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1.
Biomolecules ; 11(6)2021 05 28.
Article in English | MEDLINE | ID: covidwho-1256422

ABSTRACT

The urgent need for novel and effective drugs against the SARS-CoV-2 coronavirus pandemic has stimulated research worldwide. The Papain-like protease (PLpro), which is essential for viral replication, shares a similar active site structural architecture to other cysteine proteases. Here, we have used representatives of the Ovarian Tumor Domain deubiquitinase family OTUB1 and OTUB2 along with the PLpro of SARS-CoV-2 to validate and rationalize the binding of inhibitors from previous SARS-CoV candidate compounds. By forming a new chemical bond with the cysteine residue of the catalytic triad, covalent inhibitors irreversibly suppress the protein's activity. Modeling covalent inhibitor binding requires detailed knowledge about the compounds' reactivities and binding. Molecular Dynamics refinement simulations of top poses reveal detailed ligand-protein interactions and show their stability over time. The recently discovered selective OTUB2 covalent inhibitors were used to establish and validate the computational protocol. Structural parameters and ligand dynamics are in excellent agreement with the ligand-bound OTUB2 crystal structures. For SARS-CoV-2 PLpro, recent covalent peptidomimetic inhibitors were simulated and reveal that the ligand-protein interaction is very dynamic. The covalent and non-covalent docking plus subsequent MD refinement of known SARS-CoV inhibitors into DUBs and the SARS-CoV-2 PLpro point out a possible approach to target the PLpro cysteine protease from SARS-CoV-2. The results show that such an approach gives insight into ligand-protein interactions, their dynamic character, and indicates a path for selective ligand design.


Subject(s)
Deubiquitinating Enzymes/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/metabolism , Viral Proteases/chemistry , Binding Sites , COVID-19/pathology , Catalytic Domain , Deubiquitinating Enzymes/metabolism , Drug Design , Female , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Dynamics Simulation , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Protease Inhibitors/metabolism , SARS-CoV-2/isolation & purification , Viral Proteases/metabolism
2.
J Ovarian Res ; 14(1): 39, 2021 Feb 25.
Article in English | MEDLINE | ID: covidwho-1105725

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide is a major public health concern. Cancer patients are considered a vulnerable population to SARS-CoV-2 infection and may develop several COVID-19 symptoms. The heightened immunocompromised state, prolonged chronic pro-inflammatory milieu coupled with comorbid conditions are shared in both disease conditions and may influence patient outcome. Although ovarian cancer (OC) and COVID-19 are diseases of entirely different primary organs, both diseases share similar molecular and cellular characteristics in their microenvironment suggesting a potential cooperativity leading to poor outcome. In COVID-19 related cases, hospitalizations and deaths worldwide are lower in women than in males; however, comorbidities associated with OC may increase the COVID-19 risk in women. The women at the age of 50-60 years are at greater risk of developing OC as well as SARS-CoV-2 infection. Increased levels of gonadotropin and androgen, dysregulated renin-angiotensin-aldosterone system (RAAS), hyper-coagulation and chronic inflammation are common conditions observed among OC and severe cases of COVID-19. The upregulation of common inflammatory cytokines and chemokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-2, IL-6, IL-10, interferon-γ-inducible protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage colony-stimulating factor (M-CSF), among others in the sera of COVID-19 and OC subjects suggests potentially similar mechanism(s) involved in the hyper-inflammatory condition observed in both disease states. Thus, it is conceivable that the pathogenesis of OC may significantly contribute to the potential infection by SARS-CoV-2. Our understanding of the influence and mechanisms of SARS-CoV-2 infection on OC is at an early stage and in this article, we review the underlying pathogenesis presented by various comorbidities of OC and correlate their influence on SARS-CoV-2 infection.


Subject(s)
COVID-19/epidemiology , COVID-19/etiology , Inflammation/epidemiology , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/pathology , Comorbidity , Cytokines/metabolism , Female , Humans , Inflammation/virology , Middle Aged , Renin-Angiotensin System/physiology , Tumor Microenvironment
3.
Int J Gynecol Cancer ; 30(12): 1935-1942, 2020 12.
Article in English | MEDLINE | ID: covidwho-894884

