Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation Via LAMA5/ITGA4 Axis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplastic stroma surrounding most tumors. Activated stromal fibroblasts, namely cancer-associated fibroblasts (CAFs), play a major role in PDAC progression. We analyzed whether CAFs influence acinar cells and impact PDAC initiation, that is, acinar-to-ductal metaplasia (ADM). ADM connection with PDAC pathophysiology is indicated, but not yet established. We hypothesized that CAF secretome might play a significant role in ADM in PDAC initiation. METHODS: Mouse and human acinar cell organoids, acinar cells cocultured with CAFs and exposed to CAF-conditioned media, acinar cell explants, and CAF cocultures were examined by means of quantitative reverse transcription polymerase chain reaction, RNA sequencing, immunoblotting, and confocal microscopy. Data from liquid chromatography with tandem mass spectrometry analysis of CAF-conditioned medium and RNA sequencing data of acinar cells post-conditioned medium exposure were integrated using bioinformatics tools to identify the molecular mechanism for CAF-induced ADM. Using confocal microscopy, immunoblotting, and quantitative reverse transcription polymerase chain reaction analysis, we validated the depletion of a key signaling axis in the cell line, acinar explant coculture, and mouse cancer-associated fibroblasts (mCAFs). RESULTS: A close association of acino-ductal markers (Ulex europaeus agglutinin 1, amylase, cytokeratin-19) and mCAFs (α-smooth muscle actin) in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1Cre (KPC) and LSL-KrasG12D/+; Pdx1Cre (KC) autochthonous progression tumor tissue was observed. Caerulein treatment-induced mCAFs increased cytokeratin-19 and decreased amylase in wild-type and KC pancreas. Likewise, acinar-mCAF cocultures revealed the induction of ductal transdifferentiation in cell line, acinar-organoid, and explant coculture formats in WT and KC mice pancreas. Proteomic and transcriptomic data integration revealed a novel laminin α5/integrinα4/stat3 axis responsible for CAF-mediated acinar-to-ductal cell transdifferentiation. CONCLUSIONS: Results collectively suggest the first evidence for CAF-influenced acino-ductal phenotypic switchover, thus highlighting the tumor microenvironment role in pancreatic carcinogenesis inception.

Meta-Analysis of Endoscopic Full-Thickness Resection Versus Endoscopic Submucosal Dissection for Complex Colorectal Lesions.

BACKGROUND: Studies evaluating endoscopic full-thickness resection (EFTR) and endoscopic submucosal dissection (ESD) for complex colorectal lesions have shown variable results. We conducted a meta-analysis of the available data. METHODS: Online databases were searched for studies comparing EFTR versus ESD for complex colorectal lesions. The outcomes of interest were resection rates, procedure time (min), and complications. Pooled odds ratios (OR) and standardized mean difference (SMD) along with 95% CI were calculated. RESULTS: A total of 4 studies with 530 patients (n=215 EFTR, n=315 ESD) were included. The mean follow-up duration was 5 months. The mean age of the patients was 68 years and 64% were men. The EFTR and ESD groups had similar rates of en bloc resection (OR: 1.73, 95% CI: 0.60-4.97, P=0.31) and R0 resection (OR: 1.52, 95% CI: 0.55-4.14, P=0.42). The EFTR group had significantly reduced procedure time (SMD -1.87, 95% CI: -3.13 to -0.61, P=0.004), total complications (OR: 0.24, 95% CI: 0.13-0.44, P<0.00001), perforation (OR: 0.12, 95% CI: 0.03-0.39, P=0.0005) and postresection electrocoagulation syndrome (OR: 0.06, 95% CI: 0.01-0.48, P=0.008). Delayed bleeding was similar in the 2 groups (OR: 0.80, 95% CI: 0.30-2.12, P=0.66). Residual/recurrent lesions were significantly higher in the EFTR group (OR: 4.67, 95% CI: 1.39-15.66, P=0.01). DISCUSSION: This meta-analysis of small studies with high heterogeneity showed that EFTR and ESD have comparable resection rates for complex colorectal lesions. EFTR is faster and has fewer complications, but it increases residual or recurrent lesions.

