Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease.

BACKGROUND: Intra-ductal cancer (IDC) is the most common type of breast cancer, with intra-lobular cancer (ILC) coming in second. Surgery is the primary treatment for early stage breast cancer. There are now irrefutable data demonstrating that the immune context of breast tumors can influence growth and metastasis. Adjuvant chemotherapy may be administered in patients who are at a high risk of recurrence. Our goal was to identify the processes underlying both types of early local recurrences. METHODS: This was a case-control observational study. Within 2 years of receiving adjuvant taxan and anthracycline-based chemotherapy, as well as modified radical mastectomy (MRM), early stage IDC and ILC recurred. Vimentin, α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF), matrix metalloproteinase (MMP1), and clustered differentiation (CD95) were investigated. RESULTS: Of the samples in the ductal type group, 25 showed local recurrence, and 25 did not. Six individuals in the lobular-type group did not experience recurrence, whereas seven did. Vimentin (p = 0.000 and 0.021), PDGF (p = 0.000 and 0.002), and CD95 (p = 0.000 and 0.045) expressions were significantly different in ductal and lobular carcinoma types, respectively. Measurement of ductal type was the sole significant difference found in MMP1 (p = 0.000) and α-SMA (p = 0.000). α-SMA and CD95 were two variables that helped the recurrence mechanism in the ductal type according to the pathway analysis. In contrast, the CD95 route is a recurrent mechanism for the lobular form. CONCLUSIONS: While the immune system plays a larger role in ILC, the tumor microenvironment and immune system both influence the recurrence of IDC. According to this study, improving the immune system may be a viable cancer treatment option.

Phenolic Profiles, Antihyperglycemic, Anti-Diabetic, and Antioxidant Properties of Egyptian Sonchus oleraceus Leaves Extract: An In Vivo Study.

This study aimed to investigate the phenolic and antioxidant properties of Egyptian Sonchus oleraceus leaves extract (SOE) while comparing the antihyperglycemic efficacy of SOE with that of conventional medicines (glibenclamide) in vivo as a substitution for insulin-deficient patients. Total phenolic (TPC) and flavonoid contents (TFC) in SOE contributed around 127.66 ± 0.56 mg GAE/gm as gallic acid equivalent (GAE) and 74.80 ± 0.55 mg QE/gm as quercetin equivalent (QE). SOE also showed significant DPPH scavenging activity at 43.46%. The presence of five phenolic and six flavonoid compounds in SOE was discovered by HPLC analysis. For the in vivo assay, 42 rats were distributed into six groups (7 Wister albino rats each). The standard control group was fed a basal diet. While the 35 rats were induced with a single dose of 100 mg kg-1 body weight (b.w.) alloxan, then treated orally with glibenclamide (GLI) at 10 mg kg-1, 100, 200, and 300 mg kg-1 SOE (positive control group) for 56 days of routine gastric oral gavages and compared to the effects of GLI, the treatment of SOE 200 and 300 mg kg-1 in diabetic rats for two months dramatically decreased blood glucose, total lipid, total cholesterol, and low-density lipoprotein cholesterol (LDLC) while boosting high-density lipoprotein cholesterol (HDLC) levels and improving liver and kidney functions. The histological assay revealed that the SOE 300 mg kg-1 treatment significantly improved the pancreas tissues, implying the potential application of Egyptian SOE as a diabetes treatment.

Effect of silymarin on the relative gene expressions of some inflammatory cytokines in the liver of CCl4-intoxicated male rats.

