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Consistent with the Plan-Do-Check-Act (PDCA) design of ISO 9001:2015, performance evaluation of policies pertaining to the University's main functions, i.e., instruction, research, and extension, should be pursued, especially for a newly implemented policy. Small Private Online Courses (SPOCs) at Bulacan State University were crafted, developed, and enhanced not only in compliance with the demands of continuing education but also to suit the standard of learning that is equal to classroom instruction catered physically. Whether these courses became effective and efficient within the duration of implementation remains to be determined. In the hope of having a fair and honest assessment that will lead towards relevant refinement of offering SPOCs, this mixed method of research undertaking aims to re-examine its efficiency and effectiveness, specifically, the learnings, issues and challenges encountered by the faculty members and students when using SPOC as modality. The survey questionnaire and interview questions were developed and validated and the interview among faculty members were face to face while the survey questionnaire for the SPOC students was through Google form for answering online, and the respondents were five thousand and eight students and twenty-five faculty members were interviewed. The findings indicate the factors that may impede the success of the implementation of SPOCs, aside from personal logistic challenges, the lack of discipline to manage time and sustain the interest in a given lesson are problems that require attention and further innovation. While connectivity can be identified as a personal logistic challenge, it can also be a challenge on the part of the University. The problem of connectivity may be seen as an opportunity for the University to create its own Learning Management System that can be customized to suit fit according to bandwidth, accessible and affordable to students. It can be concluded that SPOC is a promising learning platform in a world where hybrid interactions are highly relevant and can help save a lot of time and resources which brings in the recommendation to revisit, redesign, and recalibrate it for the ever-changing landscape of education. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is the deadliest gynecological malignancy worldwide, and the biggest issue faced by patients is disease relapse after primary treatment. Understanding up front how patients will respond to therapy is an important and compelling challenge. On these premises, our goal was to understand if a simple blood sample can give us this information, before the patients start chemotherapy. We determined that circulating extracellular vesicles isolated at diagnosis can distinguish between patients who will respond differently to the treatment. These results, if corroborated, will pave the way for a novel, much needed predictive marker of response. Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy. [ABSTRACT FROM AUTHOR]

Some low-grade oligodendrogliomas may be made up of proliferating glial progenitor cells blocked in ability to differentiate based on new research. Malignant gliomas have acquired other mutations as well. Chronic autocrine PDGF signaling can promote a proliferating population of glial precursors potentially adequate to bring on gliomagenesis.

Background: Early detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early-stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen-autoantibody (Ag-AAb) complexes have received relatively little attention.Methods: Luminex-based immunoassays were used to measure human epididymis protein 4 (HE4), anti-HE4 autoantibody, and HE4 Ag-AAb complexes in sera from patients with early- (n = 73) and late-stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study.Results: At 98% specificity for healthy, asymptomatic women, 7% of patients with early-stage (I/II) ovarian cancer and 4% of patients with late-stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag-AAb complexes were detected in sera from 38% of early-stage cases and 31% of late-stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag-AAb complexes and CA 125 levels in early-stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag-AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early-stage patients (P = .039). HE4 Ag-AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time.Conclusions: HE4 Ag-AAb complexes could complement CA 125 in detecting a higher fraction of early-stage ovarian cancers. [ABSTRACT FROM AUTHOR]

Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher’s exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations. Methods: The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor α (ERα) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences. Results: KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ERα (P G 0.001) and progesterone receptor (P = 0.001). Although total ERα is decreased in KRas mutant cells, phospho-ERα S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ERα S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wildtype cells, phospho-ERK1/2 and phospho-p90RSK were substantially increased in KRas mutants. KRas mutant EC tumor specimens showed similar changes, with increased phospho-ERα S118 and phospho-ERα S167 compared with wild-type EC tumors. Conclusions: MEK inhibition in KRas mutant cells results in activation of ER signaling and prevents the abrogation of signaling through ERK1/2 and p90RSK that is achieved in KRas wild-type EC cells. Combination therapy with MEK inhibition plus antiestrogen therapy may be necessary to improve response rates in patients with KRas mutant EC. Key Words: Endometrial cancer, Estrogen signaling, KRas, MEK inhibitor [ABSTRACT FROM AUTHOR]