Safety and efficacy of thalidomide in treatment of gastrointestinal bleeding secondary to angioectasias: a systematic review and meta-analysis.

BACKGROUND: Thalidomide has been used for angioectasia-associated refractory gastrointestinal bleeding (GIB), with studies showing variable efficacy and side effects profile. We conducted a meta-analysis to reconcile the data. METHODS: Online databases were searched for studies evaluating thalidomide in patients with refractory/recurrent GIB due to angioectasias. The outcomes of interest were cessation of bleeding, rebleeding, need for blood transfusion, hospitalization and adverse events. Pooled proportions for incidence, and odds ratios (OR) for comparison with control were calculated along with 95% confidence interval (CI). RESULTS: A total of seven studies with 346 patients (n = 269 thalidomide, n = 77 control) were included. Thalidomide dose was usually started at 50-100mg/day. The mean age was 65 years, 45% patients were men, and mean follow-up was 1.8 years. The pooled clinical outcomes with thalidomide were: cessation of bleeding 42.2% (95% CI 36.02 to 48.41), rebleeding 30%, need for blood transfusion 20.1%, hospitalization 40% and adverse events 55.9%. When compared with the control group in 2 studies, patients on thalidomide had significantly higher odds of cessation of bleeding (OR 21.40, 95% CI 5.78 to 79.29, p < 0.00001) and adverse events, with lower need for blood transfusion and hospitalization. DISCUSSION: In patients with angioectasias-related refractory/recurrent GIB, the use of thalidomide results in significantly decreased bleeding risk and may play a role in the management of such patients.

Single-incision needle-knife biopsy for the diagnosis of GI subepithelial tumors: a systematic review and meta-analysis.

BACKGROUND AND AIMS: A histologic diagnosis of GI subepithelial tumors (SETs) is important because of the malignant potential of these lesions. The current modalities of choice, including EUS-guided FNA and biopsy (EUS-FNA/FNB) have demonstrated suboptimal diagnostic success. Single-incision with needle-knife (SINK) biopsy has emerged as an alternative diagnostic approach to increase tissue acquisition and diagnostic success. The aim of this study was to perform a systematic review and meta-analysis to evaluate the technical success, diagnostic success, and adverse events of SINK biopsy. METHODS: We searched multiple databases including PubMed, EMBASE, CINAHL, Cochrane, Web of Science, and Google Scholar from inception to July 2022. The primary outcomes assessed were the technical success and diagnostic success of SINK in GI SETs. The secondary outcomes assessed were adverse events and whether immunohistochemical analysis could be successfully performed on tissue samples obtained via SINK. RESULTS: Seven studies with a total of 219 SINK biopsy procedures were included in this meta-analysis. The technical success rate was 98.1% (95% CI, 94.9%-99.3%; P = .000; I2 = .0%), and the diagnostic success rate was 87.9% (95% CI, 82.6%-91.7%; P = .000; I2 = .0%). The immunohistochemical success rate was 88.3% (95% CI, 78.7%-93.9%; P = .000; I2 = 3.5%). The rate of adverse events was 7.5% (95% CI, 4.3%-12.7%; P = .00; I2 = 7.2%), and bleeding was the most common adverse event. CONCLUSION: SINK biopsy is a safe diagnostic procedure with a high technical and diagnostic success in patients with GI SET. Further randomized controlled trials and direct comparison studies are needed to validate these findings.