The intensive exposure of the liver cells to any type of noxae, such as viruses, drugs, alcohols, and xenobiotics could induce hepatic inflammation through the upregulation of gene expression of several fibrotic and inflammatory mediators. So, our study assessed the role of silymarin on the inflammatory response induced by carbon tetrachloride (CCl4) as an example of xenobiotics on liver tissues in male rats. Forty-eight Wister male rats (weight: 130 ± 10) were housed for 14 days and then divided randomly into six groups: control, SLY: rats received only silymarin orally for 12 weeks (daily), CO: rats were injected with corn oil for 8 weeks (3 times weekly), CCl4: rats were injected with CCl4 solubilized in corn oil for 8 weeks (day by day), Treated: rats received silymarin for 4 weeks after CCl4 injection, Protected: rats received silymarin for 4 weeks before and 8 weeks during CCl4 injection. When the treatment period for the rats was over, they underwent scarification after anesthesia. Then, the sera were extracted from the collected blood for the determination of irisin levels, liver functions, and lipid profiles. Liver tissues were separated for the histopathological examinations, the determination of oxidative stress (OS) parameters content, and the relative gene expression of inflammatory cytokines; nuclear factor kappa (NF)-κB, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, cyclooxygenase (COX)-2, and transforming growth factor beta (TGF-ß). The findings showed that silymarin reduced liver inflammation by overcoming the OS process and inflammatory cytokines production which was stimulated by CCl4. These results were confirmed by histopathology of liver tissues.

Academic productivity of Iraqi medical students in the field of neurosurgery: A literature review.

Background: The interest in clinical research is growing worldwide, and the involvement of medical students in academic and clinical research is increasing. Medical students in Iraq have started to focus on academic activities. However, this trend is in its infancy due to limited resources and the war burden. Their interest in the field of Neurosurgery has been evolving recently. This is the first paper that aims to assess the status of the academic productivity of Iraqi medical students within the neurosurgical field. Methods: We searched the PubMed Medline database and Google scholar between January 2020 and December 2022 with a different combination of keywords. Additional results were obtained by individually searching for all the medical universities in Iraq that participated in the neurosurgical literature. Results: Between January 2020 and December 2022, 60 neurosurgical publications included Iraqi medical students. 47 Iraqi medical students from 9 universities (the University of Baghdad 28 students, followed by 6 students from the University of Al-Nahrain, and others) were involved in these 60 neurosurgery publications. The topics of these publications are "vascular neurosurgery" (n = 36) followed by "neurotrauma" (n = 11). Conclusion: Academic productivity of Iraqi medical students in the field of Neurosurgery has surged in the last 3 years. In the past 3 years, 47 Iraqi medical students from nine different Iraqi universities contributed to sixty international neurosurgical publications. However, there are challenges that are required to be tackled to establish a research-friendly environment despite wars and restrained resources.

Disseminated Peritoneal Leiomyomatosis With Unusual Lung Mesenchymal Malignant Transformation.

Disseminated peritoneal leiomyomatosis (DPL) is a benign metastasis of leiomyoma mimicking metastasis of malignancy. It usually affects premenopausal women. Malignant transformation is a rare clinical scenario of DPL. However, its etiology is unknown with unusual growth patterns, either of which makes the diagnosis difficult. It was postulated that the pathophysiology of DPL is metaplasia of mesothelial cells under the effect of hormonal stimulation. Hence, we reported the case of a 62-year-old woman with a history of left breast cancer, who presented with DPL and metastasis to the lung with malignant transformation after two years of starting prophylactic tamoxifen therapy. The influence of tamoxifen use on the development of DPL is not fully understood; this is a rare case that highlights a possible association between tamoxifen and the malignancy transformation of DPL. Hence, it may help raise awareness among clinicians dealing with women using tamoxifen or other hormonal therapy, and the risk of DPL development with potential malignant transformation in such patients.

Effect of explant type (leaf, stem) and 2,4-D concentration on callus induction: influence of elicitor type (biotic, abiotic), elicitor concentration and elicitation time on biomass growth rate and costunolide biosynthesis in gazania (Gazania rigens) cell suspension cultures.

