Using shock generator for the fuel mixing of the extruded single 4-lobe nozzle at supersonic combustion chamber.

The importance of the fuel injection configuration on the propulsion efficiency of high-speed vehicles is apparent. In this article, the use of an annular extruded 4-lobe nozzle for the injection of fuel jet in a supersonic combustor of a scramjet engine in the existence of a shock generator is examined. The main aim of this study is to obtain the efficient jet arrangement for efficient fuel mixing inside the engine of hypersonic vehicles. A numerical approach is used to model the supersonic air stream and cross-jet flow with the SST turbulence model. The role of nozzle altitude and internal air jet on the fuel mixing of the hydrogen within the high-speed domain are disclosed. The importance of the horseshoe vortex and counter-rotating vortex on the fuel distribution is also presented. Our results show that the usage of a coaxial jet instead of an annular jet would increase fuel mixing by more than 40% in the combustion chamber.

Conventional natural killer cells control vascular remodeling in the uterus during pregnancy by acidifying the extracellular matrix with a2V.

Vascular remodeling within the uterus immediately before and during early pregnancy increases blood flow in the fetus and prevents the development of gestational hypertension. Tissue-resident natural killer (trNK) cells secrete pro-angiogenic growth factors but are insufficient for uterine artery (UtA) remodeling in the absence of conventional natural killer (cNK) cells. Matrix metalloproteinase-9 (MMP9) is activated in acidic environments to promote UtA remodeling. We have previously shown that ATPase a2V plays a role in regulating the function of cNK cells during pregnancy. We studied the effect of a2V deletion on uterine cNK cell populations and pregnancy outcomes in VavCrea2Vfl/fl mice, where a2V is conditionally deleted in hematopoietic stem cells. Conventional NKcells were reduced but trNK cells were retained in implantation sites at gestational day 9.5, and UtA remodeling was inhibited despite no differences in concentrations of pro-angiogenic growth factors. The ratio of pro-MMP9 to total was significantly elevated in VavCrea2Vfl/fl mice, and MMP9 activity was significantly reduced. The pH of implantation sites was significantly elevated in VavCrea2Vfl/fl mice. We concluded that the role of cNK cells in the uterus is to acidify the extracellular matrix (ECM) using a2V, which activates MMP9 to degrade the ECM, release bound pro-angiogenic growth factors, and contribute to UtA remodeling. Our results are significant for the understanding of the development of gestational hypertension.

Bloodstream infection in cancer patients; susceptibility profiles of the isolated pathogens, at Khartoum Oncology Hospital, Sudan.

Introduction: Bloodstream infection is one of the major causes of mortality in patients with malignancies. This study aimed to determine the local profile of blood culture isolates and their antibiotic sensitivities in febrile neutropenic cancer patients and to decide if any modifications to antibiotics policies are necessary. Methods: This is a cross-sectional study conducted between the first of October to the end of December 2018 at Khartoum Oncology Hospital, Sudan. Blood samples from febrile neutropenic patients were collected for culture. Isolates were identified, and their antimicrobial susceptibility was determined by standard laboratory procedures. Results: Bloodstream infections were confirmed in 12 % (n = 69/569) of total blood cultures. Gram negative bacilli were the dominant causative agents (63.8%) while (36.2%) of infections were caused by gram positive cocci. Escherichia coli was the most common isolate (30.4%).The proportions of resistance among gram negative bacilli were high for cefuroxime, amoxicillin/clavulanic acid, Ceftazidime, and ceftriaxone. Extended-spectrum ß-lactamase producing isolates were identified in 34.1% of the positive cultures. Gram positive cocci showed high resistance to tetracycline, penicillin and erythromycin but were completely sensitive to vancomycin and gentamicin. Most of Staphylococcus aureus isolates were methicillin resistant. Conclusion: Gram negative bacilli were the predominant etiologic agents of bloodstream infections in our patients. Both Gram-positive and Gram-negative bacteria showed high levels of resistance for most of the common antibiotics used for empiric treatment. Regular surveillance to study bacterial resistance patterns must be conducted to modify antibiotics stewardship in our institution.

