Evaluation of Pyrazolyl-Indolizine Derivatives as Antimicrobial Agents: Synthesis, In vitro, In silico ADMET and Molecular Docking Studies.

Herein, we report analogues of s-indacene by the synthesis of novel indolizine derivatives. Using chloroform as an appropriate solvent, sixteen derivatives of pyrazolyl-indolizine (4--19) were prepared by the reaction of 3-(dimethylamino)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (1) with hydrazonoyl chloride derivatives (2) in the presence of triethylamine in good to excellent yields. We used NMR spectra, IR, mass spectrometry, as well as elemental analyses to prove the chemical structures and the purity of the synthesized compounds 4-19. Among all tested compounds 5, 9, 13 and 19 had a potent antimicrobial efficiency against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aerginousea, Sallmonella typhemerium, and Candida albicans. Furthermore, a significant increase in lipid peroxidation (LPO) toward the Gram-negative bacteria, Pseudomonas aeruginosa when treated with compound 9 was observed, while compound 13 remarkably increased the cell membrane oxidation of Salmonella typhimurium. Additionally, we utilized docking studies and in silico methods to evaluate the drug-likeness, physicochemical properties, and ADMET profiles of the compounds. The results of the molecular docking simulation revealed that the synthesized compounds displayed decreased binding energy when interacting with the active sites of important enzymes, including Sterol 14-demethylase of C. albicans, Dihydropteroate synthase of S. aureus, LasR of P. aeruginosa, Glucosamine-6-phosphate synthase of S. typhimurium, and Gyrase B of B. subtilis.

Design, synthesis, structure elucidation, antimicrobial, molecular docking, and SAR studies of novel urea derivatives bearing tricyclic aromatic hydrocarbon rings.

The targeted compounds were prepared using both (9H-fluoren-9-ylidene)hydrazine (1) and 10H-phenothiazine (2) as starting materials. The treatment of 1 or 2 with different isocyanates afforded the title compounds 7a-d, 8a, and 8b in excellent yield. All compounds were characterized and ascertained by infrared, nuclear magnetic resonance, and elemental analyses as well as single-crystal X-ray diffraction. The antimicrobial efficiency of all was tested in vitro, and a noticeable inhibition activity against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans was obtained by compounds 7a, 7b, 8a, and 8b. Moreover, the biofilm mechanism activity was strongly inhibited by compounds 7b and 8b for all bacterial pathogens, with a percentage ratio of more than 55%. The findings from the molecular docking simulation revealed that compounds 7a, 7b, 8a, and 8b exhibited favorable binding energies and interacted effectively with the active sites of sterol 14-demethylase, dihydropteroate synthase, gyrase B, LasR (major transcriptional activator of P. aeruginosa), and carbapenemase for C. albicans, S. aureus, B. subtills, K. pneumoniae, and P. aeruginosa, respectively. These results suggest that the compounds have the potential to inhibit the activity of these enzymes and demonstrate promising antimicrobial properties. Moreover, the in silico evaluation of drug likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles for compounds 7a, 7b, 8a, and 8b demonstrated their compatibility with Lipinski's, Ghose's, Veber's, Muegge's, and Egan's rules. These findings suggest that these compounds possess favorable physicochemical properties, making them promising candidates for continued drug development efforts.

Potential Binding Sites of Pharmacological Chaperone NCGC00241607 on Mutant ß-Glucocerebrosidase and Its Efficacy on Patient-Derived Cell Cultures in Gaucher and Parkinson's Disease.

Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson's disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD (n = 9) and GBA-PD (n = 5) patients as well as in induced human pluripotent stem cells (iPSC)-derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation (p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold (p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients.

A THOROUGH STUDY AND META-ANALYSIS OF THE PROGNOSTIC RELEVANCE OF THE C-REACTIVE-ALBUMIN RATIO IN ACUTE PANCREATITIS.

