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Article ; Online: Apoptosis versus necrosis in tubal ectopic pregnancies following Methotrexate.

Gil, Yaron / Zubkov, Asia / Balayla, Jacques / Cohen, Aviad / Levin, Ishai

International journal of experimental pathology

2023 Volume 104, Issue 2, Page(s) 76–80

Abstract: Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and ... ...

Abstract	Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required.
MeSH term(s)	Pregnancy ; Humans ; Female ; Animals ; Rabbits ; Methotrexate/adverse effects ; Abortifacient Agents, Nonsteroidal/adverse effects ; Pregnancy, Ectopic/chemically induced ; Pregnancy, Ectopic/surgery ; Necrosis/chemically induced ; Apoptosis
Chemical Substances	Methotrexate (YL5FZ2Y5U1) ; Abortifacient Agents, Nonsteroidal
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article
ZDB-ID	1016006-1
ISSN	1365-2613 ; 0958-4625 ; 0007-1021 ; 0959-9673
ISSN (online)	1365-2613
ISSN	0958-4625 ; 0007-1021 ; 0959-9673
DOI	10.1111/iep.12465
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Article ; Online: The risk of PD-L1 expression misclassification in triple-negative breast cancer.

Ben Dori, Shani / Aizic, Asaf / Zubkov, Asia / Tsuriel, Shlomo / Sabo, Edmond / Hershkovitz, Dov

Breast cancer research and treatment

2022 Volume 194, Issue 2, Page(s) 297–305

Abstract: Purpose: Stratification of patients with triple-negative breast cancer (TNBC) for anti-PD-L1 therapy is based on PD-L1 expression in tumor biopsies. This study sought to evaluate the risk of PD-L1 misclassification.: Methods: We conducted a high- ... ...

Abstract	Purpose: Stratification of patients with triple-negative breast cancer (TNBC) for anti-PD-L1 therapy is based on PD-L1 expression in tumor biopsies. This study sought to evaluate the risk of PD-L1 misclassification. Methods: We conducted a high-resolution analysis on ten surgical specimens of TNBC. First, we determined PD-L1 expression pattern distribution via manual segmentation and measurement of 6666 microscopic clusters of positive PD-L1 immunohistochemical staining. Then, based on these results, we generated a computer model to calculate the effect of the positive PD-L1 fraction, aggregate size, and distribution of PD-L1 positive cells on the diagnostic accuracy. Results: Our computer-based model showed that larger aggregates of PD-L1 positive cells and smaller biopsy size were associated with higher fraction of false results (P < 0.001, P < 0.001, respectively). Additionally, our model showed a significant increase in error rate when the fraction of PD-L1 expression was close to the cut-off (error rate of 12.1%, 0.84%, and 0.65% for PD-L1 positivity of 0.5-1.5%, ≤ 0.5% ,and ≥ 1.5%, respectively, P < 0.0001). Interestingly, false positive results were significantly higher than false negative results (0.51-22.62%, with an average of 6.31% versus 0.11-11.36% with an average of 1.58% for false positive and false negative results, respectively, P < 0.05). Furthermore, heterogeneous tumors with different aggregate sizes in the same tumor, were associated with increased rate of false results in comparison to homogenous tumors (P < 0.001). Conclusion: Our model can be used to estimate the risk of PD-L1 misclassification in biopsies, with potential implications for treatment decisions.
MeSH term(s)	B7-H1 Antigen/genetics ; B7-H1 Antigen/metabolism ; Humans ; Prognosis ; Triple Negative Breast Neoplasms/diagnosis ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	B7-H1 Antigen
Language	English
Publishing date	2022-05-27
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-022-06630-3
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Zs.A 1655: Show issues

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Article ; Online: Electrolyte Imbalance in Anti-LGI1 Encephalitis: It Is Not All in Your Head.

Gadoth, Avi / Nisnboym, Michal / Alcalay, Yifat / Zubkov, Asia / Schwartz, Idit / Schwartz, Doron / Abboud, Marana / Rubinek, Tamar / Yossepowitch, Ofer / Weinstein, Talia

Neurology(R) neuroimmunology & neuroinflammation

2023 Volume 10, Issue 6

Abstract: Background and objectives: Antileucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis was first described in 2010 and is today the most common type of limbic encephalitis. During the course of the disease, 60%-88% of the patients develop ... ...