Gazania rigens (L.) Gaertn. (Asteraceae) is a medicinal plant with high ornamental potential and use in landscaping. The therapeutic potential of sesquiterpene lactones (SLs) as plant natural products for pharmaceutical development has gained extensive interest with costunolide (chemical name: 6E,10E,11aR-6,10-dimethyl-3-methylidene-3a,4,5,8,9,11a-hexahydrocyclodeca[b]furan-2-one) used as a popular herbal remedy due to its anti-cancer, antioxidant, anti-inflammatory, anti-microbial, anti-allergic, and anti-diabetic activities, among others. In the present study, two explant types (leaf, stem) and four 2,4-dichlorophenoxy acetic acid (2,4-D) concentrations (0, 0.5, 1 and 2 mg/L) were tested for callusing potential. The results showed that stem explants treated with 1.5 mg/L 2,4-D exhibited higher callus induction percentage (90%) followed by leaf explants (80%) with 1 mg/L 2,4-D, after a 4-week period. Cell suspension cultures were established from friable callus obtained from stem explants following a sigmoid pattern of growth curve with a maximum fresh weight at 20 days of subculture and a minimum one at 5 days of subculture. In the following stage, the effects of elicitation of cell suspension cultures with either yeast extract (YE) or methyl jasmonate (MeJA), each applied in five concentrations (0, 100, 150, 200 and 250 mg/L) on cell growth (fresh and dry biomass) and costunolide accumulation were tested. After 20 days of culture, YE or MeJA suppressed cell growth as compared to the non-elicited cells, while costunolide accumulation was better enhanced under the effect of 150 mg/L MeJA followed by 200 mg/L YE, respectively. In the subsequent experiment conducted, the optimal concentration of the two elicitors (200 mg/L YE, 150 mg/L MeJA) was selected to investigate further elicitation time (0, 5, 10, 15 and 20 days). The results revealed that YE biotic elicitation stimulated cell growth and costunolide production, being maximum on day 20 for fresh biomass, on day 5 for dry biomass and on day 15 for the bioactive compound. Accordingly, cell growth parameters were maximized under the effect of abiotic elicitation with MeJA for 15 days, while highest costunolide content was achieved after 10 days. Overall, MeJA served as a better elicitor type than YE for biomass and costunolide production. Irrespective of elicitor type, elicitor concentration and elicitation time, maximal response was obtained with 150 mg/L MeJA for 10 days regarding costunolide accumulation (18.47 ppm) and 15 days for cell growth (fresh weight: 954 mg and dry weight: 76.3 mg). The application of elicitors can lead the large quantity of costunolide to encounter extensive range demand through marketable production without endangering of G. rigens.

Structural and Functional Characterization of Legionella pneumophila Effector MavL.

Legionella pneumophila is a Gram-negative intracellular pathogen that causes Legionnaires' disease in elderly or immunocompromised individuals. This bacterium relies on the Dot/Icm (Defective in organelle trafficking/Intracellular multiplication) Type IV Secretion System (T4SS) and a large (>330) set of effector proteins to colonize the host cell. The structural variability of these effectors allows them to disrupt many host processes. Herein, we report the crystal structure of MavL to 2.65 Å resolution. MavL adopts an ADP-ribosyltransferase (ART) fold and contains the distinctive ligand-binding cleft of ART proteins. Indeed, MavL binds ADP-ribose with Kd of 13 µM. Structural overlay of MavL with poly-(ADP-ribose) glycohydrolases (PARGs) revealed a pair of aspartate residues in MavL that align with the catalytic glutamates in PARGs. MavL also aligns with ADP-ribose "reader" proteins (proteins that recognize ADP-ribose). Since no glycohydrolase activity was observed when incubated in the presence of ADP-ribosylated PARP1, MavL may play a role as a signaling protein that binds ADP-ribose. An interaction between MavL and the mammalian ubiquitin-conjugating enzyme UBE2Q1 was revealed by yeast two-hybrid and co-immunoprecipitation experiments. This work provides structural and molecular insights to guide biochemical studies aimed at elucidating the function of MavL. Our findings support the notion that ubiquitination and ADP-ribosylation are global modifications exploited by L. pneumophila.

One pot synthesis of new cross-linked chitosan-Schiff' base: Characterization, and anti-proliferative activities.

