MicroRNA Nano-Shuttles: Engineering Extracellular Vesicles as a Cutting-Edge Biotechnology Platform for Clinical Use in Therapeutics.

Extracellular vesicles (EVs) are nano-sized, membranous transporters of various active biomolecules with inflicting phenotypic capabilities, that are naturally secreted by almost all cells with a promising vantage point as a potential leading drug delivery platform. The intrinsic characteristics of their low toxicity, superior structural stability, and cargo loading capacity continue to fuel a multitude of research avenues dedicated to loading EVs with therapeutic and diagnostic cargos (pharmaceutical compounds, nucleic acids, proteins, and nanomaterials) in attempts to generate superior natural nanoscale delivery systems for clinical application in therapeutics. In addition to their well-known role in intercellular communication, EVs harbor microRNAs (miRNAs), which can alter the translational potential of receiving cells and thus act as important mediators in numerous biological and pathological processes. To leverage this potential, EVs can be structurally engineered to shuttle therapeutic miRNAs to diseased recipient cells as a potential targeted 'treatment' or 'therapy'. Herein, this review focuses on the therapeutic potential of EV-coupled miRNAs; summarizing the biogenesis, contents, and function of EVs, as well as providing both a comprehensive discussion of current EV loading techniques and an update on miRNA-engineered EVs as a next-generation platform piloting benchtop studies to propel potential clinical translation on the forefront of nanomedicine.

Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .

Impact of media supplements FGF2, LIF and IGF1 on the genome activity of porcine embryos produced in vitro.

In this article, we focused on the impact of precisely chemically modified FLI maturation medium enriched with fibroblast growth factor 2 (FGF2), leukemia inhibitory factor (LIF), insulin-like growth factor 1 (IGF1), and polyvinyl alcohol (PVA) and its potential to improve the efficiency of in vitro production of porcine embryos. We hypothesized that enhancing the composition of the maturation medium could result in an elevated production of embryos in vitro and can affect EGA. FLI medium resulted in a significantly higher rate of oocyte blastocyst maturation and formation compared to the control DMEM medium. In addition, immunocytochemical labelling confirmed the detection of UBF in 4-cell FLI parthenogenic embryos, suggesting similarities with natural embryo development. Through RNAseq analysis, upregulated genes present in 4-cell FLI embryos were found to play key roles in important biological processes such as cell proliferation, cell differentiation, and transcriptional regulation. Based on our findings, we demonstrated the positive influence of FLI medium in the evaluation of in vitro embryo production, EGA detection, transcriptomic and proteomic profile, which was confirmed by the positive activation of the embryonal genome in the 4-cell stage of parthenogenetically activated embryos.

Arthroscopic biceps tenodesis using press-fit bony plug: a case series study.

PURPOSE: To assess the feasibility, operative time, clinical outcomes, possible complications, and failure rates of all-through arthroscopic biceps tenodesis using press-fit bony plug technique. METHODS: This prospective case series study involved 30 skeletally mature patients with long head of biceps pathology (tendinitis after failure of conservative treatment, subluxation, dislocation, or tendon tears). All patients were followed up for 24 months at least. RESULTS: Twenty-nine patients regained full shoulder and elbow range of motion; one case suffered from reflex sympathetic dystrophy. There was a significant improvement in the constant, ASES, and VAS scores when comparing the pre-operative and post-operative values. The average biceps strength was 96% compared to the opposite healthy side. No cases were complicated by neuro-vascular deficits or failure of the tenodesis. CONCLUSION: Press-fit biceps tenodesis is safe and accessible with low economic demands. We recommend this technique to be used more often when addressing patients with long head of biceps pathologies. REGISTRATION DATA: Registration number: N-1562023. Registration date: June 2022 "Retrospectively registered".

Analysis of the outcomes of three different cross-linking protocols for treatment of paediatric keratoconus: A multicentre randomized controlled trial.