Prevalence of Hepatitis B and C Virus Infection among Pregnant Women in Sharkia Governorate, Egypt

Viral infections is the cause of liver inflammation, cirrhosis and even liver hepatocellular carcinoma (HCC). Despite the availability of HBV vaccine and antiviral treatment for HBV and HCV both remain a major health problem. The aim of this study To determine the seroprevalence of HBV and HCV infection among pregnant women in Sharkia governorate, Egypt.

The value of amniopatch in pregnancies associated with spontaneous preterm premature rupture of fetal membranes: a randomized controlled trial.

Objective: To evaluate the efficacy and safety of amniopatch in pregnancies associated with spontaneous preterm premature rupture of fetal membranes (PPROM).Methods: A randomized controlled trial that involved 100 women diagnosed with PPROM between 24 and 34 weeks of gestational age. Participants were randomized equally into two groups. Group I in which amniopatch was done in addition to the routine management. Group II was treated with routine management including antibiotics and corticosteroids.Results: Amniopatch was successful in complete sealing of the membrane defect in 6/50 (12%) of women while none the control group have undergone similar sealing (p = .0144, RR = 0.88). Women in the amniopatch group showed a significant increase of AFI compared to controls (12 versus 0, p = .0001, RR = 0.56).Conclusion: The amniopatch procedure is a successful technique that safely enhances sealing of fetal membranes and restore the AFI.Clinical trial registration: NCT03473210SynopsisThe amniopatch procedure is a successful technique that could be done safely to enhance sealing the fetal membranes and restoring the AFI after PPROM.

An Ultrasound Scoring Model for the Prediction of Intrapartum Morbidly Adherent Placenta and Maternal Morbidity: A Cross-Sectional Study.

OBJECTIVE: To design an ultrasound scoring model for the prediction of the intrapartum morbidly adherent placenta (MAP) and maternal morbidity. PATIENTS AND METHODS: 114 females with singleton pregnancies ≥ 28 weeks of gestation referred for suspicion of MAP were included. All patients underwent examination by two-dimensional ultrasound with the color Doppler setting. Five signs were evaluated: the retroplacental echolucent space, placental lacunae, the hyperechoic uterine-bladder interface, retroplacental myometrium thickness, and subplacental, uterine serosa-bladder wall, intraplacental and bladder wall vascularity. We designed a score ranging from 0-8.5 points, including the five signs according to their odds ratios and evaluated its prediction for MAP and maternal morbidity. RESULTS: Using multivariate logistic regression, all ultrasound signs were significant dependent predictors for both MAP and maternal morbidity (myometrium thickness < 1 mm followed by lacunae ≥ 4 and lost retroplacental echolucent space). The only independent predictors for MAP were myometrium thickness < 1 mm and lacunae ≥ 4, while myometrium thickness < 1 mm and lost retroplacental echolucent space were predictive for maternal morbidity. The score showed a perfect agreement with MAP and a good one for maternal morbidity. CONCLUSION: Application of the score we designed can improve the ultrasound diagnosis of MAP and the maternal outcome.

Validity and Reproducibility of the ADNEX MR Scoring System in the Diagnosis of Sonographically Indeterminate Adnexal Masses.