Adenoma and polyp detection rates during insertion versus withdrawal phase of colonoscopy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colonoscopy is the preferred modality for colorectal cancer screening because it has both diagnostic and therapeutic capabilities. Current consensus states that colonoscopy should be performed with initial rapid passage of the instrument to the cecum, followed by thorough evaluation for and removal of all polyps during a deliberate slow withdrawal. Reports have suggested that polyps that are seen but not removed during insertion are sometimes quite difficult to find during withdrawal. METHODS: We performed a comprehensive literature search of several major databases (from inception to March 2020) to identify randomized controlled trials comparing inspection and polypectomy during the insertion phase as opposed to the traditional practice of inspection and polypectomy performed entirely during the withdrawal phase. We examined differences in terms of adenoma detection rate (ADR), polyps detected per patient (PDPP), cecal intubation time (CIT), withdrawal time, and total procedure time. RESULTS: Seven randomized controlled trials, including 3834 patients, were included in our final analysis. The insertion/withdrawal cohort had 1951 patients and the withdrawal-only cohort 1883 patients. Pooled odds of adenoma detection in the insertion/withdrawal cohort was .99 (P = .8). ADR was 47.2% in the insertion/withdrawal cohort and 48.6% in the withdrawal-only cohort. Although total procedure and withdrawal times were shorter in the insertion/withdrawal cohort, PDPP in both cohorts were not statistically significant (1.4 vs 1.5, P = .7). CONCLUSIONS: Additional inspection and polypectomy during the insertion and withdrawal phases of colonoscopy offer no additional benefit in terms of ADR or PDPP.

A2B- and A3-Type Boron(III)Subchlorins Derived from meso-Diethoxycarbonyltripyrrane: Synthesis and Photophysical Exploration.

The first direct fabrication of A2B- and A3-type B(III)subchlorins from meso-ethoxycarbonyl-substituted tripyrrane has been realized by condensation with appropriate acid chlorides (benzoyl chloride, butyryl chloride, and ethyl chlorooxoacetate). The aliphatic acid chloride-based annulation reaction is new to subporphyrinoid chemistry. The phenyl (6a)- or n-propyl (6b)-substituted derivatives could be oxidized to the corresponding B(III)subporphyrins upon refluxing with DDQ, whereas the triethoxycarbonyl moiety (6c) was found to be resistant to oxidation and exhibits the most red-shifted absorption (587 nm) and emission (604 nm). The study indicates that absorption and emission behaviors of the B(III)subchlorin can be tuned by the introduction of electron-rich or electron-deficient substituents at the meso-position. B(III)subchlorins 6a and 6c generate singlet oxygen efficiently (44 and 40%, respectively) and, thus, may find application as potential photosensitizers in photodynamic therapy (PDT).

Clinical efficacy of gastric per-oral endoscopic myotomy (G-POEM) in the treatment of refractory gastroparesis and predictors of outcomes: a systematic review and meta-analysis using surgical pyloroplasty as a comparator group.

BACKGROUND AND AIMS: Gastric peroral endoscopic myotomy (G-POEM) is a novel minimally invasive technique in endosurgery. Data is limited as to its efficacy, safety, and predictive factors. We conducted this meta-analysis to evaluate the clinical outcomes of G-POEM and used the outcomes of surgical pyloroplasty as a comparator group in the treatment of refractory gastroparesis. METHODS: We searched multiple databases from inception through March 2019 to identify studies that reported on G-POEM and pyloroplasty in gastroparesis. Our primary outcome was to analyze and compare the pooled rates of clinical success, in terms of Gastroparesis Cardinal Symptom Index (GCSI) score and 4-h gastric emptying study (GES) results, with G-POEM and pyloroplasty. RESULTS: Three hundred and thirty-two and 375 patients underwent G-POEM (11 studies) and surgical pyloroplasty (seven studies), respectively. The pooled rate of clinical success, based on the GCSI score, with G-POEM was 75.8% (95% CI 68.1-82.1, I2 = 50) and with surgical pyloroplasty was 77.3% (95% CI 66.4-85.4, I2 = 0), with no significance, p = 0.81. The pooled rate of clinical success, based on the 4-hour GES results, with G-POEM was 85.1% (95% CI 68.9-93.7, I2 = 74) and with surgical pyloroplasty was 84% (95% CI 64.4-93.8, I2 = 81), with no significance, p = 0.91. The overall adverse events were comparable. Based on meta-regression analysis, idiopathic gastroparesis, prior treatment with botulinum toxin and gastric stimulator seemed to predict clinical success with G-POEM. CONCLUSION: G-POEM demonstrates clinical success in treating refractory gastroparesis. Idiopathic gastroparesis, prior treatment with botulinum injections and gastric stimulator appear to have positive predictive effects on the 4-h GES results after G-POEM. Outcomes seem comparable to surgical pyloroplasty.