Four novel chitosan hydrogels were successfully synthesized through the cross-linking reaction of chitosan with different concentrations of ethyl 5-(3,5-dihydroxy-1,4-dioxan-2-yl)-2-methylfuran-3-carboxylate. Their structures were confirmed by Fourier transform infrared spectroscopy (FT-IR), 13C Cross polarization magic angle spinning nuclear magnetic resonance spectroscopy (CP/MAS 13C NMR), ultraviolet-visible spectroscopy, thermogravimetric analysis (TGA, DTA), and X-ray diffraction (XRD). Cytotoxicity on hepatocellular carcinoma (HepG-2) cell line and a normal African green monkey kidney (Vero) cell line were studied using the MTT assay. The resultant hydrogels showed a good inhibitory effect comparing to the un-modified parent; the hydrogels with the lowest degree cross-linking (0.125 and 0.25 mol cross-linker per one chitosan residue) showed potent anticancer activity in the HepG2 cells with IC50 of 57.9 and 80.9 µg/ml, respectively. These results show that the newly synthesized cross-linked chitosan derivatives demonstrated more selectivity to the HepG2 than the Vero cells, indicating its potential for Investigation in the cure of hepatocellular carcinoma.

Synthesis and characterization of chitosan-pyrazoloquinoxaline Schiff bases for Cr (VI) removal from wastewater.

Two novel chitosan Schiff bases namely chitosan pyrazolo[3,4-b]quinoxaline Schiff base (Ch-PQ1) and chitosan phenyl-1H-pyrazolo[3,4-b]quinoxaline Schiff base (Ch-PQ2) were synthesized as a modification of chitosan in order to increase its ability in heavy metal removal from wastewater. Their structures were characterized by FT-IR spectroscopy, TGA analysis and X-ray diffraction. They were tested for the removal of hexavalent chromium from synthetic samples. In addition pH conditions, polymer dosage, Cr (VI) initial concentration and contact time were studied as a key factor for the adsorption process. Kinetic studies of the removal process were also clarified. Furthermore, experimental equilibrium data were fitted to Langmuir and Freundlich adsorption isotherms. Both chitosan Schiff bases showed high removal efficiency, the result indicated that Cr (VI) removal using Ch-PQ1 and Ch-PQ2 was 96.4% and 98.8% respectively.

Cytotoxicity influence of new chitosan composite on HEPG-2, HCT-116 and MCF-7 carcinoma cells.

Chitosan/aroylhydrazine composite were synthesized in hydrogel form in which aroylhyrazines, heteroaroylhydrazines as well as p-tolylsulphonylhydrazine embedded in the cross linked Chitosan/oxalic acid network. Their structures were characterized by (elemental analysis, FT-IR, 1H NMR, and XRD). Antimicrobial behavior and Cytotoxicity screening of the examined compounds against breast, colon and hepatocellular cancer were investigated. The obtained data revealed that the examined compounds have promising cell growth inhibitory effect on the cell lines as compared to standard. Also, some of the newly synthesized derivatives had shown better antibacterial and antifungal activities, comparing with that of the parent chitosan.

The relationship between study skills and depressive symptoms among medical residents.

BACKGROUND: The cost of depression among residents is staggering as it extends into the quality and safety of patient care. Finding an explanation to resident depression by investigating the associated factors is therefore important. Study skills can be a possible factor, and a clear gap in the literature exists in this regard. We sought to investigate the relationship between depressive symptoms among residents and their study skills. METHODS: This was a correlational study and a non-probability sample of 240 residents completed the Beck Depression Inventory II (BDI-II) and the Study Skills Inventory (SSI). Chi-square test was used to compare different categorical variables, while student t-test and ANOVA for continuous data. Pearson's correlation coefficient was performed to find the relationship between depressive symptoms and study skills and the association that these measures have with the demographic variables. RESULTS: Overall, 186 residents (76%) filled out the questionnaire. The SSI total score was found to have a significant negative association with the BDI-II depression score (Pearson correlation = - 0.447and p < 0.000). No significant association was found between the total SSI score and the residents' sex, age, marital status, smoking status, training years or specialties. CONCLUSION: Poor study skills were found to be correlated with higher depressive symptoms. Future studies are required to develop a deeper understanding of this relationship and reconfigure the approach to study skills for the well-being of the future physicians.

A follow-up study on thyroid aspirates reported as atypia of undetermined significance/follicular lesion of undetermined significance and follicular neoplasm/suspicious for follicular neoplasm: A multicenter study from the Arabian Gulf region.