Abstract	Background and objectives: Antileucine-rich glioma-inactivated 1 (anti-LGI1) autoimmune encephalitis was first described in 2010 and is today the most common type of limbic encephalitis. During the course of the disease, 60%-88% of the patients develop hyponatremia. The etiology of the sodium disorder is unclear, often presumed to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Other electrolyte abnormalities have not been reported in association with anti-LGI1 antibody encephalitis. Due to the presence of hypomagnesemia and hypophosphatemia in our patients, we set out to try to find the expression of LGI1 protein in the kidney as an explanation for these abnormalities. Methods: We reviewed the medical files of all patients diagnosed with anti-LGI1 antibody encephalitis, at the Department of Neurology in the Tel Aviv Medical Center between January 2011 and December 2020, exploring for electrolyte abnormalities. Using tissue staining, Western blot, mass spectrometry, and RNA expression techniques, we tried to demonstrate the expression of LGI1 protein in the human kidney. Results: We identified 15 patients diagnosed with anti-LGI1 antibody encephalitis. Their average age was 65 years (44-80), and 9 were male individuals. Thirteen of the 15 patients (87%) developed varying degrees of hyponatremia. Laboratory studies demonstrated low serum osmolality, low serum blood urea nitrogen, and low uric acid, with a high urinary sodium and inappropriately high urine osmolality, supporting the presumable diagnosis of SIADH. One patient with hyponatremia that was tested, had high levels of copeptin, supporting the diagnosis of SIADH. In addition to hyponatremia, 7 patients (47%) exhibited other electrolyte abnormalities; 5 patients (33%) had overt hypophosphatemia, 4 patients (27%) had overt hypomagnesemia, and 2 other patients (13%) had borderline low magnesium levels. Western blot analysis of human kidney lysate, mass spectrometry, and qRT-PCR failed to demonstrate the expression of LGI1 protein in the kidney. Discussion: Hyponatremia in patients with anti-LGI1 antibody encephalitis is due to SIADH as previously assumed. Other electrolyte abnormalities such as hypomagnesemia and hypophosphatemia occur in at least 40% of patients and may be another clue for the diagnosis of anti-LGI1 antibody encephalitis. Because we failed to demonstrate LGI1 expression in the kidney, the results of our study suggest that renal losses lead to these disturbances, most probably due to SIADH.
MeSH term(s)	Humans ; Male ; Aged ; Female ; Inappropriate ADH Syndrome ; Hyponatremia/diagnosis ; Hyponatremia/etiology ; Encephalitis/diagnosis ; Antibodies ; Hypophosphatemia ; Electrolytes ; Sodium
Chemical Substances	Antibodies ; Electrolytes ; Sodium (9NEZ333N27)
Language	English
Publishing date	2023-08-17
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2767740-0
ISSN	2332-7812 ; 2332-7812
ISSN (online)	2332-7812
ISSN	2332-7812
DOI	10.1212/NXI.0000000000200155
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Article ; Online: Automatic ganglion cell detection for improving the efficiency and accuracy of hirschprung disease diagnosis.

Greenberg, Ariel / Aizic, Asaf / Zubkov, Asia / Borsekofsky, Sarah / Hagege, Rami R / Hershkovitz, Dov

Scientific reports

2021 Volume 11, Issue 1, Page(s) 3306

Abstract: Histopathologic diagnosis of Hirschsprung's disease (HSCR) is time consuming and requires expertise. The use of artificial intelligence (AI) in digital pathology is actively researched and may improve the diagnosis of HSCR. The purpose of this research ... ...

Abstract	Histopathologic diagnosis of Hirschsprung's disease (HSCR) is time consuming and requires expertise. The use of artificial intelligence (AI) in digital pathology is actively researched and may improve the diagnosis of HSCR. The purpose of this research was to develop an algorithm capable of identifying ganglion cells in digital pathology slides and implement it as an assisting tool for the pathologist in the diagnosis of HSCR. Ninety five digital pathology slides were used for the construction and training of the algorithm. Fifty cases suspected for HSCR (727 slides) were used as a validation cohort. Image sets suspected to contain ganglion cells were chosen by the algorithm and then reviewed and scored by five pathologists, one HSCR expert and 4 non-experts. The algorithm was able to identify ganglion cells with 96% sensitivity and 99% specificity (in normal colon) as well as to correctly identify a case previously misdiagnosed as non-HSCR. The expert was able to achieve perfectly accurate diagnoses based solely on the images suggested by the algorithm, with over 95% time saved. Non-experts would require expert consultation in 20-58% of the cases to achieve similar results. The use of AI in the diagnosis of HSCR can greatly reduce the time and effort required for diagnosis and improve accuracy.
MeSH term(s)	Artificial Intelligence ; Female ; Hirschsprung Disease/diagnosis ; Hirschsprung Disease/pathology ; Humans ; Image Processing, Computer-Assisted ; Male
Language	English
Publishing date	2021-02-08
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Validation Study
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-82869-y
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Article: Renal Tubular CD24 Upregulation Aggravates Folic Acid Induced Acute Kidney Injury: A Possible Role for T Regulatory Cells Inhibition in Mice.