PURPOSE: To analyse long-term outcomes of standard cross-linking (SCXL), accelerated cross-linking (ACXL) and transepithelial cross-linking (TCXL) in the treatment of progressive paediatric keratoconus regarding stability, safety and efficacy. METHODS: This prospective multicentre randomized controlled trial included 97 eyes of 97 paediatric patients with stages I-III ABCD keratoconus grading system, who were randomized into three groups; SCXL group (control group, n = 32; 3 mW/cm2 × 30 min/5.4 J/cm2 ), ACXL (n = 33; 18 mW/cm2 × 5 min/5.4 J/cm2 ) and TCXL (n = 32; 18 mW/cm2 × 5 min/5.4 J/cm2 ). Subjective refraction, uncorrected and corrected visual acuity, keratometry and pachymetry measurements using corneal topography were recorded preoperatively and 1, 2 and 3 years postoperatively. RESULTS: SCXL group exhibited significant successive improvements in the mean visual, refractive and keratometric parameters throughout the entire postoperative 3 years while ACXL group exhibited significant improvements in visual and keratometric parameters in the first postoperative year that remained stable in second and third postoperative years. TCXL group exhibited significant progressive deterioration in all mean parameters compared to SCXL and ACXL (p < 0.0001). Both SCXL and ACXL revealed final 100% success rate with good stability while TCXL revealed final 22% failure rate with keratoconus progression (p < 0.0001). CONCLUSION: SCXL and ACXL were comparable in halting keratoconus progression and achieved good stability and safety; however, SCXL was more efficient than ACXL as it yielded greater significant postoperative mean visual, refractive and keratometric improvements achieving smoother corneal remodelling. Both SCXL and ACXL were much superior to TCXL. SCXL is the best CXL treatment option for paediatric keratoconus while ACXL is a good and effective alternative.

Combining Sunitinib and Bevacizumab for the Management of Advanced Renal Cell Carcinoma: A Phase I/II Trial.

BACKGROUND: Tyrosine kinase inhibitors remain a cornerstone in managing metastatic clear cell renal cell carcinoma (RCC). The 4 weeks on/2 weeks off intermittent sunitinib schedule could result in rebound angiogenesis and tumor progression in the 2-week rest period. We propose using bevacizumab during this period for continuous antiangiogenic effects. METHOD: This was a phase I/II study of patients with advanced clear cell RCC. Sunitinib was given 50 mg daily on a 4-week on/2-week off schedule. Bevacizumab was given on day 29 of each sunitinib cycle. The bevacizumab starting dose was 5 mg/kg, and the dose was escalated to 10 mg if there was no dose-limiting toxicity. The primary endpoints were response rate and progression-free survival (PFS). RESULTS: Twenty-five patients were recruited. The study was closed prematurely because of poor accrual. No dose-limiting toxicity was observed with 5 mg bevacizumab. One patient achieved a complete response, and 12 achieved a partial response (52% response rate). At a median follow-up of 42.2 months (95%, confidence interval (CI) 32.9 to 51.4), the median PFS duration was 16.5 months (95% CI 4.1-28.8), and the median overall survival time was 33.3 months (95% CI 19.4-47.3). Twenty-two patients (88%) had at least one grade 3 or 4 toxicity; the most common were thrombocytopenia (32%), lymphopenia (32%), hypertension (28%), and fatigue (24%). CONCLUSION: Continuous angiogenesis blockade by adding bevacizumab to the sunitinib on/off regimen for advanced RCC yields significant antitumor activity with manageable increased toxicity.

Combined Prophylactic Hyperthermic Intraperitoneal Chemotherapy and Intraoperative Radiotherapy for Localized Gastroesophageal Junction and Gastric Cancer: A Comparative Nonrandomized Study.

BACKGROUND: The peritoneum frequently is the only recurrence site after radical resection of gastric cancer. Data suggest that hyperthermic intraperitoneal chemotherapy (HIPEC) and intraoperative radiotherapy (IORT) reduce peritoneal recurrence and possibly improve survival for patients with resected gastric and serosal involvement. This study aimed to evaluate the efficacy of combining prophylactic HIPEC and IORT after radical resection of localized gastric cancer. METHODS: In this retrospective study, the medical records of adult patients with histologically proven gastric/gastroesophageal adenocarcinoma who underwent radical resection with curative intent were evaluated for recurrence and survival according to whether they received prophylactic HIPEC and IORT. RESULTS: The eligibility criteria were met by 58 patients, 33 of whom underwent prophylactic HIPEC and IORT after radical surgery. Overall, 91% the HIPEC/IORT group and 72% of the surgery-only group had ≤pT3 disease. The median follow-up period was 26.6 months for the HIPEC/IORT group and 50.6 months for the surgery group. Locoregional recurrence occurred for six patients (18.1%) in the HIPEC/IORT group and five patients (20%) in the surgery-only group, with peritoneal metastasis (PM) occurring in respectively three (9%) and six (24%) patients. The median recurrence-free survival (RFS) duration was 23.2 months (95% confidence interval [CI] 6.5-39.9 months) for the HIPEC/IORT group versus 24.8 months (95% CI 0.0-51.1 months) for the surgery-only group (p = 0.88), and the corresponding 5-year overall survival (OS) estimates were 69% and 58%. CONCLUSION: Prophylactic HIPEC and IORT after radical surgery for localized gastric or gastroesophageal cancer did not improve RFS or OS for an unselected group of patients at risk for peritoneal recurrence.