BACKGROUND: The diagnosis of sonographically indeterminate adnexal masses (AM) signifies a major challenge in clinical practice. Early detection and characterization have increased the need for accurate imaging evaluation before treatment. PURPOSE: To assess the validity and reproducibility of the ADNEX MR Scoring system in the diagnosis of sonographically indeterminate AM. STUDY TYPE: A prospective multicenter study. POPULATION: In all, 531 women (mean age, 44 ± 11.2 years; range, 21-79 years) with 572 sonographically indeterminate AM. FIELD STRENGTH/SEQUENCE: 1.5T/precontrast T1 -weighted imaging (WI) fast spin echo (FSE) (in-phase and out-of-phase, with and without fat suppression); T2 -WI FSE; diffusion-WI single-shot echo planner with b-values of 0 and 1000 s/mm2 ; and dynamic contrast-enhanced perfusion T1 -WI liver acquisition with volume acceleration (LAVA). ASSESSMENT: All MRI examinations were evaluated by three radiologists, and the AM were categorized into five scores based on the ADNEX MR Scoring system. Score 1: no AM; 2: benign AM; 3: probably benign AM; 4: indeterminate AM; 5: probably malignant AM. Histopathology and imaging follow-up were used as the standard references for evaluating the validity of the ADNEX MR Scoring system for detecting ovarian malignancy. STATISTICAL TESTS: Four-fold table test, kappa statistics (κ), and receiver operating characteristic (ROC) curve. RESULTS: In all, 136 (23.8%) AM were malignant, and 436 (76.2%) were benign. Of the 350 AM classified as score 2, one (0.3%) was malignant; of the 62 AM classified as score 3, six (9.7%) were malignant; of the 73 AM classified as score 4, 43 (58.9%) were malignant; and of the 87 AM categorized as score 5, 86 (98.9%) were malignant. The best cutoff value for predicting malignant AM was score >3 with sensitivity and specificity of 92.9% and 94.9%, respectively. The interreader agreement of the ADNEX MR Scoring was very good (κ = 0.861). DATA CONCLUSION: The current study supports the high validity and reproducibility of the ADNEX MR Scoring system for the diagnosis of sonographically indeterminate AM. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Comparison of O-RADS, GI-RADS, and IOTA simple rules regarding malignancy rate, validity, and reliability for diagnosis of adnexal masses.

OBJECTIVE: The American College of Radiology (ACR) recently published the ovarian-adnexal reporting and data system (O-RADS) to provide guidelines to physicians who interpret ultrasound (US) examinations of adnexal masses (AM). This study aimed to compare the O-RADS with two other well-established US classification systems for diagnosis of AM. METHODS: This retrospective multicenter study between May 2016 and December 2019 assessed consecutive women with AM detected by the US. Five experienced consultant radiologists independently categorized each AM according to O-RADS, gynecologic imaging reporting and data system (GI-RADS), and international ovarian tumor analysis (IOTA) simple rules. Pathology and adequate follow-up were used as reference standards for calculating the validity of three US classification systems for diagnosis of AM. Kappa statistics were used to assess the inter-reviewer agreement (IRA). RESULTS: A total of 609 women (mean age, 48 ± 13.7 years; range, 18-72 years) with 647 AM were included. Of the 647 AM, 178 were malignant and 469 were benign. Malignancy rates were comparable to recommended rates by previous literature in O-RADS and IOTA, but higher in GI-RADS. O-RADS had significantly higher sensitivity for malignancy than GI-RAD and IOTA (p = 0.003 and 0.0007, respectively), but non-significant slightly lower specificity (p > 0.05). O-RADS, GI-RADS, and IOTA showed similar overall IRA (κ = 0.77, 0.69, and 0.63, respectively) with a tendency toward higher IRA with O-RADS than with GI-RADS and IOTA. CONCLUSIONS: O-RADS compares favorably with GI-RADS and IOTA. O-RADS had higher sensitivity than GI-RADS and IOTA simple rules with relatively similar specificity and reliability. KEY POINTS: • The malignancy rates were comparable to recommended rates by previous literature in O-RADS and IOTA, but higher in GI-RADS. • The O-RADS had significantly higher sensitivity for malignancy than GI-RADS and IOTA (96.8% vs 92.7% and 92.1%; p = 0.003 and 0.0007, respectively), but non-significant slightly lower specificity (92.8% vs 93.6% and 93.2%, respectively; p > 0.05). • The O-RADS, GI-RADS, and IOTA showed similar overall inter-reviewer agreement (IRA) (κ = 0.77, 0.69, and 0.63, respectively), with a tendency toward higher IRA with O-RADS than with GI-RADS and IOTA.

Inner Ear Complications in Children and Adolescents with Sickle Cell Disease.

