the morphologic similarity between hamartomatous polyp and mucosal prolapse histology. Since MPS is a rare diagnosis even among the adult population, it has not been well described in pediatrics. This syndrome should be on the differential diagnosis for pediatric rectal polyps to prevent unnecessary invasive testing and a delay in treatment.
PubMed: 38756112
DOI: 10.1002/jpr3.12022 -
Diagnostics (Basel, Switzerland) Apr 2024A retrospective study in patients who underwent video capsule endoscopy (VCE) between 2006 and 2016 was conducted in the Clinic for gastroenterology and Hepatology,...
A retrospective study in patients who underwent video capsule endoscopy (VCE) between 2006 and 2016 was conducted in the Clinic for gastroenterology and Hepatology, University Clinical Center of Serbia. A total of 245 patients underwent VCE. In 198 patients the indication was obscure gastrointestinal bleeding (OGIB), with 92 patients having overt and the other 106 occult bleeding. The remaining 47 patients underwent VCE due to suspected small bowel (SB) disease (i.e., Von Hippel-Lindau syndrome, familial adenomatous polyposis, Peutz Jeghers syndrome, Crohn's disease, prolonged diarrhea, abdominal pain, congenital lymphangiectasia, protein-losing enteropathy, tumors, refractory celiac disease, etc.). VCE identified a source of bleeding in 38.9% of patients (in the obscure overt group in 48.9% of patients, and in the obscure occult group in 30.2% of patients). The most common findings were angiodysplasias, tumors, Meckel's diverticulum and Crohn's disease. In the smaller group of patients with an indication other than OGIB, 38.3% of patients had positive VCE findings. The most common indication is OGIB, and the best candidates are patients with overt bleeding; patients with IBD should be evaluated in this setting.
PubMed: 38732278
DOI: 10.3390/diagnostics14090862 -
BJR Case Reports May 2024We report a case of a cystic liver tumour in a 47-year-old man with Peutz-Jeghers syndrome (PJS) who had undergone sclerotherapy at another hospital for a cyst in...
We report a case of a cystic liver tumour in a 47-year-old man with Peutz-Jeghers syndrome (PJS) who had undergone sclerotherapy at another hospital for a cyst in hepatic segment IV (S4) 7 years earlier. Based on the preoperative imaging findings, the patient was diagnosed with an intraductal papillary neoplasm of the bile duct. Percutaneous transhepatic portal vein embolization was performed to increase the residual liver volume, followed by resection of the three right hepatic lobes and the caudate lobe, biliary reconstruction, and portal vein reconstruction. Pathological examination revealed an adenoma arising in an intrahepatic biliary duplication cyst. Retrospectively, the preoperative diagnosis was difficult, but it aligned with previous reports of biliary duplication cysts due to its continuity with the bile duct. Additionally, intrahepatic biliary duplication cysts with tumour lesions or cases in which 18F-fluorodeoxyglucose positron emission tomography was performed have not been previously reported. Therefore, preoperatively listing this disease as a differential diagnosis was difficult. PJS and chronic inflammation associated with cyst sclerotherapy may have contributed to tumour development in the intrahepatic biliary duplication cyst.
PubMed: 38716145
DOI: 10.1093/bjrcr/uaae012 -
Gut Pathogens Apr 2024Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots, gastrointestinal polyps and increased susceptibility to...
BACKGROUND
Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots, gastrointestinal polyps and increased susceptibility to cancers. Currently, most studies have investigated intestinal microbiota through fecal microbiota, and there are few reports about mucosa-associated microbiota. It remains valuable to search for the key intestinal microbiota or abnormal metabolic pathways linked to PJS.
AIM
This study aimed to assess the structure and composition of mucosa-associated microbiota in patients with PJS and to explore the potential influence of intestinal microbiota disorders and metabolite changes on PJS.
METHODS
The bacterial composition was analyzed in 13 PJS patients and 12 controls using 16S rRNA gene sequencing (Illumina MiSeq) for bacteria. Differential analyses of the intestinal microbiota were performed from the phylum to species level. Liquid chromatography-tandem mass spectrometry (LC‒MS) was used to detect the differentially abundant metabolites of PJS patients and controls to identify different metabolites and metabolic biomarkers of small intestinal mucosa samples.
RESULTS
High-throughput sequencing confirmed the special characteristics and biodiversity of the mucosa microflora in patients with PJS. They had lower bacterial biodiversity than controls. The abundance of intestinal mucosal microflora was significantly lower than that of fecal microflora. In addition, lipid metabolism, amino acid metabolism, carbohydrate metabolism, nucleotide metabolism and other pathways were significantly different from those of controls, which were associated with the development of the enteric nervous system, intestinal inflammation and development of tumors.
