TRIANGLE operation, combined with adequate adjuvant chemotherapy, can improve the prognosis of pancreatic head cancer: A retrospective study.

BACKGROUND: The TRIANGLE operation involves the removal of all tissues within the triangle bounded by the portal vein-superior mesenteric vein, celiac axis-common hepatic artery, and superior mesenteric artery to improve patient prognosis. Although previously promising in patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), data are limited regarding the long-term oncological outcomes of the TRIANGLE operation among resectable PDAC patients undergoing pancreaticoduodenectomy (PD). AIM: To evaluate the safety of the TRIANGLE operation during PD and the prognosis in patients with resectable PDAC. METHODS: This retrospective cohort study included patients who underwent PD for pancreatic head cancer between January 2017 and April 2023, with or without the TRIANGLE operation. Patients were divided into the PDTRIANGLE and PDnon-TRIANGLE groups. Surgical and survival outcomes were compared between the two groups. Adequate adjuvant chemotherapy was defined as adjuvant chemotherapy ≥ 6 months. RESULTS: The PDTRIANGLE and PDnon-TRIANGLE groups included 52 and 55 patients, respectively. There were no significant differences in the baseline characteristics or perioperative indexes between the two groups. Furthermore, the recurrence rate was lower in the PDTRIANGLE group than in the PDnon-TRIANGLE group (48.1% vs 81.8%, P < 0.001), and the local recurrence rate of PDAC decreased from 37.8% to 16.0%. Multivariate Cox regression analysis revealed that PDTRIANGLE (HR = 0.424; 95%CI: 0.256-0.702; P = 0.001), adequate adjuvant chemotherapy ≥ 6 months (HR = 0.370; 95%CI: 0.222-0.618; P < 0.001) and margin status (HR = 2.255; 95%CI: 1.252-4.064; P = 0.007) were found to be independent factors for the recurrence rate. CONCLUSION: The TRIANGLE operation is safe for PDAC patients undergoing PD. Moreover, it reduces the local recurrence rate of PDAC and may improve survival in patients who receive adequate adjuvant chemotherapy.

Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions.

Pancreatic ductal adenocarcinoma (PDAC), characterized by heightened neural density, presents a challenging prognosis primarily due to perineural invasion. Recognized for their crucial roles in neural support and myelination, Schwann cells (SCs) significantly influence the process of tumorigenesis. This review succinctly outlines the interplay between PDAC and neural systems, positioning SCs as a nexus in the tumor-neural interface. Subsequently, it delves into the cellular origin and influencers of SCs within the pancreatic tumor microenvironment, emphasizing their multifaceted roles in tumor initiation, progression, and modulation of the neural and immune microenvironment. The discussion encompasses potential therapeutic interventions targeting SCs. Lastly, the review underscores pressing issues, advocating for sustained exploration into the diverse contributions of SCs within the intricate landscape of PDAC, with the aim of enhancing our understanding of their involvement in this complex malignancy.

Radiological classification of the Heidelberg triangle and its application in laparoscopic pancreaticoduodenectomy for malignancies.

BACKGROUND: The TRIANGLE operation benefits patients with pancreatic cancer; however, the Heidelberg triangle, where the operation occurs, contains vessels that can impact safety, especially in laparoscopic pancreaticoduodenectomy (LPD) with the TRIANGLE operation. This study aimed to identify Heidelberg triangle vessel types and their implications in pancreaticoduodenectomy (PD). METHODS: Retrospective collection of radiographic data was performed from January 2017 to April 2023. Three-dimensional (3D) CT reconstructions were performed on patients. Vascular types in the Heidelberg triangle were classified based on named vessels crossing its interior. The impact of these types on surgical outcomes and complications in PD with the TRIANGLE operation was assessed. RESULTS: Preoperative CT reconstruction was conducted on 184 pancreatic surgery patients. The findings revealed 99 patients (53.8%) with the type I Heidelberg triangle, lacking named vessels crossing the interior. Type II (n = 85, 46.2%), with named vessels crossing the interior, was identified. Among reconstructed patients who underwent PD with the TRIANGLE operation (n = 103), they were categorized as type I (n = 57) or type II (n = 46). The results showed that LPD patients with type II had significantly higher median intraoperative blood loss (300 mL vs. 200 mL, P = 0.030) and mean examined lymph nodes (17.2 ± 7.6 vs. 13.4 ± 5.2, P = 0.019) compared to those with type I. No significant differences were found in operative time or postoperative complications. CONCLUSION: The presence of named vessels crossing the interior of the Heidelberg triangle was associated with increased intraoperative bleeding during LPD combined with the TRIANGLE operation. Therefore, targeted preoperative planning is required before the operation, thus improving the safety of the TRIANGLE operation in minimally invasive surgery.

