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Severe disease from SARS-CoV-2 infection often progresses to multi-organ failure and results in an increased mortality rate amongst these patients. However, underlying mechanisms of SARS- CoV-2-induced multi-organ failure and subsequent death are still largely unknown. Cytokine storm, increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs contribute to the pathogenesis of COVID-19. One potential consequence of immune/inflammatory events is the acute progression of generalized edema, which may lead to death. We, therefore, examined the involvement of water channels in the development of edema in multiple organs and their contribution to organ dysfunction in a Murine Hepatitis Virus-1 (MHV-1) mouse model of COVID-19. Using this model, we recently reported multi-organ pathological abnormalities and animal death similar to that reported in humans with SARS-CoV-2 infection. We now identified an alteration in protein levels of AQPs 1, 4, 5, and 8 and associated oxidative stress, along with various degrees of tissue edema in multiple organs, which correlate well with animal survival post-MHV-1 infection. Furthermore, our newly created drug (a 15 amino acid synthetic peptide, known as SPIKENET) that was designed to prevent the binding of spike glycoproteins with their receptor(s), angiotensin- converting enzyme 2 (ACE2), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively), ameliorated animal death and reversed altered levels of AQPs and oxidative stress post-MHV-1 infection. Collectively, our findings suggest the possible involvement of altered aquaporins and the subsequent edema, likely mediated by the virus-induced inflammatory and oxidative stress response, in the pathogenesis of COVID- 19 and the potential of SPIKENET as a therapeutic option.

We recently reported acute COVID-19 symptoms, clinical status, weight loss, multi-organ pathological changes, and animal death in a murine hepatitis virus-1 (MHV-1) coronavirus mouse model of COVID-19, which were similar to that observed in humans with COVID-19. We further examined long-term (12 months post-infection) sequelae of COVID-19 in these mice. Congested blood vessels, perivascular cavitation, pericellular halos, vacuolation of neuropils, pyknotic nuclei, acute eosinophilic necrosis, necrotic neurons with fragmented nuclei, and vacuolation were observed in the brain cortex 12 months post-MHV-1 infection. These changes were associated with increased reactive astrocytes and microglia, hyperphosphorylated TDP-43 and tau, and a decrease in synaptic protein synaptophysin-1, suggesting the possible long-term impact of SARS-CoV-2 infection on defective neuronal integrity. The lungs showed severe inflammation, bronchiolar airway wall thickening due to fibrotic remodeling, bronchioles with increased numbers of goblet cells in the epithelial lining, and bronchiole walls with increased numbers of inflammatory cells. Hearts showed severe interstitial edema, vascular congestion and dilation, nucleated red blood cells (RBCs), RBCs infiltrating between degenerative myocardial fibers, inflammatory cells and apoptotic bodies and acute myocyte necrosis, hypertrophy, and fibrosis. Long-term changes in the liver and kidney were less severe than those observed in the acute phase. Noteworthy, the treatment of infected mice with a small molecule synthetic peptide which prevents the binding of spike protein to its respective receptors significantly attenuated disease progression, as well as the pathological changes observed post-long-term infection. Collectively, these findings suggest that COVID-19 may result in long-term, irreversible changes predominantly in the brain, lung, and heart.

This is a retrospective study of patients treated for early-stage cervical cancer to identify pathologic risk factors associated with ovarian metastases and, therefore, to establish when ovarian preservation can be performed without increasing the risk of relapse in order to improve the quality of life in premenopausal patients. Between 1982 and 2004, 1965 patients with FIGO stage IA2–IB–IIA cervical squamous cell carcinoma and nonsquamous histology types were surgically treated; 1695 (86%) patients underwent primary radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection, the remaining 270 patients (14%) had their ovaries preserved. The clinical records were reviewed for all patients and clinical features at presentation, the histopathology and follow-up data were recorded. Overall, ovarian metastases were diagnosed in 16 of 1695 patients, for an incidence rate of 0.9%. Univariate analysis shows age (≤45 vs >45 years: P= 0.0079), FIGO stage (IB1–IIA ≤4 cm vs IB2–IIA >4 cm: P= 0.0133), histology (squamous vs nonsquamous, P= 0.0014), noninvolved peripheral stromal thickness (<3 vs >3 mm: P= 0.0001), lymphvascular space involvement (present vs absent, P= 0.0007), lymph node status (positive vs negative, P= 0.00009) to be statistically associated with the presence of ovarian metastases. Multivariate analysis shows only age (P= 0.0119), FIGO stage (P= 0.011), histology (P= 0.001), and unaffected peripheral stromal thickness (<3 mm: P= 0.037) to be independent risk factors for ovarian metastases. Based on the present data and on the data available in the literature, ovarian preservation could be safely performed in young patients with early-stage squamous cell carcinoma (histology as the most significant risk factor), with macroscopically normal ovaries, and with preserved peripheral unaffected cervical stroma.