Hearing impairment is a reported complication of sickle cell disease, yet inner ear pathology is not fully understood. The study purpose was to examine the patterns of inner ear involvement in patients with sickle cell disease by magnetic resonance imaging (MRI) and to assess its association with auditory functions. A cross-sectional study included 22 children with sickle cell disease examined for inner ear pathology by audiogram, MRI inner ear and transcranial Doppler (TCD) with revision of their hospital records for transfusion, chelation and hydroxyurea (HU) therapy. Abnormal MRI in the form of intrinsic T1 hyperintensity within the lumen of inner ear structures and cochlear neuropathy was found in five (22.7%) patients; left middle cerebral artery (MCA) flow velocity was higher in patients with abnormal MRI (83.4 ± 5.3 cm/sec) compared to normal MRI (68.2 ± 11.1 cm/sec) (p = 0.015), however, none of the patients had TCD of >170 cm/sec. There was no significant difference between patients with normal and abnormal MRI as regards hearing level and speech audiometry. Sensorineural hearing loss (SNHL) was present in two (9.1%) and conductive hearing loss (CHL) in two (9.1%) patients. There was a significant negative correlation between right ear mean hearing level and right MCA flow velocity and significant negative correlation between left ear mean hearing level and basilar artery (BA) flow velocity. We concluded that inner ear pathology is not uncommon in asymptomatic patients with sickle cell anemia, yet it did not correlate with hearing impairment and may occur with normal TCD results.

In vivo anti-V-ATPase antibody treatment delays ovarian tumor growth by increasing antitumor immune responses.

Tumor acidity is the key metabolic feature promoting cancer progression and is modulated by pH regulators on a cancer cell's surface that pump out excess protons/lactic acid for cancer cell survival. Neutralizing tumor acidity improves the therapeutic efficacy of current treatments including immunotherapies. Vacuolar-ATPase (V-ATPase) proton pumps encompass unique plasma membrane-associated subunit isoforms, making this molecule an important target for anticancer therapy. Here, we examined the in vivo therapeutic efficacy of an antibody (a2v-mAB) targeting specific V-ATPase-'V0a2' surface isoform in controlling ovarian tumor growth. In vitro a2v-mAb treatment inhibited the proton pump activity in ovarian cancer (OVCA) cells. In vivo intraperitoneal a2v-mAb treatment drastically delayed ovarian tumor growth with no measurable in vivo toxicity in a transplant tumor model. To explore the possible mechanism causing delayed tumor growth, histochemical analysis of the a2v-mAb-treated tumor tissues displayed high immune cell infiltration (M1-macrophages, neutrophils, CD103+ cells, and NK cells) and an enhanced antitumor response (iNOS, IFN-y, IL-1α) compared to control. There was marked decrease in CA-125-positive cancer cells and an enhanced active caspase-3 expression in a2v-mAb-treated tumors. RNA-seq analysis of a2v-mAb tumor tissues further revealed upregulation of apoptosis-related and toll-like receptor pathway-related genes. Indirect coculture of a2v-mAb-treated OVCA cells with human PBMCs in an unbuffered medium led to an enhanced gene expression of antitumor molecules IFN-y, IL-17, and IL-12-A in PBMCs, further validating the in vivo antitumor responses. In conclusion, V-ATPase inhibition using a monoclonal antibody directed against the V0a2 isoform increases antitumor immune responses and could therefore constitute an effective treatment strategy in OVCA.

The value of fetal Doppler indices as predictors of perinatal outcome in women with preeclampsia with severe features.