Using the Rendezvous Technique Through Choledochoduodenostomy for Malignant Biliary Obstruction.

Endoscopic transpapillary biliary stenting via endoscopic retrograde cholangiopancreatography is the preferred therapy for benign and malignant distal biliary obstruction. In cases of failed endoscopic retrograde cholangiopancreatography, endoscopic ultrasound-guided choledochoduodenostomy has been shown to be as effective as percutaneous methods with an improved safety profile. Despite its efficacy, it is complicated by stent occlusion in 9%-26% of cases. To our knowledge, this is the first case in which biliary obstruction was relieved by performing a rendezvous procedure utilizing a pre-existing choledochoduodenostomy.

Endoscopic ultrasound-guided portal pressure gradient measurement: a systematic review and meta-analysis.

Background: Endoscopic ultrasound-guided portal pressure gradient measurement (EUS-PPG) is a new modality where the portal pressure is measured by directly introducing a needle into the hepatic vein and portal vein. This is the first systematic review and meta-analysis to evaluate the efficacy and safety of EUS-PPG. Methods: A comprehensive literature search was performed to identify pertinent studies. The primary outcomes assessed were the technical and clinical success of EUS-PPG. Technical success was defined as successful introduction of the needle into the desired vessel, while clinical success was defined as the correlation of the stage of fibrosis on the liver biopsy to EUS-PPG, or concordance of HVPG and EUS-PPG. The secondary outcomes were pooled rates for total and individual adverse events related to EUS-PPG. Pooled estimates were calculated using random-effects models with a 95% confidence interval (CI). Results: Eight cohort studies with a total of 178 patients were included in our analysis. The calculated pooled rates of technical success and clinical success were 94.6% (95%CI 88.5-97.6%; P=<0.001; I2=0) and 85.4% (95%CI 51.5-97.0%; P=0.042; I2=70), respectively. The rate of total adverse events was 10.9% (95%CI 6.5-17.7%; P=<0.001; I2=4), and 93.7% of them were mild, as defined by the American Society for Gastrointestinal Endoscopy. Abdominal pain (11%) was the most common adverse event, followed by bleeding (3.6%). There were no cases of perforation or death reported in our study. Conclusions: EUS-PPG is a safe and effective modality for diagnosing portal hypertension. Further randomized controlled trials are needed to validate our findings.

Vortex nucleation in rotating Bose-Einstein condensates with density-dependent gauge potential.

We study numerically the vortex dynamics and vortex-lattice formation in a rotating density-dependent Bose-Einstein condensate (BEC), characterized by the presence of nonlinear rotation. By varying the strength of nonlinear rotation in density-dependent BECs, we calculate the critical frequency, Ω_{cr}, for vortex nucleation both in adiabatic and sudden external trap rotations. The nonlinear rotation modifies the extent of deformation experienced by the BEC due to the trap and shifts the Ω_{cr} values for vortex nucleation. The critical frequencies, and thereby the transition to vortex-lattices in an adiabatic rotation ramp, depend on conventional s-wave scattering lengths through the strength of nonlinear rotation, C, such that Ω_{cr}(C>0)<Ω_{cr}(C=0)<Ω_{cr}(C<0). In an analogous manner, the critical ellipticity (ε_{cr}) for vortex nucleation during an adiabatic introduction of trap ellipticity (ε) depends on the nature of nonlinear rotation besides trap rotation frequency. The nonlinear rotation additionally affects the vortex-vortex interactions and the motion of the vortices through the condensate by altering the strength of Magnus force on them. The combined result of these nonlinear effects is the formation of the non-Abrikosov vortex-lattices and ring-vortex arrangements in the density-dependent BECs.

Synthesis of Trifluoromethyl-Substituted [14]Triphyrin(2.1.1), Its Selective Reduction to Triphachlorin, and Stable Isomeric Triphabacteriochlorins via Direct Detrifluoromethylation.