Duplications of Human Longevity-Associated Genes Across Placental Mammals.

Natural selection has shaped a wide range of lifespans across mammals, with a few long-lived species showing negligible signs of ageing. Approaches used to elucidate the genetic mechanisms underlying mammalian longevity usually involve phylogenetic selection tests on candidate genes, detections of convergent amino acid changes in long-lived lineages, analyses of differential gene expression between age cohorts or species, and measurements of age-related epigenetic changes. However, the link between gene duplication and evolution of mammalian longevity has not been widely investigated. Here, we explored the association between gene duplication and mammalian lifespan by analyzing 287 human longevity-associated genes across 37 placental mammals. We estimated that the expansion rate of these genes is eight times higher than their contraction rate across these 37 species. Using phylogenetic approaches, we identified 43 genes whose duplication levels are significantly correlated with longevity quotients (False Discovery Rate (FDR) < 0.05). In particular, the strong correlation observed for four genes (CREBBP, PIK3R1, HELLS, FOXM1) appears to be driven mainly by their high duplication levels in two ageing extremists, the naked mole rat (Heterocephalus glaber) and the greater mouse-eared bat (Myotis myotis). Further sequence and expression analyses suggest that the gene PIK3R1 may have undergone a convergent duplication event, whereby the similar region of its coding sequence was independently duplicated multiple times in both of these long-lived species. Collectively, this study identified several candidate genes whose duplications may underlie the extreme longevity in mammals, and highlighted the potential role of gene duplication in the evolution of mammalian long lifespans.

Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming.

Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an in vitro coculture model, it was shown that adipocytes promoted tumor progression, and an intricate metabolic network between PC cells and adipocytes was identified and elucidated. First, the proteome of Panc­1 PC cells cultured with or without mature adipocytes was identified. This revealed activated hypoxia signaling in cocultured Panc­1 cells, which was confirmed by the increased expression of factors downstream of hypoxia signaling, such as ANGPTL4 and glycolytic genes, as determined by reverse transcription­quantitative PCR and western blot analysis. In addition, it was demonstrated that coculture with cancer cells activated STAT3 and induced an insulin­resistant phenotype in adipocytes. Furthermore, enhanced fatty acid ß­oxidation and increased lipid droplets (LDs) were observed in the cocultured cancer cells. In contrast, downregulated lipid metabolism and a decrease in the size of LDs were found in cocultured adipocytes. Finally, it was shown that the increase in LDs contributed to the increased metastatic capacity of the cocultured PC cells. These data demonstrated that interrupting the mechanisms of lipid uptake from adipocytes in the microenvironment may offer a potential strategy for attenuating PC metastasis.

RET rearrangement-positive pancreatic cancer has remarkable response to pralsetinib: a case report.

Patients with metastatic pancreatic cancer have limited treatment options and a dismal prognosis. While RET fusion is rare (0.6%) in pancreatic cancer, the efficacy of RET-targeted treatment in patients with TRIM33-RET fusion has not been previously reported. Herein, we presented a case of a 68-year-old man with pancreatic cancer harboring TRIM33-RET fusion who responded remarkably to pralsetinib despite being intolerant to chemotherapy. To our knowledge, this is the first report on the clinical value of a single TRIM33-RET fusion in pancreatic cancer, which may benefit from the targeted therapy.

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

Application of omental interposition to reduce pancreatic fistula and related complications in pancreaticoduodenectomy: A propensity score-matched study.

BACKGROUND: The life-threatening complications following pancreatoduodenectomy (PD), intra-abdominal hemorrhage, and postoperative infection, are associated with leaks from the anastomosis of pancreaticoduodenectomy. Although several methods have attempted to reduce the postoperative pancreatic fistula (POPF) rate after PD, few have been considered effective. The safety and short-term clinical benefits of omental interposition remain controversial. AIM: To investigate the safety and feasibility of omental interposition to reduce the POPF rate and related complications in pancreaticoduodenectomy. METHODS: In total, 196 consecutive patients underwent PD performed by the same surgical team. The patients were divided into two groups: An omental interposition group (127, 64.8%) and a non-omental interposition group (69, 35.2%). Propensity score-matched (PSM) analyses were performed to compare the severe complication rates and mortality between the two groups. RESULTS: Following PSM, the clinically relevant POPF (CR-POPF, 10.1% vs 24.6%; P = 0.025) and delayed postpancreatectomy hemorrhage (1.4% vs 11.6%; P = 0.016) rates were significantly lower in the omental interposition group. The omental interposition technique was associated with a shorter time to resume food intake (7 d vs 8 d; P = 0.048) and shorter hospitalization period (16 d vs 21 d; P = 0.031). Multivariate analyses showed that a high body mass index, nonapplication of omental interposition, and a main pancreatic duct diameter < 3 mm were independent risk factors for CR-POPF. CONCLUSION: The application of omental interposition is an effective and safe approach to reduce the CR-POPF rate and related complications after PD.