Human-mediated range expansions have increased in recent decades and represent unique opportunities to evaluate genetic outcomes of establishing peripheral populations across broad expansion fronts. Over the past century, coyotes (Canis latrans) have undergone a pervasive range expansion and now inhabit every state in the continental United States. Coyote expansion into eastern North America was facilitated by anthropogenic landscape changes and followed two broad expansion fronts. The northern expansion extended through the Great Lakes region and southern Canada, where hybridization with remnant wolf populations was common. The southern and more recent expansion front occurred approximately 40 years later and across territory where gray wolves have been historically absent and remnant red wolves were extirpated in the 1970s. We conducted a genetic survey at 10 microsatellite loci of 482 coyotes originating from 11 eastern U.S. states to address how divergent demographic histories influence geographic patterns of genetic diversity. We found that population structure corresponded to a north–south divide, which is consistent with the two known expansion routes. Additionally, we observed extremely high genetic diversity, which is atypical of recently expanded populations and is likely the result of multiple complex demographic processes, in addition to hybridization with other Canis species. Finally, we considered the transition of allele frequencies across geographic space and suggest the mid-Atlantic states of North Carolina and Virginia as an emerging contact zone between these two distinct coyote expansion fronts.

Cervical cancer patients with distant or loco-regional recurrences not amenable by surgery or radiotherapy have limited treatment options, and their 5-year overall survival (OS) rates range from 5% to 16%. The purpose of this paper is to assess the results obtained with chemotherapy and biological agents in this clinical setting. Several phase II trials of different cisplatin (CDDP)-based doublets and a phase III randomized trial showing a trend in response rate, progression-free survival, and OS in favor of CDDP + paclitaxel (PTX) compared with other CDDP-based doublets have been reviewed. The factors predictive of response to chemotherapy as well as the benefits and risks of the addition of bevacizumab to CDDP + PTX have been analyzed. The FDA has recently approved pembrolizumab for patients with recurrent or metastatic cervical cancer in progression on or after chemotherapy whose tumors were PD-L1 positive. Interesting perspectives of clinical research are represented by the use of immune checkpoint inhibitors alone or in addition to chemotherapy, whereas PARP inhibitors and PI3K inhibitors are still at the basic research phase, but promising.

Background/Aim: Screening for ovarian cancer in the general population is a challenging issue. The aim of this review was to analyze both the studies based on serum CA125 assay and ultrasound (US) and the novel perspectives of clinical and biological research on this issue. Materials and Methods: The trials on the combination of serum CA125 and vaginal/pelvic US as well as the investigations on microRNA (miRNA)s, circulating tumor DNA and tumor protein 53 (TP53) variants in DNA purified from Pap smears have been critically analyzed. Results: Two large randomized trials failed to detect a reduction in ovarian cancer-related deaths in women who underwent serum CA125- and US-based screening compared to those who had no screening. The United Kingdom Collaborative Trial of Ovarian Cancer Screening reported a 39.2% higher incidence of stage I-II and 10.2% lower incidence of stage III-IV disease in women who underwent annual multimodal screening with serum CA125 and vaginal US compared to women who had no screening, but this stage shifting did not translate into a survival benefit. A longitudinal, multiple biomarker algorithm-based strategy might improve ovarian cancer detection compared with serial CA125 alone. The use of serum tumor-associated autoantibodies, circulating tumor DNA and microRNA is still investigational. The identification of TP53 clonal variants in DNA purified from Pap smears can detect early steps of serous ovarian carcinogenesis. Conclusion: The availability of sensitive next-generation sequencing-based approaches for TP53 assessment in PAP smears may allow the reliability of this genetic marker for early detection of ovarian cancer to be verified.

ObjectiveThe objective of this retrospective study was to assess the clinical outcome of patients with advanced epithelial ovarian cancer in complete response after primary debulking surgery (PDS) or neoadjuvant chemotherapy followed by interval debulking surgery (IDS]).MethodsThe authors reviewed the hospital records of 384 patients who underwent PDS (n = 322) or IDS (n = 62) and who were in complete response after primary treatment.ResultsOptimal (residual disease [RD] < 1 cm) and complete (no gross RD) cytoreduction rates were higher after IDS than after PDS (71.0% vs 55.9%; P = 0.001 and 51.6% vs 35.7%, respectively; P = 0.02). Tumor recurred in 73.0% of the 322 complete responders after PDS versus 87.1% of the 62 complete responders after IDS (P = 0.01). The IDS group showed a higher recurrence rate within 6 months (11.3% vs 3.1%: P = 0.01) and a trend to higher recurrence rate between 6 and 12 months (30.6% vs 19.9%). Tumor recurred in 57.4% of the 115 completely cytoreduced patients after PDS versus 87.5% of the 32 completely cytoreduced patients after IDS (P = 0.001). The IDS group showed a trend to higher recurrence rate within 6 months (6.2% vs 1.7%) and a higher recurrence rate between 6 and 12 months (37.5% vs 15.6%; P = 0.01). Two-year, 5-year, and 7-year progression-free survival were 65.8%, 40.8%, and 39.3% for completely cytoreduced patients after PDS versus 43.8%, 12.5%, and 12.5% for completely cytoreduced patients after IDS (P = 0.001); and 2-year, 5-year, and 7-year overall survival were 96.4%, 69.3%, and 50.4% for the former versus 87.1%, 41.8%, and 32.6% for the latter (P = 0.001).ConclusionsThe clinical outcome of completely cytoreduced patients was significantly better for PDS group than for IDS group, and therefore, the achievement of no gross RD after surgery seemed to have a different prognostic relevance for the 2 groups.