Although most cases of acute pancreatitis (AP) are minor, severe cases are associated with a substantial risk of death. Acute pancreatitis (AP) is a common illness. Therefore, it is critical to assess AP severity as soon as possible. This review aimed to ascertain the predictive significance of the CRP to albumin ratio in individuals with AP. We searched PubMed, Science Direct, and Cochrane Library electronic databases Until January 2023. Studies that reported the CRP/alb ratio at admission and its relationship to the severity or death of patients with AP were included. Using a random-effects model, we computed the pooled mean difference (MD) and 95% confidence interval (CI). The quality of the included studies was evaluated using the Newcastle-Ottawa scale. This meta-analysis combined data from six trials with a total of 2244 patients. Upon admission, the CRP/alb ratio was higher in patients with severe AP than in those with mild to moderate AP (pooled MD:3.59; 95% CI:2.51-4.68; p<0.00001). Additionally, non-survivor AP patients had a substantially higher CRP/alb ratio than survivor AP patients (pooled MD:2.12; 95% CI:0.43-3.8; p<0.01). Individuals with AP may benefit from a high CRP/ALB ratio as a preliminary indicator of poor prognosis.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Anticancer activity of novel 3-(furan-2-yl)pyrazolyl and 3-(thiophen-2-yl)pyrazolyl hybrid chalcones: Synthesis and in vitro studies.

Twelve novel chalcone derivatives were prepared using the Claisen-Schmidt condensation reaction. The reaction of 4-acetyl-5-furan/thiophene-pyrazole derivatives 5 with the corresponding aldehydes 6 afforded the targeted chalcone derivatives 7a-l in good yields. The newly synthesized chalcones were fully characterized by spectrometric and elemental analyses. The in vitro anticancer activities of the novel compounds 7a-l were evaluated against four human cancer cell lines: HepG2 (human hepatocellular carcinoma), MCF7 (human Caucasian breast adenocarcinoma), A549 (lung carcinoma), and BJ1 (normal skin fibroblasts). Compound 7g emerged as the most promising compound, with IC50 = 27.7 µg/ml against A549 cells compared to the reference drug doxorubicin (IC50 = 28.3 µg/ml), and IC50 = 26.6 µg/ml against HepG2 cells compared to the reference drug doxorubicin (IC50 = 21.6 µg/ml). The gene expression and DNA damage values and the DNA fragmentation percentages for compound 7g were determined on the lung and liver cell lines. The expression levels of the AMY2A and FOXG1 genes increased significantly (p < 0.01) in the negative samples of lung cancer cells compared with treated cells. Also, the expression values of the PKM and PSPH genes improved significantly (p < 0.01) in the negative samples compared with treated samples of liver cancer cells. The DNA damage values increased significantly (p < 0.01) in treated lung cell line samples (7g) and the positive control. The results showed a significant decrease (p < 0.05) in DNA damage values in the negative samples of liver cancer cells compared to those treated with 7g. However, the DNA fragmentation values increased significantly (p < 0.01) in the treated lung and liver cell line samples compared with the negative control.

Prevalence of Ruminant Paramphistomosis and Comparative Histopathology of the Infected Rumens in Narowal District, Punjab, Pakistan.

The present study reports the prevalence of Paramphistomum spp. in small and large ruminants and their association with the histopathology of the infected rumens. A total of 384 animals were screened for Paramphistomum spp. The animals found positive for Paramphistomum spp. were divided into three groups according to the worm load/5 cm2 (G1: 10 - 20 worms/5 cm2 = Low, G2: 20 - 40 worms/5 cm2 = Medium, and G3: >41 worms/5 cm2 = High). Tissue slides were prepared from samples of the rumen (1 cm2) taken from animals positive for ruminal fluke to determine the histological parameters, including epithelial length or thickness, length and width of the ruminal papilla, and thickness of tunica submucosa and mucularis externae. The overall prevalence of Paramphistomum spp. in the ruminant population of district Narowal was 56.25 % with a significant (P < 0.05) variation among different species of ruminants. The highest prevalence was in cattle, followed in order by buffalo, goat, and sheep. Epithelium thickness was significantly correlated with parasite load in large ruminants and the most significant (P < 0.05) decrease in epithelium thickness was in Group B (31.12 ± 1.82 µm) and Group C (31.07 ± 1.68 µm) and a same trend was recorded in small ruminants. Histopathological changes due to Paramphistomum spp. are reported for the first time, which explained the histomorphological and physiological changes in Paramphistomum-infected rumens which might be associated with lowered feed efficiency and productivity in ruminants.

Novel [l,2,4]triazolo[3,4-a]isoquinoline chalcones as new chemotherapeutic agents: Block IAP tyrosine kinase domain and induce both intrinsic and extrinsic pathways of apoptosis.

Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis. Graphical abstract Novel chalcones were prepared and confirmed by different spectral tools. Docking simulations were done to detect the mechanism of action. In vitro cytotoxicity indicated a strong effect against different cancer cell lines and low toxic effects against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies that include Real-time PCR, Flow-cytometry, Cytochrome c oxidase, and ELISA assay. SEM and TEM tool were used to follow the morphological changes occurred on the cell surface.

Synthesis, antimicrobial, anti-cancer and in silico studies of new urea derivatives.

The reaction of an alkyl or aryl isocyanates with some primary amines in acetonitrile at room temperature afforded the corresponding alkyl- and aryl-urea derivatives. All the prepared urea compounds have been elucidated by FTIR, NMR, and elemental analysis. The compounds 1 and 3 were confirmed by single-crystal X-ray diffraction. The 4-tolylsulfonyl isocyanate reacted with the aryl amines 1, 2, 3, and 2,4-dichloroaniline to afford the corresponding sulfonylurea derivatives 5-8. Likewise, the reaction of the isocyanates with 2,4-dichloroaniline, 5-methyl isoxazole-3-amine, and 2-aminothiazole derivatives gave the corresponding urea derivatives 9-17. All the prepared compounds 5-17 were tested in vitro as anti-microbial and anti-HepG2 agents. Moreover, analyzing gene expression of TP53-exon4 and TP53-exon7, DNA damage values, and DNA fragmentation percentages have been discussed. The compounds 5 and 8 recorded the highest activity against the tested microbial strains with maximum activity against C. albicans (50 mm) and B. mycoides (40 mm), respectively. The compounds 5 inhibited the growth of E. coli, S. aureus, and C. Albicans at the MIC level of 0.0489 µM, while the compound 8 was able to inhibit the visible growth of E. coli and C. albicans at MIC value of 3.13 µM and S. aureus at 0.3912 µM. In the same line, compound 5 showed the best cytotoxic activity against the HepG2 cell line (IC50 = 4.25 µM) compared to 5 fluorouracil with IC50 = 316.25 µM. Expression analysis of liver cancer related to a gene including TP53-exon4 and TP53-exon7 was used in HepG2 Liver cancer cell lines using RT-qPCR. The expression values of TP53-exon4 and TP53-exon7 genes were decreased. The DNA damage values and DNA fragmentation percentages were increased significantly (P < 0.01) in the treated HepG2 (5) sample compared with the negative control. Docking studies were performed for the synthetic compounds against 2 bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics, and one cell division protein kinase 2 (CDK2) as target for anticancer drugs.

Relentless pulsatile tinnitus secondary to dural sinovenous stenosis: is endovascular sinus stenting the answer?

AIM: To assess the efficacy of endovascular venous sinus stenting (EVSS) in treating pulsatile tinnitus (PT) caused by dural venous sinus stenosis (DVSS), and to determine whether it is an adequate remedy in cases with concurrent venous anomalies. MATERIALS AND METHODS: Seventeen patients (13 female and four male) with PT due to DVSS were treated using EVSS. The trans-stenotic pressure gradient (PG) was measured before and after stenting. The effect of stenting on the tinnitus was evaluated by questioning the patients at day 0, and at 3, 6, and 9 months after stenting. RESULTS: Except for one patient who continued to complain of PT, all of the patients, including two with concomitant sinus diverticula, described complete resolution of the tinnitus immediately following stenting. The post-stenting PG was significantly lower than the pre-stenting PG (p<0.0001). No procedure related complications occurred and no recurrence was recorded during the follow-up period. CONCLUSION: EVSS is a safe and successful treatment for PT due to DVSS even in cases with coexistent sinus diverticula.

Histological Assessment of Wallerian Degeneration of the Rat Tibial Nerve Following Crush and Transection Injuries.

BACKGROUND: Wallerian degeneration (WD) following peripheral nerve injury (PNI) is an area of growing focus for pharmacological developments. Clinically, WD presents challenges in achieving full functional recovery following PNI, as prolonged denervation of distal tissues for an extended period of time can irreversibly destabilize sensory and motor targets with secondary tissue atrophy. Our objective is to improve upon histological assessments of WD. METHODS: Conventional methods utilize a qualitative system simply describing the presence or absence of WD in nerve fibers. We propose a three-category assessment that allows more quantification: A fibers appear normal, B fibers have moderate WD (altered axoplasm), and C fibers have extensive WD (myelin figures). Analysis was by light microscopy (LM) on semithin sections stained with toluidine blue in three rat tibial nerve lesion models (crush, partial transection, and complete transection) at 5 days postop and 5 mm distal to the injury site. The LM criteria were verified at the ultrastructural level. This early outcome measure was compared with the loss of extensor postural thrust and the absence of muscle atrophy. RESULTS: The results showed good to excellent internal consistency among counters, demonstrating a significant difference between the crush and transection lesion models. A significant decrease in fiber density in the injured nerves due to inflammation/edema was observed. The growth cones of regenerating axons were evident in the crush lesion group. CONCLUSION: The ABC method of histological assessment is a consistent and reliable method that will be useful to quantify the effects of different interventions on the WD process.