Calculating and comparing codon usage values in rare disease genes highlights codon clustering with disease-and tissue- specific hierarchy.

We designed a novel strategy to define codon usage bias (CUB) in 6 specific small cohorts of human genes. We calculated codon usage (CU) values in 29 non-disease-causing (NDC) and 31 disease-causing (DC) human genes which are highly expressed in 3 distinct tissues, kidney, muscle, and skin. We applied our strategy to the same selected genes annotated in 15 mammalian species. We obtained CUB hierarchical clusters for each gene cohort which showed tissue-specific and disease-specific CUB fingerprints. We showed that DC genes (especially those expressed in muscle) display a low CUB, well recognizable in codon hierarchical clustering. We defined the extremely biased codons as "zero codons" and found that their number is significantly higher in all DC genes, all tissues, and that this trend is conserved across mammals. Based on this calculation in different gene cohorts, we identified 5 codons which are more differentially used across genes and mammals, underlining that some genes have favorite synonymous codons in use. Since of the muscle genes clear clusters, and, among these, dystrophin gene surprisingly does not show any "zero codon" we adopted a novel approach to study CUB, we called "mapping-on-codons". We positioned 2828 dystrophin missense and nonsense pathogenic variations on their respective codon, highlighting that its frequency and occurrence is not dependent on the CU values. We conclude our strategy consents to identify a hierarchical clustering of CU values in a gene cohort-specific fingerprints, with recognizable trend across mammals. In DC muscle genes also a disease-related fingerprint can be observed, allowing discrimination between DC and NDC genes. We propose that using our strategy which studies CU in specific gene cohorts, as rare disease genes, and tissue specific genes, may provide novel information about the CUB role in human and medical genetics, with implications on synonymous variations interpretation and codon optimization algorithms.

T Cell Repertoire Abnormality in Immunodeficiency Patients with DNA Repair and Methylation Defects.

Both DNA damage response and methylation play a crucial role in antigen receptor recombination by creating a diverse repertoire in developing lymphocytes, but how their defects relate to T cell repertoire and phenotypic heterogeneity of immunodeficiency remains obscure. We studied the TCR repertoire in patients with the mutation in different genes (ATM, DNMT3B, ZBTB24, RAG1, DCLRE1C, and JAK3) and uncovered distinct characteristics of repertoire diversity. We propose that early aberrancies in thymus T cell development predispose to the heterogeneous phenotypes of the immunodeficiency spectrum. Shorter CDR3 lengths in ATM-deficient patients, resulting from a decreased number of nucleotide insertions during VDJ recombination in the pre-selected TCR repertoire, as well as the increment of CDR3 tyrosine residues, lead to the enrichment of pathology-associated TCRs, which may contribute to the phenotypes of ATM deficiency. Furthermore, patients with DNMT3B and ZBTB24 mutations who exhibit discrepant phenotypes present longer CDR3 lengths and reduced number of known pathology-associated TCRs.

Low preoperative skeletal muscle index increases the risk of mortality among resectable pancreatic cancer patients: A retrospective study.