OBJECTIVE: This is a multicenter study which was conducted to evaluate the follow-up on thyroid aspirate cases with atypia of undetermined significance/follicular cells of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) using the Bethesda system for reporting thyroid cytology (TBSRTC). MATERIALS AND METHODS: The archival materials of all thyroid fine-needle aspirates over a 5-year period were retrieved from 3 institutions in the Arabian Gulf Region. All cytology slides and follow-up material for cases interpreted as AUS/FLUS and FN/SFN were reviewed. The revised diagnoses and follow-up were recorded. Analysis of risk of malignancy was calculated for the 2 entities. RESULTS: A total number of 2592 thyroid fine-needle aspirates were performed, out of which AUS/FLUS was found in 115 (4.4%) while FN/SFN in 39 (1.5%). Follow-up by surgery or repeat FNA was conducted on 42 (27%) and 10 (7%) patients on these 2 categories, respectively. The risk of malignancy was found to be 29% and 45%, respectively. CONCLUSION: The risk of malignancy for AUS/FLUS and FN/SFN are 29% and 45%, respectively. This risk of malignancy in our study is on the higher range of that reported in the literature.

Synthesis and Characterization of Glutamic-Chitosan Hydrogel for Copper and Nickel Removal from Wastewater.

Chitosan was reacted with four concentrations (2.5, 5, 10 and 20 mmol) of glutamic acid resulting in four types of glutamic-chitosan hydrogels (GCs), the activity of the resulted compounds on the removal of copper(II) and nickel(II) from wastewater were tested. The results indicated that by increasing glutamic acid concentration from GCs-1 to GCs-4, the efficiency of removing Cu(II) and Ni(II) were decreased, which may be due to a decrease in the pore size of the hydrogels as a result of the increased degree of crosslinking.

Synthesis and bioassay of a new class of furanyl-1,3,4-oxadiazole derivatives.

Tyrosinase enzyme is a monophenol monoxygenase enzyme, which plays an important role in human as a rate limiting step enzyme for different specific metabolic pathways, as well as its useful application in industry and agriculture. So this study was carried out to test the effect of newly prepared compounds containing 1,3,4-oxadiazoles with different substituted groups on tyrosinase enzyme activity, hoping to use them in the treatment of some diseases arising from tyrosinase activity disorders such as Parkinson's disease, schizophrenia, autism, attention deficit, hyperactivity disorder, and cancer.

Synthesis of new 1,3,4-thiadiazole and 1,2,3,4-oxathiadiazole derivatives from carbohydrate precursors and study of their effect on tyrosinase enzyme.

5-(1,2,3,4-Tetrahydroxybutyl)-2-methylfuran-3-carbohydrazide (2) was condensed with a variety of ketones to afford carbohydrazide derivatives 3-6. Acetylation of 3-5 afforded the acetyl derivatives 7-9, while periodate oxidation of 3-6 afforded the formyl derivatives 10-13. Acid catalyzed condensation of thiosemicarbazide or o-tolylthiosemicarbazide with the prepared aldehydes 10-12 gave thiosemicarbazone derivatives 14-19. Cyclization of the latter with acetic anhydride afforded 4,5-dihydro-1,3,4-thiadiazolyl derivatives 20-25. On the other hand, condensation of p-tosylhydrazine with the prepared aldehydes 10-12 afforded p-tosylhydrazone derivatives 26-28. Cyclization of 26-28 with acetic anhydride afforded 1,2,3,4-oxathiadiazole derivatives 29-31 respectively. Moreover, the obtained results regarding to the effect of some of the prepared compounds on tyrosinase enzyme showed that the majority of these compounds having an inhibitory effect; especially compounds 12, 16, 17, and 28.

Peroxynitrite mediates diabetes-induced endothelial dysfunction: possible role of Rho kinase activation.