Selective use of Peptide Receptor Radionuclide Therapy following comparative imaging of Ga-68 DOTATATE PET/CT against I-131 MIBG scintigraphy in a small Asian cohort of Adult Neuroblastoma.

Adult neuroblastoma (AN) is rare with an extremely poor prognosis. No standard therapy exists for this entity and treatment options are limited in recurrent or refractory disease. 131I-MIBG has been used in combination with myeloablative therapy before autologous bone marrow transplantation or in a salvage therapy setting. However, myelotoxicity is a dose-limiting factor in heavily pre-treated patients and response is not always sustained. Somatostatin receptor scintigraphy and theranostics with radiolabelled somatostatin receptor analogues are becoming more commonplace with the recognition of these receptors in over 90% of neuroblastoma cells. We describe three AN patients assessed for somatostatin receptor status and the novel use of 177Lu-based peptide recep-tor radionuclide therapy (PRRT) in two of them and a literature review.

Utility of the Mansoura Numeroalphabetic Constipation Score in detection of obstructed defaecation syndrome and prediction of the outcome of treatment.

AIM: Thorough assessment of obstructed defaecation syndrome (ODS) is imperative for the selection of treatment options. The present study aimed to examine the utility of the Mansoura Numeroalphabetic Constipation Score (MNCS) in distinguishing patients with ODS from healthy control subjects and in predicting the outcome of treatment of ODS. METHODS: Patients with ODS associated with anterior rectocele and/or rectoanal intussusception were assessed with the MNCS at the first visit to the clinic. All patients were offered conservative treatment for 3 months and patients who improved were continued on conservative treatment for six more months while patients who failed were treated surgically. The MNCS was reassessed at the end of follow-up in both groups. A cohort of healthy controls was compared to ODS patients with regard to age, sex and baseline MNCS. RESULTS: In all, 124 ODS patients and 53 healthy controls were included. The ODS patients had a significantly higher baseline MNCS than controls (9.5 ± 1.5 vs 0.76 ± 0.71, P < 0.0001). Forty of 124 patients improved after conservative management and showed a significant decrease in MNCS (6.9 ± 1.08 to 3.1 ± 1.2, P < 0.0001). Eighty-four (67.8%) patients failed to respond to conservative measures and were surgically treated, 77 (91.6%) of whom showed significant improvement in symptoms postoperatively while seven (8.4%) failed to improve; the difference in postoperative MNCS between the two groups was significant. CONCLUSION: The MNCS successfully distinguished ODS patients from controls and was able to predict the outcome of ODS treatment.

Novel 2-cyanoacrylamido-4,5,6,7-tetrahydrobenzo[b]thiophene derivatives as potent anticancer agents.

Ethyl 2-acrylamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate as well as its corresponding bis-derivatives, 5-10, with aliphatic linkers were synthesized, fully characterized, and tested as novel anticancer agents. The targeted compounds, 5-10, were obtained by the Knoevenagel condensation reactions of bis-o- or -p-aldehyde with a molar ratio of ethyl 2-(2-cyanoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate of 2 in the presence of piperidine in excellent yields (93-98%). The in vitro anticancer activities of the prepared compounds were evaluated against HepG2, MCF-7, HCT-116, and BJ1 cells. Compounds 7 and 9 emerged as the most promising compounds, with IC50 values of 13.5 and 32.2 µg/ml, respectively, against HepG2 cells, compared with the reference drug doxorubicin (IC50 : 21.6 µg/ml). Real-time reverse-transcription polymerase chain reaction was used to measure the changes in expression levels of the COL10A1 and COL11A1, ESR1, and ERBB2, or AXIN1 and CDKN2A genes within the treated cells, as genetic markers for colon, breast, or liver cancers, respectively. Treatment of the colon cancer cells with compounds 5, 9, and 10, or breast and liver cancers cells with compounds 7, 8, 9, and 10 downregulated the expression of the investigated tumor markers. The DNA damage values (depending on comet and DNA fragmentation assays) increased significantly upon treatment of colon cancer cells with compounds 5, 9, and 10, and breast and liver cells with compounds 8, 9, and 10. The structure-activity relationship suggested that the increase of the chain of the alkyl linker increases the anticancer activity and the compounds with bis-cyanoacrylamide moieties are more active than those with one cyanoacrylamide moiety.