Objective: To evaluate the diagnostic performance of Doppler sonography of umbilical artery (UA), fetal middle cerebral artery (MCA), ductus venosus (DV) & umbilical vein (UV) for prediction of adverse perinatal outcome.Material and Methods: A prospective cohort study conducted on 60 women diagnosed  with preeclampsia with severe features divided into two groups based on adverse perinatal outcome.Results: Statistically Significant differences were demonstrated UA PI (1.28 ± 0.23 vs. 0.96 ± 0.21, P <0.001), UA RI (0.78 ± 0.09 vs. 0.62 ± 0.09, P <0.001), MCA PI (1.27 ± 0.28 vs. 1.45±0.20, P 0.005), MCA RI (0.67 ± 0.10 vs. 0.76 ± 0.08, P<0.001), Cerebroplacental ratio (1.01 ± 0.36 vs. 1.57 ± 0.35, P <0.001), DV PVIV (0.67 ± 0.20 vs. 0.51 ± 0.14, P= 0.004), DV PSV (54.74 ± 17.11 vs. 42.15 ± 9.42, P= 0.004)  and abnormal DV a wave (23.8 vs. 0%, P = 0.004) in women with adverse and normal perinatal outcome respectively. UA PI and CPR had the highest specificity while UA RI had the highest sensitivity for detection of adverse perinatal outcome.Conclusion: CPR < 1 can be used to identify fetuses at risk of morbidity and mortality among such cases.

Evaluation and ranking of different interventions for pain relief during outpatient hysteroscopy: A systematic review and network meta-analysis.

AIM: To identify the highest-ranked pharmacological and nonpharmacological interventions for pain relief during outpatient hysteroscopy. METHODS: We conducted an online bibliographic search in different databases from inception till July 2019. We included randomized controlled trials assessing effect of pharmacological and nonpharmacological interventions on pain relief during outpatient hysteroscopy. Our main outcomes were pain scores at different endpoints of the procedure. We applied this network meta-analysis based on the frequentist approach using statistical package 'netmeta' (version 1.0-1) in R. RESULTS: The review included 39 randomized controlled trials (Women n = 3964). Misoprostol plus intracervical block anesthesia (mean difference [MD] = -3.32, 95% confidence interval [CI] [-6.06, -0.59]), misoprostol (MD = -1.92, 95% CI [-3.04, -0.81]) and IV analgesia (MD = -2.01, 95% CI [-3.27, -0.25]) were effective in reducing pain during the procedure compared to placebo. Ranking probability showed that misoprostol plus intracervical block anesthesia was the highest ranked pharmacological treatment for pain relief during the procedure (P score = 0.92) followed by misoprostol alone (P score = 0.78), and IV analgesia (P score = 0.76). Regarding nonpharmacological treatments, transcutaneous electrical nerve stimulation (TENS) showed a significant pain reduction compared to placebo (MD = -1.80, 95% CI [-3.31, -0.29]). TENS ranked as the best nonpharmacological treatment (P score = 0.80) followed by CO2 distention (P score = 0.65) and bladder distention (P score = 0.60). CONCLUSION: Combination of misoprostol plus local anesthesia appears to be the most effective pharmacological approach for pain reduction during and after outpatient hysteroscopy. Nonpharmacological approaches as TENS and bladder distention showed considerable efficacy but should be further investigated.

Cancer-associated V-ATPase induces delayed apoptosis of protumorigenic neutrophils.

Tumors and neutrophils undergo an unexpected interaction, in which products released by tumor cells interact to support neutrophils that in turn support cancer growth, angiogenesis, and metastasis. A key protein that is highly expressed by cancer cells in tumors is the a2 isoform V-ATPase (a2V). A peptide from a2V (a2NTD) is secreted specifically by cancer cells, but not normal cells, into the tumor microenvironment. This peptide reprograms neutrophils to promote angiogenesis, cancer cell invasiveness, and neutrophil recruitment. Here, we provide evidence that cancer-associated a2V regulates the life span of protumorigenic neutrophils by influencing the intrinsic pathway of apoptosis. Immunohistochemical analysis of human cancer tissue sections collected from four different organs shows that levels of a2NTD and neutrophil counts are increased in cancer compared with normal tissues. Significant increases in neutrophil counts were present in both poorly and moderately differentiated tumors. In addition, there is a positive correlation between the number of neutrophils and a2NTD expression. Human neutrophils treated with recombinant a2NTD show significantly delayed apoptosis, and such prolonged survival was dependent on NF-κB activation and ROS generation. Induction of antiapoptotic protein expression (Bcl-xL and Bcl-2A1) and decreased expression of proapoptotic proteins (Bax, Apaf-1, caspase-3, caspase-6, and caspase-7) were a hallmark of these treated neutrophils. Autocrine secretion of prosurvival cytokines of TNF-α and IL-8 by treated neutrophils prolongs their survival. Our findings highlight the important role of cancer-associated a2V in regulating protumorigenic innate immunity, identifying a2V as a potential important target for cancer therapy.