Objectives: Obesity is a major risk factor for endometrial cancer. We evaluated whether obesity exacerbates progression of endometrial hyperplasia (EH) using the PRCre/+ PTENflox/+ mouse model and examined if the type 2 diabetes drug, metformin, could prevent EH. Methods: Twenty obese (PRCre/+ PTENflox/+) mice were maintained on a high-fat diet, while 20 lean mice ate a matching low-fat diet. Ten mice from each group received metformin (1,000 mg/day) in drinking water. Mice were euthanized at 26 weeks. Uterine tissue was scored for degree of EH. Immunohistochemical staining for Ki67 was used to evaluate cellular proliferation. Markers of PI3K/AKT/mTOR activity were evaluated by immunohistochemistry using activation-specific antibodies. Serum adiponectin was quantified by ELISA. Results: Obesity had no effect on the extent of EH in (PRCre/+ PTENflox/+) mice. While metformin significantly altered circulating adiponectin levels in obese and lean animals, it had no effect on EH. There were no differences in endometrial proliferation as measured by Ki67 staining. Neither obesity nor metformin altered PI3K/AKT/mTOR activity in these animals. Conclusions: Weight and metformin did not affect the severity of EH resulting from PTEN inactivation. Alternative mouse models of early endometrial cancer are required for preclinical cancer prevention studies. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a need for additional marker(s) to detect early-stage ovarian cancer that would augment the performance of CA125. Herein, we report a polyamine signature that is detected in the blood and that has value for detecting ovarian cancers at an early stage. The polyamine signature was able to complement CA125 in identifying more ovarian cancer cases that would have been missed by CA125 alone. Our validation of a polyamine signature provides compelling evidence for the value of blood polyamine metabolites as markers for ovarian cancer detection. MYC is an oncogenic driver in the pathogenesis of ovarian cancer. We previously demonstrated that MYC regulates polyamine metabolism in triple-negative breast cancer (TNBC) and that a plasma polyamine signature is associated with TNBC development and progression. We hypothesized that a similar plasma polyamine signature may associate with ovarian cancer (OvCa) development. Using mass spectrometry, four polyamines were quantified in plasma from 116 OvCa cases and 143 controls (71 healthy controls + 72 subjects with benign pelvic masses) (Test Set). Findings were validated in an independent plasma set from 61 early-stage OvCa cases and 71 healthy controls (Validation Set). Complementarity of polyamines with CA125 was also evaluated. Receiver operating characteristic area under the curve (AUC) of individual polyamines for distinguishing cases from healthy controls ranged from 0.74–0.88. A polyamine signature consisting of diacetylspermine + N-(3-acetamidopropyl)pyrrolidin-2-one in combination with CA125 developed in the Test Set yielded improvement in sensitivity at >99% specificity relative to CA125 alone (73.7% vs 62.2%; McNemar exact test 2-sided P: 0.019) in the validation set and captured 30.4% of cases that were missed with CA125 alone. Our findings reveal a MYC-driven plasma polyamine signature associated with OvCa that complemented CA125 in detecting early-stage ovarian cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyper-insulinemia and insulin resistance. In this study, we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen. STUDY DESIGN: Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with streptozotocin, or modulated by metformin treatment. The number of BrdU-incorporated cells, estrogen-dependent proliferative and antiproliferative gene expression, and activation of mTOR and ERK1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro. RESULTS: Streptozotocin lowered circulating insulin levels in obese rats and decreased the number of BrdU-labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulin-sensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRβ/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose-dependent manner. CONCLUSION: These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women. [ABSTRACT FROM AUTHOR]

Harnessing the immune response to tumor antigens in the form of autoantibodies, which occurs early during tumor development, has relevance to the detection of cancer at early stages. We conducted an initial screen of antigens associated with an autoantibody response in serous ovarian cancer using recombinant protein arrays. The top 25 recombinants that exhibited increased reactivity with cases compared to controls revealed TP53 and MYC, which are ovarian cancer driver genes, as major network nodes. A mass spectrometry based independent analysis of circulating immunoglobulin (Ig)-bound proteins in ovarian cancer and of ovarian cancer cell surface MHC-II bound peptides also revealed a TP53–MYC related network of antigens. Our findings support the occurrence of a humoral immune response to antigens linked to ovarian cancer driver genes that may have utility for early detection applications. [ABSTRACT FROM AUTHOR]

Gliomas are the most common primary malignant brain tumours and are classified into four clinical grades, with the most aggressive tumours being grade 4 astrocytomas (also known as glioblastoma multiforme; GBM). Frequent genetic alterations in GBMs (refs 2-5) result in stimulation of common signal transduction pathways involving Ras, Akt and other proteins. It is not known which of these pathways, if any, are sufficient to induce GBM formation. Here we transfer, in a tissue-specific manner, genes encoding activated forms of Ras and Akt to astrocytes and neural progenitors in mice. We found that although neither activated Ras nor Akt alone is sufficient to induce GBM formation, the combination of activated Ras and Akt induces highgrade gliomas with the histological features of human GBMs. These tumours appear to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs (ref. 11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease. [ABSTRACT FROM AUTHOR]