Synthesis, structural characterization and in vivo anti-diabetic evaluation of some new sulfonylurea derivatives in normal and silicate coated nanoparticle forms as anti-hyperglycemic agents.

Series of new sulfonylurea derivatives (gliclazide analogues) was synthesized and characterized. Thus, p-tolylsulfonylisocyanate was left to react with different amino derivatives under mild conditions to afford the desired sulfonylurea derivatives 1-5. The molecular structure of the compound N-(2,6-Dichlorophenylcarbamoyl)-4-methylbenzenesulfonamide, 1c has been elucidated by single crystal X-ray diffraction. Anti-diabetic properties of the synthesized compounds relative to anti-diabetic drug (gliclazidem MR60) were carried out, where most of the tested compounds showed significant activity for reducing the blood glucose level. The results revealed that compounds 1c and 5 showed better anti-diabetic activities compared with gliclazide. Activity of the most potent derivatives of sulfonylurea compounds namely 1c and 5 were increased using coated nanostructure tetraethyl orthosilicate (TEOS) as a modified release (MR) agent. The effect of the prepared sulfonylurea compounds against the diabetic condition was investigated using specific selected biomarkers as of liver enzyme activities as transaminases (AST, ALT) and alkaline phosphatase (ALP), lipids profiles; total cholesterol (TC), triacylglycerols (TG) and total lipid (TL). The antioxidants, oxidative stress biomarkers and histological examination were also examined and discussed.

Transcriptional and Hormonal Regulation of Gravitropism of Woody Stems in Populus.

Angiosperm trees reorient their woody stems by asymmetrically producing a specialized xylem tissue, tension wood, which exerts a strong contractile force resulting in negative gravitropism of the stem. Here, we show, in Populus trees, that initial gravity perception and response occurs in specialized cells through sedimentation of starch-filled amyloplasts and relocalization of the auxin transport protein, PIN3. Gibberellic acid treatment stimulates the rate of tension wood formation and gravibending and enhances tissue-specific expression of an auxin-responsive reporter. Gravibending, maturation of contractile fibers, and gibberellic acid (GA) stimulation of tension wood formation are all sensitive to transcript levels of the Class I KNOX homeodomain transcription factor-encoding gene ARBORKNOX2 (ARK2). We generated genome-wide transcriptomes for trees in which gene expression was perturbed by gravistimulation, GA treatment, and modulation of ARK2 expression. These data were employed in computational analyses to model the transcriptional networks underlying wood formation, including identification and dissection of gene coexpression modules associated with wood phenotypes, GA response, and ARK2 binding to genes within modules. We propose a model for gravitropism in the woody stem in which the peripheral location of PIN3-expressing cells relative to the cambium results in auxin transport toward the cambium in the top of the stem, triggering tension wood formation, while transport away from the cambium in the bottom of the stem triggers opposite wood formation.

Impact of surgical approach on perioperative and long-term outcomes following esophagectomy for esophageal cancer.