ABSTRACT

OBJECTIVE: Interval cytoreduction following neoadjuvant chemotherapy is a well-recognized treatment alternative to primary debulking surgery in the treatment of advanced epithelial ovarian cancer where patient and/or disease factors prevent complete macroscopic disease resection to be achieved. More recently, the strain of the global COVID-19 pandemic on hospital resources has forced many units to alter the timing of interval surgery and extend the number of neoadjuvant chemotherapy cycles. In order to support this paradigm shift and provide more accurate counseling during these unprecedented times, we investigated the survival outcomes in advanced epithelial ovarian cancer patients with the intent of maximal cytoreduction following neoadjuvant chemotherapy with respect to timing of surgery and degree of cytoreduction. METHODS: A retrospective review of all patients aged 18 years and above with FIGO (2014) stage III/IV epithelial ovarian cancer treated with neoadjuvant chemotherapy and the intention of interval cytoreduction surgery between January 2008 and December 2017 was conducted. Overall and progression-free survival outcomes were analyzed and compared with patients who only received chemotherapy. Outcome measures were correlated with the number of neoadjuvant chemotherapy cycles and amount of residual disease following surgery. RESULTS: Six hundred and seventy-one patients (median age 67 (range 20-91) years) were included in the study with 572 patients treated with neoadjuvant chemotherapy and surgery and 99 patients with chemotherapy only. There was no difference in the proportion of patients in whom complete cytoreduction was achieved based on number of cycles of neoadjuvant chemotherapy (2-4 cycles: 67.7%, n=337/498); ≥5 cycles: 62.2%, n=46/74). Patients undergoing cytoreduction surgery after neoadjuvant chemotherapy had a median 5-year progression-free and overall survival of 24 and 38 months, respectively. No significant difference in overall survival between surgical groups was observed (interval cytoreduction: 41 months vs delayed cytoreduction: 43 months, p=0.52). Those who achieved complete cytoreduction to R0 (no macroscopic disease) had a significant median overall survival advantage compared with those with any macroscopic residual disease (R0: 49-51 months vs R<1: 22-39 months, p<0.001 vs R≥1: 23-26 months, p<0.001). CONCLUSIONS: Survival outcomes do not appear to be worse for patients treated with neoadjuvant chemotherapy if cytoreduction surgery is delayed beyond three cycles. In advanced epithelial ovarian cancer patients the imperative to achieve complete surgical cytoreduction remains gold standard, irrespective of surgical timing, for best survival benefit.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/surgery , Cytoreduction Surgical Procedures/methods , Ovarian Neoplasms/mortality , Ovarian Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/pathology , Chemotherapy, Adjuvant , Female , Follow-Up Studies , Humans , Middle Aged , Neoadjuvant Therapy , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Retrospective Studies , Survival Analysis , Time Factors , Treatment Outcome
4.
Tumori ; 106(6): NP73-NP75, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-788438

ABSTRACT

BACKGROUND: The differential diagnosis of lung and pleural metastases and coronavirus disease 2019 (COVID-19) can be challenging. CASE: We report a case of a 41-year-old woman with FIGO (International Federation of Gynecology and Obstetrics) stage IV ovarian cancer with pleural and pulmonary spread. After primary cytoreduction was performed, she developed a high fever and worsening dyspnea with desaturation (92% in ambient air). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was suspected, but three swabs gave negative results. Computed tomographic scan showed radiologic imaging strongly suspect for COVID-19 and the patient was transferred to a COVID-19 ward. The final diagnosis was paraneoplastic fever. CONCLUSION: Lung and pleural metastases can mimic SARS-CoV-2 infection.


Subject(s)
COVID-19/diagnosis , Lung Neoplasms/diagnosis , Lung Neoplasms/secondary , Ovarian Neoplasms/pathology , Pleural Neoplasms/diagnosis , Pleural Neoplasms/secondary , Adult , COVID-19/virology , Diagnosis, Differential , Female , Humans , Neoplasm Staging , Symptom Assessment , Tomography, X-Ray Computed
5.
Eur J Cancer Care (Engl) ; 29(6): e13309, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-780845

ABSTRACT

INTRODUCTION: Today, COVID-19 pandemic is still the most critical problem in the global health agenda. Since the awareness of the public in general and particularly awareness of those with comorbidities, such as cancer, determine the rate of mortality, the primary goal of this study was to assess the knowledge, perceptions and attitude of the patients with cancer towards the COVID-19 pandemic. The secondary objective of this study was also to measure the effect of COVID-19 on cancer patients' ongoing treatments. METHODS: This study recruited 300 oncology patients through an outpatient community-based oncology clinic in one of the 30 major cities of Turkey, which had taken a lockdown at weekends during April 2020. A questionnaire measuring the knowledge, attitudes and preventive behaviour was completed by each patient either face-to-face or through telephone survey. RESULTS: In general, participants had a positive attitude towards protective measures. No delay for current cancer treatments or appointments has been observed in 98% of patients. More than half of the patients(52.3%) were using some kind of nutritional supplement to increase their body resistance. Nearly two-third of patients could not identify the three most common symptoms of COVID-19 (fever, cough, dyspnoea), and half of them were not aware of the routes of transmission (by contact and droplets). It was observed that patients with stage 1 cancer were tend to stay at home, while patients with stage 4 cancer were prone to leave their houses for the hospital at a higher ratio. The rate of people leaving houses was significantly higher for male patients and for patients with a university degree, whereas patients who were older than 65 were tend to go only to the hospital when they leave their houses. CONCLUSION: This study suggests that routine follow-up and guidance for cancer patients seems to provide significant benefit to increase the knowledge and awareness of patients with cancer.