Two novel classes of reduced triphyrin(2.1.1), namely, triphachlorin and triphabacteriochlorin, are realized via selective reduction of the newly synthesized 7,12-bis(trifluoromethyl)triphyrin(2.1.1) 1 using p-tosylhydrazide. Triphachlorin 2 displayed red-shifted absorption (580 nm). Harsher conditions, however, led to a unique direct detrifluoromethylation of one CF3 moiety to form two isomeric triphabacteriochlorins 3 and 4, which exhibit blue-shifted intense lowest-energy absorption bands and intense emission (ϕf = 0.52 and 0.36, respectively) while generating singlet oxygen very efficiently (Ï•Δ = 0.88 and 0.86, respectively). These reduced porphyrinoids show very high oxidative stability as they remain unchanged upon refluxing with 2,3-dichloro-5,6-dicyanobenzoquinone in toluene.

Nanotechnological Approaches for the Treatment of Triple-Negative Breast Cancer: A Comprehensive Review.

Breast cancer is the most prevalent cancer in women around the world, having a sudden spread nowadays because of the poor sedentary lifestyle of people. Comprising several subtypes, one of the most dangerous and aggressive ones is triple-negative breast cancer or TNBC. Even though conventional surgical approaches like single and double mastectomy and preventive chemotherapeutic approaches are available, they are not selective to cancer cells and are only for symptomatic treatment. A new branch called nanotechnology has emerged in the last few decades that offers various novel characteristics, such as size in nanometric scale, enhanced adherence to multiple targeting moieties, active and passive targeting, controlled release, and site-specific targeting. Among various nanotherapeutic approaches like dendrimers, lipid-structured nanocarriers, carbon nanotubes, etc., nanoparticle targeted therapeutics can be termed the best among all for their specific cytotoxicity to cancer cells and increased bioavailability to a target site. This review focuses on the types and molecular pathways involving TNBC, existing treatment strategies, various nanotechnological approaches like exosomes, carbon nanotubes, dendrimers, lipid, and carbon-based nanocarriers, and especially various nanoparticles (NPs) like polymeric, photodynamic, peptide conjugated, antibody-conjugated, metallic, inorganic, natural product capped, and CRISPR based nanoparticles already approved for treatment or are under clinical and pre-clinical trials for TNBC.

Analysis of Feasibility and Acceptability of an E-Learning Module in Anatomy.

Recent advance in medical education is in correlation with the advances in information technology and thus computer-based learning is being increasingly employed. The objective of the present study was to design and evaluate an e-learning module in anatomy and assess the perceptions of students and faculty about this e-learning module. The participating students were randomized into three groups by block stratified randomization and Google groups were created for each of the three groups. The e-learning module was implemented in three sessions by rotating the three groups. Validated questionnaires were sent to faculty and participating students via Google forms to obtain feedback. The results of ANOVA showed that there was a significant difference among the groups in terms of marks obtained with conventional (F = 2.403, P = 0.103), online (F = 6.050, P = 0.005), and blended (F = 5.801, P = 0.006). Post hoc comparisons using the Tukey HSD test, about the gain of knowledge, indicated that the results were insignificant when comparing the conventional group with the online group, but were significant when comparing the blended group with the conventional and online group. The qualitative data regarding the perception of students toward e-learning were analyzed using thematic analysis. The introduction of an interactive e-learning module in anatomy was effective and well received by the students and faculty. The study showed that blended learning has a positive impact on the students' learning by improving cognitive gain and receptive perception for e-learning.

Safety and efficacy of EUS-guided ablation of pancreatic lesions with ethanol versus ethanol with paclitaxel: A systematic review and meta-analysis.