BACKGROUND: Surgical resection remains a critical component of esophageal cancer treatment with curative-intent. The aim of this study was to compare open (OE) to minimally invasive Ivor Lewis esophagectomy (MIE) with respect to perioperative and oncologic outcomes. METHODS: Retrospective single-institution review of MIE and OE patients operated between 2001 and 2015 was conducted. Univariable and multivariable models were created using Cox regression. The Kaplan-Meier method was used to compare oncologic outcomes. Propensity score matching was used to compare oncological outcomes in MIE and OE patients. RESULTS: Of 210 esophageal resection patients, 47% had OE (137/291) and 25% had MIE (73/291). The MIE and OE groups were comparable with respect to patient factors and operative details. Fewer OE patients received neoadjuvant chemoradiation. MIE was associated with improved lymph node yield, (MIE = 30 [IQR:22-39]; OE = 14 [IQR:7-19], p < 0.001), less intraoperative blood loss (MIE = 312 mL [100-400]; OE = 657 mL [350-700], p < 0.001), and shorter median length of stay (MIE = 10 days [IQR = 8-14]; OE = 14 days [IQR = 11-22] p < 0.01). The OE group had significantly more adverse events resulting in reoperation or intensive care unit admission (MIE = 21%; OE = 34%; p < 0.01). On multivariable analysis, age and positive resection margins were associated with decreased odds of survival. The number of lymph nodes retrieved, positive resection margins, and pathologic stage were significant predictors of disease-free survival. Analysis of 69 matched pairs showed equivalent median overall survival (MIE = 49 months [18-67]; OE = 29 months [17-69]; p = 0.26) and disease-free survival (MIE = 9 [6-22]; OE = 13 [6-22]; p = 0.45) between the two groups. CONCLUSIONS: Although long-term oncologic outcomes appear to be similar, MIE is associated with significantly less intraoperative blood loss, improved lymph node yield, less risk of severe postoperative adverse events, and shorter length of stay.

Abdominal rectopexy for the treatment of internal rectal prolapse: a systematic review and meta-analysis.

AIM: Internal rectal prolapse (IRP) is a unique functional disorder that presents with a wide spectrum of clinical symptoms, including constipation and/or faecal incontinence (FI). The present review aims to analyse the results of trials evaluating the role of abdominal rectopexy in the treatment of IRP with regard to regarding functional and technical outcomes. METHOD: A systematic review of the literature for the role of abdominal rectopexy in patients with IRP was conducted. PubMed/Medline, Embase and the Cochrane Central Register of Controlled Trials were searched for published and unpublished studies from January 2000 to December 2015. RESULTS: We reviewed 14 studies including 1301 patients (1180 women) of a median age of 59 years. The weighted mean rates of improvement of obstructed defaecation (OD) and FI across the studies were 73.9% and 60.2%, respectively. Twelve studies reported clinical recurrence in 84 (6.9%) patients. The weighted mean recurrence rate of IRP among the studies was 5.8% (95% CI: 4.2-7.5). Two hundred and thirty complications were reported with a weighted mean complication rate of 15%. Resection rectopexy had lower recurrence rates than did ventral rectopexy, whereas ventral rectopexy achieved better symptomatic improvement, a shorter operative time and a lower complication rate. CONCLUSION: Abdominal rectopexy for IRP attained satisfactory results with improvement of OD and, to a lesser extent, FI, a low incidence of recurrence and an acceptable morbidity rate. Although ventral rectopexy was associated with higher recurrence rates, lower complication rates and better improvement of bowel symptoms than resection rectopexy, these findings cannot be confirmed owing to the limitations of this review.

Laparoscopic ventral mesh rectopexy vs Delorme's operation in management of complete rectal prolapse: a prospective randomized study.

AIM: Various surgical operations have been devised for the treatment of rectal prolapse, yet no ideal procedure has been described. The present study aims to compare the clinical and functional outcome of laparoscopic ventral mesh rectopexy (LVMR) and Delorme's operation for complete rectal prolapse. METHOD: Fifty patients with complete rectal prolapse were enrolled in this study. Patients were randomly selected to undergo either LVMR or Delorme's procedure after clinical, manometric and radiological evaluation. Patient characteristics, operative data, postoperative complications, recurrence of rectal prolapse and continence state were evaluated. Patients were followed for a mean duration of 18 months. RESULTS: Thirty-one (62%) patients were women and 19 (38%) patients were men with a mean age of 39.7 ± 6.9 years. Patients were allocated into two equal groups: LVMR group and Delorme's group. Thirty-three (66%) complained of faecal incontinence preoperatively. Patients were followed for 18 months. There was no major postoperative complication or treatment death. Improvement in continence was reported in 80.9% of patients (83.3% in group 1 vs 71.4% in group 2). Recurrent prolapse was observed in 16% of patients in group 2 and 8% in group 1 (P = 0.66). The operation time was significantly greater in group 1 and the length of stay greater in group 2. There was no difference in the fall of constipation score between the groups. CONCLUSION: There was no statistically significant difference in the incidence of recurrence of complete rectal prolapse or postoperative improvement of symptoms between the two groups. Hospital stay was longer after Delorme's procedure but the operation time was shorter. Neither procedure proved definite superiority regarding the clinical and functional outcome at 18 months of follow-up.