BACKGROUND: The only potential curative treatment for patients with pancreatic cancer is surgery; however, the prognosis remains poor. Measures of body composition based on computed tomography (CT) have been established as a reliable predictor of the prognosis of cancer patients after surgery. AIM: To elucidate the associations of body composition measures derived from preoperative CT scans with the prognosis of patients with pancreatic cancer. METHODS: One hundred fifteen patients undergoing pancreatic resection with curative intent for pancreatic cancer were retrospectively enrolled. A preoperative CT scan at the third lumbar vertebral level was performed to measure the skeletal muscle index (SMI), mean skeletal muscle radiodensity, subcutaneous adipose tissue index, and visceral to subcutaneous adipose tissue area ratio. The clinical and pathological data were collected. The effects of these factors on long-term survival were evaluated. RESULTS: Among the five body composition measures, only low SMI independently predicted overall survival (OS) [hazard ratio (HR): 2.307; 95% confidence interval (CI): 1.210-4.402] and recurrence-free survival (HR: 1.907; 95%CI: 1.147-3.171). Furthermore, patients with low SMI (vs high SMI) were older (68.8 ± 9.3 years vs 63.3 ± 8.4 years); low SMI was present in 27 of 56 patients (48.2%) aged 65 years and older and in 11 of 59 younger patients (18.6%). In addition, subgroup analyses revealed that the correlation between low SMI and OS was observed only in patients aged 65 years and older. CONCLUSION: Low preoperative SMI was more prevalent in elderly patients and was associated with a poor prognosis among pancreatic cancer patients, especially elderly patients.

The anatomical features of dorsal pancreatic artery in the pancreatic head and its clinical significance in laparoscopic pancreatoduodenectomy.

BACKGROUND: Bleeding control as one of the major challenges in laparoscopic pancreaticoduodenectomy (LPD) necessitates a considerable anatomical knowledge of the blood supply to the pancreatic head so as to improve the safety of this surgery. This study aimed towards a better understanding of the anatomical features of the dorsal pancreatic artery (DPA), as well as its clinical significance in LPD. METHOD: Thirteen Chinese cadaveric specimens were used to study the blood supply of the pancreatic head. Twelve of them were perfused with latex, and the other fresh one was used to build the intraorganic structure model of the pancreas by mold casting. Between July 2018 and June 2019, a total of thirty-five consecutive patients without vascular encasement, who underwent LPD in our institute, were performed with computed tomography as a preoperative detection of the DPA. The DPA was ligated prior to uncinate process dissection in seventeen patients ("early DPA ligation" group), as the others were assigned into the control group. RESULTS: In the thirteen cadaveric specimens, the DPA originates, respectively, from the splenic artery (46.1%), superior mesenteric artery (38.5%), common hepatic artery (7.7%) and right gastroepiploic artery (7.7%). The right branch of the DPA gives off terminal arteries to form an "inner ring" in the pancreatic head, which communicates with the pancreaticoduodenal arterial arches by plenty of collateral arteries. As compared to the control group, the "early DPA ligation" group showed a significantly lower mean blood loss (218 ± 111 vs 320 ± 162, P = 0.038), as well as shorter mean resection time (121 ± 23 vs 136 ± 22, P = 0.049). CONCLUSION: The DPA is one of the major blood supplies to the pancreatic head. A ligation of DPA prior to dissection of the uncinate process can help to completely block the blood supply to the pancreatic head, and therefore improve surgical outcome and safety in LPD.

Practice Patterns and Perioperative Outcomes of Laparoscopic Pancreaticoduodenectomy in China: A Retrospective Multicenter Analysis of 1029 Patients.

OBJECTIVE: The aim of the study was to analyze the outcomes of patients who have undergone laparoscopic pancreaticoduodenectomy (LPD) in China. SUMMARY BACKGROUND DATA: LPD is being increasingly used worldwide, but an extensive, detailed, systematic, multicenter analysis of the procedure has not been performed. METHODS: We retrospectively reviewed 1029 consecutive patients who had undergone LPD between January 2010 and August 2016 in China. Univariate and multivariate analyses of patient demographics, changes in outcome over time, technical learning curves, and the relationship between hospital or surgeon volume and patient outcomes were performed. RESULTS: Among the 1029 patients, 61 (5.93%) required conversion to laparotomy. The median operation time (OT) was 441.34 minutes, and the major complications occurred in 511 patients (49.66%). There were 21 deaths (2.43%) within 30 days, and a total of 61 (5.93%) within 90 days. Discounting the effects of the early learning phase, critical parameters improved significantly with surgeons' experience with the procedure. Univariate and multivariate analyses revealed that the pancreatic anastomosis technique, preoperative biliary drainage method, and total bilirubin were linked to several outcome measures, including OT, estimated intraoperative blood loss, and mortality. Multicenter analyses of the learning curve revealed 3 phases, with proficiency thresholds at 40 and 104 cases. Higher hospital, department, and surgeon volume, as well as surgeon experience with minimally invasive surgery, were associated with a lower risk of surgical failure. CONCLUSIONS: LPD is technically safe and feasible, with acceptable rates of morbidity and mortality. Nonetheless, long learning curves, low-volume hospitals, and surgical inexperience are associated with higher rates of complications and mortality.