Background and Objectives: EUS-guided ethanol ablation has emerged as an alternative method for pancreatic lesions. Recently, paclitaxel was added to ethanol to assess ablative effects in pancreatic lesions. We performed a systematic review and meta-analysis on EUS-guided ethanol ablation (EUS E) versus EUS-guided ethanol with paclitaxel (EUS EP) ablation for the management of pancreatic lesions. Methods: Comprehensive search of multiple electronic databases and conference proceedings including PubMed, EMBASE, Google Scholar, and Web of Science databases (from inception to May 2020). The primary outcome evaluated complete ablation of the lesions radiologically and the secondary outcome evaluated adverse events (AEs). Results: Fifteen studies on 524 patients were included in our analysis. The pooled complete ablation rate was 58.89% (95% confidence interval (CI) = 38.72-77.80, I2 = 91.76%) and 55.99% (95% CI = 44.66-67.05, I2 = 0) in the EUS E and EUS EP groups (P = 0.796), respectively. The pooled AE rates were 13.92% (95% CI = 4.71-26.01, I2 = 83.43%) and 31.62% (95% CI = 3.36-68.95, I2 = 87.9%) in the EUS E and EUS EP groups (P = 0.299), respectively. The most common AE was abdominal pain at 7.27% (95% CI = 1.97-14.6, I2 = 68.2%) and 12.44% (95% CI = 0.00-39.24, I2 = 81.1%) in the EUS E and EUS EP groups (P = 0.583), respectively. Correlation coefficient (r) was ‒0.719 (P = 0.008) between complete ablation and lesion size. Conclusion: Complete ablation rates were comparable among both groups. AE rates were higher in the EUS EP group. Further randomized controlled trials are needed to validate our findings.

Efficacy of EUS-guided needle-based confocal laser endomicroscopy in the diagnosis of pancreatic lesions: A systematic review and meta-analysis.

Background and Objectives: Needle-based confocal laser endomicroscopy (nCLE) is a procedure in which an AQ-Flex nCLE mini-probe is passed through an EUS-FNA needle into a pancreatic lesion to enable subsurface in vivo tissue analysis. In this study, we conducted a systematic review and meta-analysis of nCLE for the diagnosis of pancreatic lesions. Materials and Methods: We conducted a comprehensive search of several databases and conference proceedings, including PubMed, EMBASE, Google-Scholar, MEDLINE, SCOPUS, and Web of Science databases (earliest inception to March 2020). The primary outcomes assessed the pooled rate of diagnostic accuracy for nCLE and the secondary outcomes assessed the pooled rate of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events (AE) of nCLE to diagnose premalignant/malignant pancreatic lesions. Results: Eleven studies on 443 patients were included in our analysis. The pooled rate of diagnostic accuracy of EUS nCLE was 83% (95 confidence interval [CI] = 79-87; I 2 = 0). The pooled rate of sensitivity, specificity, PPV and NPV of EUS nCLE was 85.29% (95% CI = 76.9-93.68; I 2 = 85%), 90.49% (95% CI = 82.24-98.74; I 2 = 64%), 94.15% (95% CI = 88.55-99.76; I 2 = 68%), and 73.44% (95% CI = 60.16-86.72; I 2 = 93%), respectively. The total AE rate was 5.41% (±5.92) with postprocedure pancreatitis being the most common AE at 2.28% (±3.73). Conclusion: In summary, this study highlights the rate of diagnostic accuracy, sensitivity, specificity, and PPV for distinguishing premalignant/malignant lesions. Pancreatic lesions need to be further defined with more validation studies to characterize CLE diagnosis criteria and to evaluate its use as an adjunct to EUS-FNA.

Modulational instability and soliton generation in chiral Bose-Einstein condensates with zero-energy nonlinearity.

By means of analytical and numerical methods, we address the modulational instability (MI) in chiral condensates governed by the Gross-Pitaevskii equation including the current nonlinearity. The analysis shows that this nonlinearity partly suppresses the MI driven by the cubic self-focusing, although the current nonlinearity is not represented in the system's energy (although it modifies the momentum), hence it may be considered as zero-energy nonlinearity. Direct simulations demonstrate generation of trains of stochastically interacting chiral solitons by MI. In the ring-shaped setup, the MI creates a single traveling solitary wave. The sign of the current nonlinearity determines the direction of propagation of the emerging solitons.