Chemotherapeutic management of ovarian cancers is a difficult task as these neoplasms show significant differences in chemosensitivity, even if they share identical clinicopathological features. The present study was undertaken to investigate the prognostic and predictive role of p53 alterations in ovarian cancer. To this end, using different technical approaches, i.e. genetic and immunohistochemical analyses, we analysed a series of 68 ovarian neoplasms including 15 low malignant potential (LMP) tumours and 53 invasive carcinomas. We never observed p53 abnormalities in LMP tumours. p53 alterations were present only in invasive ovarian carcinomas, and they were detected much more frequently in tumours characterized by high histological grade (P = 0.01) and advanced-stage disease (P = 0.006 and P = 0.05 for gene mutations and protein expression respectively). For 33 patients with invasive ovarian cancer, information was available concerning response to cisplatin-based chemotherapy. A strong correlation (P = 0.001) has emerged between p53 alterations and response to chemotherapy; only one (14%) of seven patients who had a pathological complete response to antiblastic drugs showed p53 aberrations, whereas 18 (82%) of 22 cases with partial response and all of the four non-responsive patients scored positive for p53 abnormalities. We also observed that patients with p53 mutations had a significantly shorter progression-free survival than patients with p53-negative tumours (P = 0.05). Taken together, our results strongly suggest that in epithelial ovarian malignancies tumours showing p53 aberrations are significantly less sensitive to chemotherapy and more aggressive than those with functional p53. Thus, a routine analysis of this gene could have profound implications for the treatment of ovarian cancer.

Gadducci A, Ferdeghini M, Cosio S, Fanucchi A, Cristofani R, Genazzani AR. The clinical relevance of serum CYFRA 21–1 assay in patients with ovarian cancer. Int J Gynecol Cancer 2001;11:277–282. CYFRA 21–1 assay, which detects serum fragments of cytokeratin 19, has been widely assessed as a serum marker of several malignancies. Preoperative serum CYFRA 21–1 levels were retrospectively measured in 60 patients with ovarian cancer and in 59 control patients with benign ovarian disease. CYFRA 21–1 levels were also serially measured in 90 serum samples drawn from patients with advanced (FIGO stage III-IV) ovarian cancer followed after surgery and chemotherapy. Preoperative serum CYFRA 21–1 levels were higher in patients with ovarian cancer compared with controls (median, range = 2.6, 0.1–51.4 ng/ml versus 0.4, 0.0–3.6 ng/ml, P < 0.0001), and among the former, antigen values were higher in the 39 patients with advanced-stage than in the 21 patients with early (FIGO stage I-II) disease (P < 0.0001). In advanced ovarian cancer patients, the 25%, 50%, and 75% quantiles of preoperative CYFRA 21–1 levels were 1.9, 4.8 and 14.4 ng/ml, respectively. Preoperative CYFRA 21–1 levels were lower in the 11 patients who achieved a pathologic complete response at second-look compared with those who had clinically or surgically detectable persistent disease after first-line chemotherapy (median, range 1.9, 0.6–9.2 ng/ml versus 10.2, 0.1–51.4 ng/ml, P = 0.007). The pathologic complete response rate was significantly greater in patients with low preoperative CYFRA 21–1 levels compared with those with elevated CYFRA 21–1 levels at any cut-off limit for the antigen (1.9,4.8 and 14.4 ng/ml). However, Cox regression analysis failed to detect a significant association between preoperative CYFRA 21–1 assay and survival. As for the follow-up of advanced ovarian cancer patients, CYFRA 21–1 levels were higher in the 42 samples drawn from patients with clinically detectable disease compared with the 48 specimens collected from patients with no clinical evidence of disease (median, range = 1.15,0.3–40.7 ng/ml versus 0.4,0.1–9.1 ng/ml, P < 0.0001). In conclusion, preoperative serum CYFRA 21–1 assay appears to be predictive of response to chemotherapy, but not prognostic of survival, for patients with advanced ovarian cancer. Moreover, the serial measurement of CYFRA 21–1 levels might have a potential clinical relevance for the assessment of disease status in patients followed after surgery and chemotherapy.