Endothelial dysfunction is characterized by reduced bioavailability of NO due to its inactivation to form peroxynitrite or reduced expression of eNOS. Here, we examine the causal role of peroxynitrite in mediating diabetes-induced endothelial dysfunction. Diabetes was induced by STZ-injection, and rats received the peroxynitrite decomposition catalyst (FeTTPs, 15 mg/Kg/day) for 4 weeks. Vasorelaxation to acetylcholine, oxidative-stress markers, RhoA activity, and eNOS expression were determined. Diabetic coronary arteries showed significant reduction in ACh-mediated maximal relaxation compared to controls. Diabetic vessels showed also significant increases in lipid-peroxides, nitrotyrosine, and active RhoA and 50% reduction in eNOS mRNA expression. Treatment of diabetic animals with FeTTPS blocked these effects. Studies in aortic endothelial cells show that high glucose or peroxynitrite increases the active RhoA kinase levels and decreases eNOS expression and NO levels, which were reversed with blocking peroxynitrite or Rho kinase. Together, peroxynitrite can suppress eNOS expression via activation of RhoA and hence cause vascular dysfunction.

Role of oxidative stress in multiparity-induced endothelial dysfunction.

Multiparity is associated with increased risk of cardiovascular disease. We tested whether multiparity induces oxidative stress in rat vascular tissue. Coronary arteries and thoracic aorta were isolated from multiparous and age-matched virgin rats. Relaxation to ACh and sodium nitroprusside (SNP) was measured by wire myography. We also tested the effect of the superoxide dismutase mimetic MnTE2PyP (30 microM), the NADPH oxidase inhibitor apocynin (10 microM), and the peroxynitrite scavenger FeTPPs (10 microM) on ACh-mediated relaxation in coronary arteries. Vascular superoxide anion was measured using the luminol derivative L-012 and nitric oxide (NO) generation by the Griess reaction. Multiparity reduced maximal response and sensitivity to ACh in coronary arteries [maximal relaxation (E(max)): multiparous 49+/-3% vs. virgins 95%+/-3%; EC(50): multiparous 135+/-1 nM vs. virgins 60+/-1 nM], and in aortic rings (E(max): multiparous 38+/-3% vs. virgins 79+/-4%; EC(50): multiparous 160+/-2 nM vs. virgins 90+/-3 nM). Coronary arteries from the two groups relaxed similarly to SNP. Superoxide anions formation was significantly higher in both coronary arteries (2.8-fold increase) and aorta (4.1-fold increase) from multiparous rats compared with virgins. In multiparous rats, incubation with MnTE2PyP, apocynin, and FeTPPs improved maximal relaxation to ACh (MnTE2PyP: 74+/-5%; vehicle: 41+/-5%; apocynin: 73+/-3% vs. vehicle: 41+/-3%; FeTPPs: 72+/-3% vs. vehicle: 46+/-3%) and increased sensitivity (EC(50): MnTE2PyP: 61+/-0.5 nM vs. vehicle: 91+/-1 nM; apocynin: 45+/-3 nM vs. vehicle: 91+/-6 nM; FeTPP: 131 +/- 2 nM vs. vehicle: 185+/-1 nM). Multiparity also reduced total nitrate/nitrite levels (multiparous: 2.5+/-2 micromol/mg protein vs. virgins: 7+/-1 micromol/mg protein) and endothelial nitric oxide synthase protein levels (multiparous: 0.53+/-0.1 protein/actin vs. virgins: 1.0+/-0.14 protein/actin). These data suggest that multiparity induces endothelial dysfunction through decreased NO bioavailability and increased reactive oxygen species formation.

Diabetes-induced coronary vascular dysfunction involves increased arginase activity.

Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver. Treatment of diabetic rats with simvastatin (5 mg/kg per day, subcutaneously) or L-citrulline (50 mg/kg per day, orally) blunted these effects. Acute treatment of diabetic coronary arteries with arginase inhibitors also reversed the impaired vasodilation to acetylcholine. Treatment of BCECs with HG (25 mmol/L, 24 hours) also increased arginase activity. This effect was blocked by treatment with simvastatin (0.1 micromol/L), the Rho kinase inhibitor Y-27632 (10 micromol/L), or L-citrulline (1 mmol/L). Superoxide and active RhoA levels also were elevated in HG-treated BCECs. Furthermore, HG significantly diminished NO production in BCECs. Transfection of BCECs with arginase I small interfering RNA prevented the rise in arginase activity in HG-treated cells and normalized NO production, suggesting a role for arginase I in reduced NO production with HG. These results indicate that increased arginase activity in diabetes contributes to vascular endothelial dysfunction by decreasing L-arginine availability to NO synthase.