Prediction of metaphase II oocytes according to different levels of serum AMH in poor responders using the antagonist protocol during ICSI: a cohort study.

The aim of our study was to assess the value of serum AMH in prediction of metaphase II oocytes in poor responders. We performed a prospective cohort study included 206 poor responders candidate for ICSI using antagonist protocol. They were classified into 3 groups. Group I included 50 women with AMH < 0.3 ng/ml, group II included 85 women with AMH 0.3-0.7 ng/ml and group III included 71 women with AMH > 0.7-1.0 ng/ml. The primary outcome parameter was the number of MII oocytes. There was a highly significant difference between the study groups regarding E2 at triggering (481.41 ± 222.653, 648.17 ± 264.353 and 728.74 ± 305.412 respectively, number of oocyte retrieved (2.37 ± 1.178, 3.38 ± 1.622 and 3.80 ± 1.427 respectively), number of MII oocytes (1.66 ± 1.039, 2.35 ± 1.171 and 2.61 ± 1.080 respectively), number of fertilized oocytes (1.39 ± 0.919, 1.91 ± 0.983 and 2.21 ± 0.937 respectively), , total number of embryos (1.34 ± 0.938, 1.76 ± 0.956 and 2.09 ± 0.907 respectively), clinical pregnancy rates (4.9 vs. 7.7 and 19.7% respectively). We concluded that AMH is a good predictor for number of MII oocytes in poor responders undergoing ICSI.

Interleukin-22 promotes development of malignant lesions in a mouse model of spontaneous breast cancer.

Interleukin (IL)-22 is recognized as a tumor-supporting cytokine and is implicated in the proliferation of multiple epithelial cancers. In breast cancer, the current knowledge of IL-22 function is based on cell line models and little is known about how IL-22 affects the tumor initiation, proliferation, invasion, and metastasis in the in vivo system. Here, we investigated the tumor stage-specific function of IL-22 in disease development by evaluating the stage-by-stage progression of breast cancer in an IL-22 knockout spontaneous breast cancer mouse model. We found that among all the stages, IL-22 is specifically upregulated in tumor microenvironment (TME) during the malignant transformation stage of breast tumor progression. The deletion of IL-22 gene leads to the arrest of malignant transition stage, and reduced invasion and tumor burden. Administration of recombinant IL-22 in the TME does not influence in vivo tumor initiation and proliferation but only promotes malignant transformation of cancer cells. Mechanistically, deletion of IL-22 gene causes downregulation of epithelial-to-mesenchymal transition (EMT)-associated transcription factors in breast tumors, suggesting EMT as the mechanism of regulation of malignancy by IL-22. Clinically, in human breast tumor tissues, increased number of IL-22+ cells in the TME is associated with an aggressive phenotype of breast cancer. For the first time, this study provides an insight into the tumor stage-specific function of IL-22 in breast tumorigenesis.

Targeting V-ATPase Isoform Restores Cisplatin Activity in Resistant Ovarian Cancer: Inhibition of Autophagy, Endosome Function, and ERK/MEK Pathway.