Subject(s)
COVID-19/prevention & control , Hand Disinfection , Health Knowledge, Attitudes, Practice , Masks , Neoplasms/therapy , Adult , Age Factors , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Cross-Sectional Studies , Dietary Supplements , Educational Status , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Surveys and Questionnaires , Transportation , Turkey , Young Adult
6.
Mol Biol Rep ; 47(6): 4857-4860, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-209514

ABSTRACT

The first person-to-person transmission of the 2019-novel coronavirus in Italy on 21 February 2020 led to an infection chain that represents one of the largest known COVID-19 outbreaks outside Asia. Hospitals have been forced to reorganized their units in response to prepare for an unforeseen healthcare emergency. In this context, our laboratory (Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS) re-modulated its priorities by temporarily interrupting most of the molecular tests guaranteeing only those considered "urgent" and not postponable. In particular, this paper details changes regarding the execution of germline BRCA (gBRCA) testing in our laboratory. A substantial reduction in gBRCA testing (about 60%) compared to the first 2 months of the current year was registered, but the requests have not been reset. The requesting physicians were mainly gynaecologists and oncologists. These evidences further emphasize the new era of gBRCA testing in the management of cancer patients and confirms definitively the integration of gBRCA testing/Next Generation Sequencing (NGS) into clinical oncology. Finally, a re-organization of gBRCA testing in our Unit, mainly related to delayed and reduced arrival of tests was necessary, ensuring, however, a high-quality standard and reliability, mandatory for gBRCA testing in a clinical setting.


Subject(s)
BRCA2 Protein/genetics , Breast Neoplasms/diagnosis , Coronavirus Infections/epidemiology , Early Detection of Cancer/statistics & numerical data , Ovarian Neoplasms/diagnosis , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/statistics & numerical data , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Early Detection of Cancer/methods , Early Diagnosis , Female , Genomics/methods , High-Throughput Nucleotide Sequencing/statistics & numerical data , Humans , Italy/epidemiology , Mutation , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Referral and Consultation/statistics & numerical data , SARS-CoV-2
7.
J Gynecol Obstet Hum Reprod ; 49(6): 101729, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-23573

ABSTRACT

INTRODUCTION: In the context of the COVID-19 pandemic, specific recommendations are required for the management of patients with gynecologic cancer. MATERIALS AND METHOD: The FRANCOGYN group of the National College of French Gynecologists and Obstetricians (CNGOF) convened to develop recommendations based on the consensus conference model. RESULTS: If a patient with a gynecologic cancer presents with COVID-19, surgical management should be postponed for at least 15 days. For cervical cancer, radiotherapy and concomitant radiochemotherapy could replace surgery as first-line treatment and the value of lymph node staging should be reviewed on a case-by-case basis. For advanced ovarian cancers, neoadjuvant chemotherapy should be preferred over primary cytoreduction surgery. It is legitimate not to perform hyperthermic intraperitoneal chemotherapy during the COVID-19 pandemic. For patients who are scheduled to undergo interval surgery, chemotherapy can be continued and surgery performed after 6 cycles. For patients with early stage endometrial cancer of low and intermediate preoperative ESMO risk, hysterectomy with bilateral adnexectomy combined with a sentinel lymph node procedure is recommended. Surgery can be postponed for 1-2 months in low-risk endometrial cancers (FIGO Ia stage on MRI and grade 1-2 endometrioid cancer on endometrial biopsy). For patients of high ESMO risk, the MSKCC algorithm (combining PET-CT and sentinel lymph node biopsy) should be applied to avoid pelvic and lumbar-aortic lymphadenectomy. CONCLUSION: During the COVID-19 pandemic, management of a patient with cancer should be adapted to limit the risks associated with the virus without incurring loss of chance.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Genital Neoplasms, Female/surgery , Pandemics , Pneumonia, Viral/epidemiology , COVID-19 , Chemotherapy, Adjuvant , Coronavirus Infections/complications , Coronavirus Infections/prevention & control , Endometrial Neoplasms/pathology , Endometrial Neoplasms/surgery , Female , France , Genital Neoplasms, Female/complications , Genital Neoplasms, Female/pathology , Genital Neoplasms, Female/therapy , Gynecology , Humans , Interdisciplinary Communication , Obstetrics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Pandemics/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/prevention & control , Receptors, Lymphocyte Homing , Risk , SARS-CoV-2 , Societies, Medical , Trophoblastic Neoplasms/drug therapy , Uterine Cervical Neoplasms/therapy , Vaginal Neoplasms/therapy , Vulvar Neoplasms/surgery
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