Shashar, Moshe / Schwartz, Doron / Zubkov, Asia / Hoffman, Sarit / Jankelson, Lior / Shapira, Shiran / Merimsky, Barak / Berman, Julia / Chernichovski, Tamara / Amitai, Oeren / Raz, Michal Ariela / Hershkovitz, Rami / Grupper, Ayelet / Weinstein, Talia / Arber, Nadir / Schwartz, Idit F

Journal of personalized medicine

2023 Volume 13, Issue 7

Abstract: Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in ... ...

Abstract	Acute kidney injury (AKI) is characterized by cell death and inflammation. CD24 is a protein induced during tissue damage and is not expressed in mature renal tissue. We explored the role of CD24 in the pathogenesis of folic acid-induced AKI (FA-AKI) in mice. A single Intraperitoneal (IP) injection of folic acid induced AKI in WT and CD24
Language	English
Publishing date	2023-07-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662248-8
ISSN	2075-4426
ISSN	2075-4426
DOI	10.3390/jpm13071134
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Article ; Online: Profound Decrease in Glomerular Arginine Transport by CAT (Cationic Amino Acid Transporter)-1 Contributes to the FLT-1 (FMS-Like Tyrosine Kinase 1) Induced Preeclampsia in the Pregnant Mice.

Shashar, Moshe / Zubkov, Asia / Chernichovski, Tamara / Hershkovitz, Rami / Hoffman, Elinoar / Grupper, Ayelet / Weinstein, Talia / Schwartz, Idit F

Hypertension (Dallas, Tex. : 1979)

2019 Volume 73, Issue 4, Page(s) 878–884

Abstract: Endothelial dysfunction because of nitric oxide inactivation has been suggested to play a role in the pathogenesis of preeclampsia. During pregnancy, L-arginine transport by CAT-1 (cationic amino acid transporter 1), the only transporter for eNOS ( ... ...

Abstract	Endothelial dysfunction because of nitric oxide inactivation has been suggested to play a role in the pathogenesis of preeclampsia. During pregnancy, L-arginine transport by CAT-1 (cationic amino acid transporter 1), the only transporter for eNOS (endothelial nitric oxide synthase) is inhibited. We hypothesize that maternal arginine deficiency contributes to the development of preeclampsia. Adenovirus-mediated overexpression of sFlt-1 (soluble fms-like tyrosine kinase 1) in virgin and pregnant mice resulted in glomerular endotheliosis, hypertension, and albuminuria. L-arginine prevented the increase in blood pressure and albuminuria in Flt-1 pregnant but not in Flt-1 virgin mice. Flt-1 augmented arginine transport in pregnant but not in virgin dames. Ex vivo inhibition of CAT-2 leaving exclusively CAT-1 activity, decreased arginine transport velocities in Flt-1 animals more prominently in pregnant dames. Phosphorylated CAT-1/CAT-1 increased in pregnant, sFlt-1-pregnant, and sFlt-1 virgin mice. CAT-2 increased in Flt-1-pregnant and Flt-1-virgin dames. L-arginine augmented arginine transport in pregnant and Flt-pregnant mice and prevented the increase in pCAT-1 and CAT-2 expression. Glomerular cGMP (cyclic guanosine monophosphate) generation as a measure of eNOS activity was decreased in all Flt-1 treated animals. L-arginine abolished the decrease in cGMP levels only in Flt-1-pregnant mice. In conclusion, glomerular endothelial NO generation is compromised in Flt-1-pregnant mice because of CAT-1 inhibition induced by a combined effect of pregnancy and preeclampsia which involves: phosphorylation of CAT-1 and induction of CAT-2. These processes contribute to the clinical syndrome of preeclampsia in mice and are prevented by L-arginine.
MeSH term(s)	Animals ; Cationic Amino Acid Transporter 1/metabolism ; Disease Models, Animal ; Endothelium/metabolism ; Female ; Ion Transport ; Kidney Glomerulus/metabolism ; Mice ; Nitric Oxide/metabolism ; Phosphorylation ; Pre-Eclampsia/chemically induced ; Pre-Eclampsia/metabolism ; Pre-Eclampsia/physiopathology ; Pregnancy ; Pregnancy, Animal ; Vascular Endothelial Growth Factor Receptor-1/toxicity
Chemical Substances	Cationic Amino Acid Transporter 1 ; Nitric Oxide (31C4KY9ESH) ; Flt1 protein, mouse (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-1 (EC 2.7.10.1)
Language	English
Publishing date	2019-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.118.12372
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Article ; Online: Thromboelastography versus bleeding time for risk of bleeding post native kidney biopsy.