Preoperative Altered Spontaneous Brain Activity and Functional Connectivity Were Independent Risk Factors for Delayed Neurocognitive Recovery in Older Adults Undergoing Noncardiac Surgery.

Objectives: Recently, it has been demonstrated that patients with subtle preexisting cognitive impairment were susceptible to delayed neurocognitive recovery (DNR). This present study investigated whether preoperative alterations in gray matter volume, spontaneous activity, or functional connectivity (FC) were associated with DNR. Methods: This was a nested case-control study of older adults (≥60 years) undergoing noncardiac surgery. All patients received MRI scan at least 1 day prior to surgery. Cognitive function was assessed prior to surgery and at 7-14 days postsurgery. Preoperative gray matter volume, amplitude of low-frequency fluctuation (ALFF), and FC were compared between the DNR patients and non-DNR patients. The independent risk factors associated with DNR were identified using a multivariate logistic regression model. Results: Of the 74 patients who completed assessments, 16/74 (21.6%) had DNR following surgery. There were no differences in gray matter volume between the two groups. However, the DNR patients exhibited higher preoperative ALFF in the bilateral middle cingulate cortex (MCC) and left fusiform gyrus and lower preoperative FC between the bilateral MCC and left calcarine than the non-DNR patients. The multivariate logistic regression analysis showed that higher preoperative spontaneous activity in the bilateral MCC was independently associated with a higher risk of DNR (OR = 3.11, 95% CI, 1.30-7.45; P = 0.011). A longer education duration (OR = 0.57, 95% CI, 0.41-0.81; P = 0.001) and higher preoperative FC between the bilateral MCC and left calcarine (OR = 0.40, 95% CI, 0.18-0.92; P = 0.031) were independently correlated with a lower risk of DNR. Conclusions: Preoperative higher ALFF in the bilateral MCC and lower FC between the bilateral MCC and left calcarine were independently associated with the occurrence of DNR. The present fMRI study identified possible preoperative neuroimaging risk factors for DNR. This trial is registered with Chinese Clinical Trial Registry ChiCTR-DCD-15006096.

Laparoscopic pancreaticoduodenectomy in elderly patients.

OBJECTIVE: The objective of the study is to evaluate the safety and feasibility of laparoscopic pancreaticoduodenectomy (LPD) in elderly patients by short-term surgical effects. METHODS: We retrospectively collected clinical data of 55 non-elderly patients (< 70 years), 27 elderly patients (≥ 70 years) underwent LPD, and 19 elderly patients underwent open pancreaticoduodenectomy (OPD) in biliopancreatic surgery department of Huadong Hospital, affiliated to Fudan University, from Jan 2015 to Jan 2018. Patients were divided into 3 groups: LPD aged < 70 years, LPD aged ≥ 70 years, and OPD aged ≥ 70 years, according to their age at admission and surgical approach in order to compare baseline characteristics and short-term surgical outcomes. RESULTS: Totally 101 patients were included in this study; 59 cases were male; 42 cases were female; mean age was 66 years old. Elderly LPD patients seemed to have higher overall morbidity (41% vs. 20%, P = 0.05) compared to non-elderly patients. This difference is even more significant in our multivariable analysis model with an odds ratio of 4.48 (95% CI 1.31-17.87, P = 0.018). The 90-days mortality, operative time, estimated blood loss (EBL), and post-operative hospital stay (POHS) were similar in two groups. Elderly LPD patients had less EBL and shorter POHS than elderly OPD patients. However, the mortality and morbidity rate were comparable in these two groups. CONCLUSIONS: Aging patients have higher overall morbidity than younger patients in LPD. However, for aging population who need to undergo pancreaticoduodenectomy, LPD might have some advantages over OPD.

Cancer­associated adipocytes exhibit distinct phenotypes and facilitate tumor progression in pancreatic cancer.