Ovarian cancer (OVCA) patients often develop tolerance to standard platinum therapy that accounts for extensive treatment failures. Cisplatin resistant OVCA cells (cis-R) display enhanced survival mechanisms to cope with therapeutic stress. In these cells, increased autophagy process assists in chemoresistance by boosting the nutrient pool under stress. To improve the treatment response, both protective autophagy inhibition and its overactivation are showing efficacy in chemosensitization. Autophagy requires a tightly regulated intracellular pH. Vacuolar ATPases (V-ATPases) are proton extruding nanomotors present on cellular/vesicular membranes where they act as primary pH regulators. V-ATPase 'a2' isoform (V0a2), the major pH sensing unit, is markedly overexpressed on the plasma membrane and the early endosomes of OVCA cells. Previously, V0a2 inhibition sensitized cis-R cells to platinum drugs by acidifying cytosolic pH that elevated DNA damage. Here, we examined how V0a2 inhibition affected endosomal function and the autophagy process as a possible factor for cisplatin sensitization. Clinically, V0a2 expression was significantly higher in tissues from drug nonresponder OVCA patients compared to treatment responders. In vitro V0a2 knockdown in cis-R cells (sh-V0a2-cisR) significantly reduced the tumor sphere-forming ability and caused complete disintegration of the spheres upon cisplatin treatment. The apoptotic capacity of sh-V0a2-cisR improved substantially with potentiation of both intrinsic and extrinsic apoptotic pathway when treated with cisplatin. Unlike the chemical V-ATPase inhibitors that acutely induce autophagy, here, the stable V0a2 inhibition dampened the protective autophagy process in sh-V0a2-cisR cells with downregulated expression of proteins beclin-1, ATG-7, and LC3B and low autophagosome numbers compared to control cis-R cells. These cells showed downregulated ERK/MEK pathway that is known to repress autophagy. Interestingly, upon cisplatin treatment of sh-V0a2-cisR, the autophagy initiation proteins (LC3B, ATG7, and Beclin 1) were found upregulated as a stress response compared to the untreated cells. However, there was a concomitant downstream autophagosome accumulation and an enhanced P62 protein levels indicating the overall block in autophagy flux. Mechanistically, V0a2 knockdown caused defects in early endosome function as the transferrin internalization was impaired. Taken together, this study provides a novel insight into the mechanism by which V-ATPase-isoform regulates autophagy that assists in chemoresistance in ovarian cancer. We conclude that V-ATPase-V0a2 is a potent target for developing an effective treatment to enhance patient survival rates in ovarian cancer.

Gynecology Imaging Reporting and Data System (GI-RADS): diagnostic performance and inter-reviewer agreement.

OBJECTIVE: To evaluate diagnostic performance and inter-reviewer agreement (IRA) of the Gynecologic Imaging Reporting and Data System (GI-RADS) for diagnosis of adnexal masses (AMs) by pelvic ultrasound (US). PATIENTS AND METHODS: A prospective multicenter study included 308 women (mean age, 41 ± 12.5 years; range, 15-73 years) with 325 AMs detected by US. All US examinations were analyzed, and AMs were categorized into five categories according to the GI-RADS classification. We used histopathology and US follow-up as the reference standards for calculating diagnostic performance of GI-RADS for detecting malignant AMs. The Fleiss kappa (κ) tests were applied to evaluate the IRA of GI-RADS scoring results for predicting malignant AMs. RESULTS: A total of 325 AMs were evaluated: 127 (39.1%) were malignant and 198 (60.9%) were benign. Of 95 AMs categorized as GI-RADS 2 (GR2), none was malignant; of 94 AMs categorized as GR3, three were malignant; of 13 AMs categorized as GR4, six were malignant; and of 123 AMs categorized as GR5, 118 were malignant. On a lesion-based analysis, the GI-RADS had a sensitivity, a specificity, and an accuracy of 92.9%, 97.5%, and 95.7%, respectively, when regarding only those AMs classified as GR5 for predicting malignancy. Considering combined GR4 and GR5 as a predictor for malignancy, the sensitivity, specificity, and accuracy of GI-RADS were 97.6%, 93.9%, and 95.4%, respectively. The IRA of the GI-RADS category was very good (κ = 0.896). The best cutoff value for predicting malignant AMs was >GR3. CONCLUSIONS: The GI-RADS is very valuable for improving US structural reports. KEY POINTS: • There is still a lack of a standard in the assessment of AMs. • GI-RADS is very valuable for improving US structural reports of AMs. • GI-RADS criteria are easy and work at least as well as IOTA.