CONCLUSION
This is the first report on the mucosa-associated microbiota and metabolite profile of subjects with PJS, which may be meaningful to provide a structural basis for further research on intestinal microecology in PJS.
PubMed: 38678229
DOI: 10.1186/s13099-024-00617-9 -
World Journal of Gastrointestinal... Apr 2024Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (/) gene mutations. Preimplantation genetic...
BACKGROUND
Peutz-Jeghers syndrome (PJS) is a rare hereditary neoplastic disorder mainly associated with serine/threonine kinase 11 (/) gene mutations. Preimplantation genetic testing can protect a patient's offspring from mutated genes; however, some variations in this gene have been interpreted as variants of uncertain significance (VUS), which complicate reproductive decision-making in genetic counseling.
AIM
To identify the pathogenicity of two missense variants and provide clinical guidance.
METHODS
Whole exome gene sequencing and Sanger sequencing were performed on the peripheral blood of patients with PJS treated at the Reproductive and Genetic Hospital of Citic-Xiangya. Software was employed to predict the protein structure, conservation, and pathogenicity of the two missense variation sites in patients with PJS. Additionally, plasmids were constructed and transfected into HeLa cells to observe cell growth. The differences in signal pathway expression between the variant group and the wild-type group were compared using western blot and immunohistochemistry. Statistical analysis was performed using one-way analysis of variance. 0.05 was considered statistically significant.
RESULTS
We identified two missense gene VUS [c.889A>G (p.Arg297Gly) and c.733C>T (p.Leu245Phe)] in 9 unrelated PJS families who were seeking reproductive assistance. The two missense VUS were located in the catalytic domain of serine/threonine kinase, which is a key structure of the liver kinase B1 (LKB1) protein. experiments showed that the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) at Thr172 and LKB1 at Ser428 were significantly higher in transfected variation-type cells than in wild-type cells. In addition, the two missense variants promoted the proliferation of HeLa cells. Subsequent immunohistochemical analysis showed that phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients. Our findings indicate that these two missense variants are likely pathogenic and inactivate the gene, causing it to lose its function of regulating downstream phosphorylated-AMPK (Thr172), which may lead to the development of PJS. The identification of the pathogenic mutations in these two clinically characterized PJS patients has been helpful in guiding them toward the most appropriate mode of pregnancy assistance.
CONCLUSION
These two missense variants can be interpreted as likely pathogenic variants that mediated the onset of PJS in the two patients. These findings not only offer insights for clinical decision-making, but also serve as a foundation for further research and reanalysis of missense VUS in rare diseases.
PubMed: 38660671
DOI: 10.4251/wjgo.v16.i4.1532 -
International Journal of Surgery Case... Apr 2024Despite being the longest and containing a greater proportion of the gastrointestinal tract's mucosal surface area, the small bowel is where <2 % to 5 % of...
INTRODUCTION AND IMPORTANCE
Despite being the longest and containing a greater proportion of the gastrointestinal tract's mucosal surface area, the small bowel is where <2 % to 5 % of gastrointestinal cancers can occur. Peutz-Jeghers syndrome is the rarest risk factor for the development of small intestinal cancers. Here we report a case of perforated poorly differentiated adenocarcinoma of the jejunum for which Peutz-Jeghers syndrome is identified.
CASE PRESENTATION
A 25-year-old male patient presented to the emergency department with generalized peritonitis caused by a perforated jejunal mass. The patient underwent an emergency exploratory laparotomy. There was 800 ml of thin pus in the peritoneal cavity and 5 cm by 6 cm perforated mass over the jejunum which extends to the mesentery. Palpable intraluminal polyps with an inverted serosal surface for some of them were identified. The pus was sucked out, and the mass was resected with its mesenteric lymph nodes and segments containing polyps. Subsequently, end-to-end hand-sewn anastomosis was performed, and the abdomen was closed. The histopathology report showed poorly differentiated adenocarcinoma, stage IIIC (PT3, PN2), and Peutz-Jeghers polyps, suggesting Peutz-Jeghers syndrome.
CLINICAL DISCUSSION
Even though small bowel malignancy is a rare entity, early detection is a challenging issue, especially when it happens below the ligaments of the trietz. Surgical resection offers the only potential cure for small bowel malignancy.
CONCLUSION
We conclude that patients with long-term, nonspecific abdominal complaints are good candidates for evaluation and investigation without overlooking small bowel malignancy. Peutz-Jeghers syndrome was a potential risk factor in our case.
PubMed: 38471213
DOI: 10.1016/j.ijscr.2024.109519