Adipocyte infiltration in pancreatic cancer (PC) has been demonstrated to be independently associated with PC risk and an active contributor to tumor progression. However, to date, little is known about these unique pancreatic tumor­surrounding adipocytes, or their response to cancer cells. The present study utilized an in vitro indirect coculture model in which the phenotypic changes of adipocytes following exposure to PC cells were directly observed. RNA­sequencing was performed on 3T3­L1 adipocytes cultured with or without Panc­1 cancer cells, and significant changes were identified at the transcriptional level. In terms of delipidation and the impaired function of glucose and lipid metabolism, coculture with tumor cells resulted in an altered metabolic phenotype in mature adipocytes. In co­cultured adipocytes, the appearance of fibroblast­like cells was observed, and the mesenchymal cell differentiation pathway was enriched following the integrated analysis into the transcriptome. In addition, reverse transcription­quantitative PCR analyses of co­cultured adipocytes revealed a loss in gene expression of mature adipocyte markers, and a gain in gene expression of fibroblast­specific markers. It was also confirmed that newly generated cancer­associated adipocytes could facilitate the invasive capacities of the tumor, and may contribute to PC stromal remodeling. The present study supports a novel concept that reprogramming of stromal adipocytes orchestrated by PC cells may generate cancer­associated adipocytes with activated phenotypes, which may ultimately drive pancreatic tumor progression.

Management of the uncinate process via the artery first approach in laparoscopic pancreatoduodenectomy.

BACKGROUND: Uncinate process dissection is one of the major challenges for surgeons when performing laparoscopic pancreatoduodenectomy. This study aimed to evaluate the artery first approach for handling uncinate process dissection in laparoscopic pancreatoduodenectomy. METHODS: Between February 2015 and June 2018, a total of 91 consecutive patients without vascular encasement underwent selective laparoscopic pancreatoduodenectomy, including the first 26 consecutive cases treated with the conventional approach and the remaining 65 with the artery first approach applied for uncinate process dissection. Here, we present and analyze the surgical outcomes and the oncological results for the two groups. RESULTS: There was no significant difference between the two groups in operative time, intraoperative blood loss, the rate of conversion to open pancreatoduodenectomy, postoperative complications, mortality, as well as the number of lymph nodes retrieved in the malignancies. In contrast, the artery first approach group showed a statistically significant shorter resection time and a higher R0 resection rate when compared with the conventional group. CONCLUSIONS: The artery first approach is a safe and feasible technique that can be used for uncinate process management in laparoscopic pancreatoduodenectomy for patients without vascular encasement. It also has the advantage of increased rate of radical resection in the surgical intervention of relevant malignancies.

Myopia disease mouse models: a missense point mutation (S673G) and a protein-truncating mutation of the Zfp644 mimic human disease phenotype.

Zinc finger 644 (Zfp644 in mouse, ZNF644 in human) gene is a transcription factor whose mutation S672G is considered a potential genetic factor of inherited high myopia. ZNF644 interacts with G9a/GLP complex, which functions as a H3K9 methyltransferase to silence transcription. In this study, we generated mouse models to unravel the mechanisms leading to symptoms associated with high myopia. Employing TALEN technology, two mice mutants were generated, either with the disease-carrying mutation (Zfp644 S673G ) or with a truncated form of Zfp644 (Zfp644 Δ8 ). Eye morphology and visual functions were analysed in both mutants, revealing a significant difference in a vitreous chamber depth and lens diameter, however the physiological function of retina was preserved as found under the high-myopia conditions. Our findings prove that ZNF644/Zfp644 is involved in the development of high-myopia, indicating that mutations such as, Zfp644 S673G and Zfp644 Δ8 are causative for changes connected with the disease. The developed models represent a valuable tool to investigate the molecular basis of myopia pathogenesis and its potential treatment.

Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency.

PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.

SNX6 predicts poor prognosis and contributes to the metastasis of pancreatic cancer cells via activating epithelial-mesenchymal transition.

Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate around 6%. Though significant progress has been made in the availability of diagnostic techniques and treatment strategies, pancreatic cancer remains a disease of high mortality rate. Therefore, there is an urgent need for a better understanding of the molecular mechanisms that governs the oncogenesis and metastasis process of pancreatic cancer. In the present study, by using the Cancer Genome Atlas (TCGA) dataset analysis, we demonstrated that sorting nexin 6 (SNX6) serves as a biomarker for predicting prognosis of pancreatic cancer. In vitro studies demonstrated that silencing of SNX6 expression reduced cell proliferation, colony formation, invasion, and metastasis. Higher level of SNX6 helps maintain the mesenchymal properties, which renders migration and invasive capacities to pancreatic cancer cells. Moreover, in the process of TGF-ß-induced epithelial to mesenchymal transition (EMT), the expression level of SNX6 was increased, and silencing of SNX6 expression could inhibit the TGF-ß-induced EMT program. These results collectively uncovered a novel predictive marker for pancreatic cancer and provided the possible underlying molecular mechanism.