Role of Multidetector Computed Tomography (CT) Virtual Hysteroscopy in the Evaluation of Abnormal Uterine Bleeding in Reproductive Age.

BACKGROUND: Abnormal uterine bleeding (AUB) may be acute or chronic and is defined as bleeding from the uterine corpus that is abnormal in regularity, volume, frequency, or duration and occurs in the absence of pregnancy. It is a widespread complaint in the primary care units. The prevalence of abnormal bleeding is up to 30% among women of reproductive age. OBJECTIVE: To assess the role of CT virtual hysteroscopy in the evaluation of the uterine cavity in cases with abnormal uterine bleeding in reproductive age. METHODS: Cross sectional study was performed at Obstetrics and Gynecology Department and Radiology Department, Zagazig University hospitals, Egypt, on 124 women with abnormal uterine bleeding in reproductive age, and their uterine cavity was evaluated by both row multidetector computed tomography (MDCT) scanner and Office hysteroscopy. RESULTS: Mean age of studied group was 28.54 ± 5.99 years, and virtual hysteroscopy showed sensitivity 91.1% and specificity 85.3% in detection of abnormalities within uterine cavity. It showed sensitivity 91.1% and specificity 85.3% in cases of endometrial polyps. It yielded 88.5 % sensitivity and 100 % specificity in cases with submucous fibroids, while it yielded only 57.9 % sensitivity and 82.9% specificity in cases of thick endometrium. CONCLUSION: Virtual CT hysteroscopy is a good negative test in cases of abnormal uterine bleeding but has some limitations that decrease its sensitivity.

Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.

The interaction of recruited immune effector cells and cancer cells within tumor microenvironment (TME) shapes the fate of cancer progression and metastasis. Many cancers including breast cancer, express a specific vacuolar ATPase (a2V) on their cell surface which acidifies the extracellular milieu helping cancer cell proliferation and metastasis. To understand the role of immune cell-associated-a2V during breast tumor pathogenesis, we knocked-out a2V (KO) from the hematopoietic stem cells (HSC) and generated breast tumors in mice. The a2V-KO mice developed faster growing, larger, and metastatic breast tumors compared to control mice. Further investigation of the TME revealed a significant reduction in the presence of CD4+ and CD8+ T cells in the a2V-KO tumors. Targeted RNA-Seq of the cells of the TME demonstrated that pro-inflammatory cytokines, death receptors, death receptor ligands, and cytotoxic effectors were significantly down-regulated within the a2V-KO TME. Interestingly, analysis of immune cells in the blood, spleen, and thymus of the non-tumor bearing a2V-KO mice revealed a significant decrease in CD4+ and CD8+ T cell populations. For the first time, this study demonstrates that inhibition of V-ATPase expression in HSC leads to a decrease in CD4+ and CD8+ T cell populations and thus promotes breast tumor growth and metastasis.

Mammary epithelium-specific inactivation of V-ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer.

Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell-associated vacuolar ATPase 'a2' isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis. Using a mammary gland-specific a2V-knockout model, we show that in the absence of a2V, breast tumors exhibit atypically soft tumor phenotype, less tumor rigidity, and necrotic tumor microenvironment. These tumors contain a decreased number of cancer cells at primary tumor site, but showed extensive metastases compared to control. Nanomechanical evaluation of normal breast tissues revealed a decrease in stiffness and collagen content in ECM of a2V-deleted breast tissues. Mechanistically, inhibition of a2V expression caused dispersed Golgi morphology with relocation of glycosyltransferase enzymes to early endosomes in mammary epithelial cells. This resulted in defective glycosylation of ECM proteins and production of compromised ECM that further influenced tumor metastasis. Clinically, in patients with cancer, low a2V expression levels in normal breast tissue correlated with lymph node metastasis. Thus, using a new knockout mouse model, we have identified a2V expression in epithelial cells as a key requirement for proper ECM formation in breast tissue and its expression levels can significantly modulate breast tumor dissemination. Evaluation of a2V expression in normal breast tissues can help in identifying patients with high risk of developing metastases.