Gal-Oz, Amir / Papushado, Amitay / Kirgner, Ilya / Meirsdorf, Shmuel / Schwartz, Doron / Schwartz, Idit Francesca / Zubkov, Asia / Grupper, Ayelet

Renal failure

2019 Volume 42, Issue 1, Page(s) 10–18

Abstract: Introduction: ...

Abstract	Introduction:
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biopsy/adverse effects ; Biopsy/methods ; Bleeding Time ; Clinical Decision-Making/methods ; Deamino Arginine Vasopressin/administration & dosage ; Female ; Hemostatics/administration & dosage ; Humans ; Kidney/diagnostic imaging ; Kidney/pathology ; Kidney Diseases/blood ; Kidney Diseases/diagnosis ; Kidney Diseases/pathology ; Male ; Middle Aged ; Point-of-Care Testing ; Postoperative Hemorrhage/blood ; Postoperative Hemorrhage/epidemiology ; Postoperative Hemorrhage/etiology ; Postoperative Hemorrhage/prevention & control ; Retrospective Studies ; Risk Assessment/methods ; Thrombelastography ; Ultrasonography, Interventional ; Young Adult
Chemical Substances	Hemostatics ; Deamino Arginine Vasopressin (ENR1LLB0FP)
Language	English
Publishing date	2019-12-17
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	632949-4
ISSN	1525-6049 ; 0886-022X
ISSN (online)	1525-6049
ISSN	0886-022X
DOI	10.1080/0886022X.2019.1700805
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Article ; Online: Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears.

Lithwick-Yanai, Gila / Dromi, Nir / Shtabsky, Alexander / Morgenstern, Sara / Strenov, Yulia / Feinmesser, Meora / Kravtsov, Vladimir / Leon, Marino E / Hajdúch, Marián / Ali, Syed Z / VandenBussche, Christopher J / Zhang, Xinmin / Leider-Trejo, Leonor / Zubkov, Asia / Vorobyov, Sergey / Kushnir, Michal / Goren, Yaron / Tabak, Sarit / Kadosh, Etti /

Benjamin, Hila / Schnitzer-Perlman, Temima / Marmor, Hagai / Motin, Maria / Lebanony, Danit / Kredo-Russo, Sharon / Mitchell, Heather / Noller, Melissa / Smith, Alexis / Dattner, Olivia / Ashkenazi, Karin / Sanden, Mats / Berlin, Kenneth A / Bar, Dganit / Meiri, Eti

Journal of clinical pathology

2017 Volume 70, Issue 6, Page(s) 500–507

Abstract: Aims: The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine ... ...

Abstract	Aims: The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. Methods: A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. Results: Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). Conclusions: A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.
MeSH term(s)	Biopsy, Fine-Needle ; Female ; Humans ; Male ; MicroRNAs/metabolism ; Middle Aged ; Observer Variation ; Predictive Value of Tests ; Thyroid Neoplasms/diagnosis ; Thyroid Nodule/diagnosis
Chemical Substances	MicroRNAs
Language	English
Publishing date	2017-06
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Validation Studies
ZDB-ID	80261-x
ISSN	1472-4146 ; 0021-9746
ISSN (online)	1472-4146
ISSN	0021-9746
DOI	10.1136/jclinpath-2016-204089
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