Early detection of ovarian cancer promises to reduce mortality. While serum CA125 can detect more than 60% of patients with early stage (I–II) disease, greater sensitivity might be observed with a panel of biomarkers. Ten protein antigens and 12 autoantibody biomarkers were measured in sera from 76 patients with early stage (I–II), 44 patients with late stage (III–IV) ovarian cancer and 200 healthy participants in the normal risk ovarian cancer screening study. A four-biomarker panel (CA125, osteopontin (OPN), macrophage inhibitory factor (MIF), and anti-IL-8 autoantibodies) detected 82% of early stage cancers compared to 65% with CA125 alone. In early stage subjects the area under the receiver operating characteristic curve (AUC) for the panel (0.985) was significantly greater (p < 0.001) than the AUC for CA125 alone (0.885). Assaying an independent validation set of sera from 71 early stage ovarian cancer patients, 45 late stage patients and 131 healthy women, AUC in early stage disease was improved from 0.947 with CA125 alone to 0.974 with the four-biomarker panel (p = 0.015). Consequently, OPN, MIF and IL-8 autoantibodies can be used in combination with CA125 to distinguish ovarian cancer patients from healthy controls with high sensitivity. Osteopontin appears to be a robust biomarker that deserves further evaluation in combination with CA125. [ABSTRACT FROM AUTHOR]

Despite similar histologic appearance amongst high-grade serous ovarian cancers (HGSOC), anecdotally there are differences in gross appearance. However, no systematic framework to classify morphologic differences exists. Therefore, we aimed to determine whether high-grade serous ovarian cancers (HGSOC) can be reliably divided into distinct gross morphologic subtypes and to assess clinical outcomes and molecular features of these subtypes. A retrospective review was performed of video-recordings from patients who underwent laparoscopic assessment of disease burden prior to primary debulking surgery (PDS) or neoadjuvant chemotherapy (NACT). Video recordings were reviewed by at least 2 physicians. A total of 4 sites (diaphragm, omentum, peritoneum, and pelvis) were assessed and classified as type I (deep, infiltrative disease with distortion of surrounding tissue) or type II (superficial, exophytic disease bordered by normal tissue). Tumor tissues from 16 of these chemotherapy-naïve patients were analyzed by multi-platform omics (RNA sequencing, proteomics). Clinical outcomes were assessed utilizing a prospectively collected database and compared by morphology using t-test or Fisher's exact test. Of the 99 evaluable patients, 60 exhibited uniform morphology at all involved metastatic sites (65% type I and 35% type II), and 81 exhibited a predominating morphology (58% type I and 42% type II). A total of 164 images were reviewed by a third physician with 83.5% inter-rater concordance (κ=0.6446). Patients with uniform type 1 (n=34)tumor morphology were more likely to exhibit an excellent response to NACT (defined as radiologic or CA-125 complete response) than those with type II (n=16) tumor morphology (47% vs 18%, p=0.13). Patients with type II predominant tumor morphology had a significantly higher estimated blood loss at the time of interval debulking surgery (p=0.008) as well as longer operative time (p=0.03) compared with type I tumor morphology. Patients with complete type II morphology were more likely to have a modified Fagotti score of <8 (p=0.026), and thus were more likely to be triaged to PDS. On histopathologic review of 7 type I cases and 4 type II cases, no obvious histo-pathological pattern dominated either type. We identified distinct molecular differences between the 2 types, including increased TGF-β expression in type I and increased MYC expression in type II. Type I tumors seem to have abundant stroma and are immunologically active, whereas type II tumors seem to be dominated by cancer cells, have little stroma, and are immunologically cold. There are at least two distinct gross morphological patterns of HGSOC with unique molecular differences and responses to chemotherapy. These findings could have major clinical implications for tailored therapeutic strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Objective. : STK15 is a serine threonine kinase which assists chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. We hypothesized that STK15 polymorphisms might modulate the risk of uterine cancer. Methods. : We used a hospital-based case–control study to assess the association between STK15 polymorphisms and risk of uterine cancer. Cases and controls were matched on age, race, and smoking status. Two common STK15 single nucleotide polymorphisms (SNPs), F31I (T/A), and V57I (G/A), were genotyped. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using unconditional logistic regression analysis. Results. : A total of 193 women with uterine cancer and 218 controls were genotyped for both SNPs. After adjustment for age, race, and smoking status for the F31I SNP, the homozygous variant genotype (AA) was associated with a significantly increased uterine cancer risk (OR 10.2; 95% CI 2.23–46.5). Individuals with the heterozygous genotype (TA) and a history of tobacco use also exhibited an increased risk for uterine cancer (OR 2.63; 95% CI 1.20–5.76). For the V57I SNP, neither the homozygous (AA) nor the heterozygous (GA) variant genotypes were associated with significantly altered risk for uterine cancer (OR 0.76; 95% CI 0.18–3.25 and OR 0.88; 95% CI 0.52–1.49). Conclusion. : Our study demonstrates that STK15 F31I SNP is associated with an increased risk for uterine cancer. Confirmation of this pilot study is needed in a larger case–control population to evaluate this genetic variant with other known risk factors for uterine cancer. [Copyright &y& Elsevier]