Outcomes of the Q value-based nomogram in managing pediatric versus adult keratoconus: a prospective interventional study.

Background: Keratoconus (KCN) is an ectatic disorder of the cornea characterized by stromal weakness and apical protrusion of the cornea, and is associated with a gradual and painless reduction in visual acuity. KCN in pediatric patients has certain important characteristics, such as a progressive and aggressive nature. We aimed to analyze the visual, refractive, and topographic outcomes of implanting a single 210° arc-length Keraring segment according to a novel, objective, Q value-based nomogram (Q-N) for the treatment of pediatric versus adult KCN. Methods: This prospective, multicenter, non-randomized, open-label trial included 47 eyes of 47 patients who were allocated to one of two groups. The adult group included 33 eyes of patients ≥ 18 years of age, whereas the pediatric group included 14 eyes of patients aged 14 - 17 years. All patients underwent femtosecond laser-assisted implantation of a single 210° arc-length Keraring segment according to the Q-N and were followed up for 6 months. All eyes underwent visual acuity measurement, cycloplegic refraction, and corneal topography at baseline and 6 months after surgery. Results: The study groups were comparable in terms of sex proportions and KCN grades (both P > 0.05). The adult group exhibited significant postoperative improvements in mean uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), sphere, cylinder, spherical equivalent (SE), and Kmax (all P < 0.001) with a mean change of -0.56 logarithm of the minimal angle of resolution (logMAR), - 0.40 logMAR, 3.07 diopters (D), 0.70 D, 3.42 D, and - 5.26 D, respectively. The pediatric group exhibited significant postoperative improvements in mean UDVA, CDVA, sphere, SE, and Kmax (all P < 0.05) with a mean change of - 0.62 logMAR, - 0.34 logMAR, 3.18 D, 3.67 D, and - 5.37 D, respectively. There were no significant differences between the groups in terms of the mean change in visual, refractive, and topographic variables (all P > 0.05). No postoperative complications were observed in either group. Conclusions: Use of the objective Q-N was efficient in the treatment of pediatric KCN, with postoperative improvements in the mean visual, refractive, and topographic parameters, comparable to outcomes in adult keratoconus. Q-N achieved good corneal remodeling with subsequent improvements in visual, refractive, and topographic outcomes in both adult and pediatric patients with keratoconus. To verify our preliminary findings, we recommend further multicenter randomized clinical trials using the Q-N nomogram in a larger sample of pediatric patients with KCN as an adjunct treatment before or after CXL.

Adult-Type Ovarian Granulosa Cell Tumour: Treatment Outcomes From a Single-Institution Experience.

OBJECTIVES:  Ovarian granulosa cell tumour is rare. This study aims to report the clinical characteristics and long-term outcomes of adult-type ovarian granulosa cell tumour (AOGCT) at King Faisal Specialist Hospital and Research Centre (KFSH&RC) and to determine the prognostic factors affecting relapse and survival. METHODS: We retrospectively reviewed patients with AOGCT, from 1988 to 2014, who were treated at our institution. Baseline characteristics, pathological findings, and outcomes were analysed and reported. RESULTS: Sixty-one patients with AOGCT were identified with a median age of 49 years. Median follow-up was 5.0 years (range 2.1-8.2 years). 74% of patients were FIGO (International Federation of Gynecology and Obstetrics) stage I, whereas 7% were stage II, 5% were stage III, and unknown in 14% of the cases. The most common presenting symptoms included abdominal pain (43%) and vaginal bleeding (43%). The majority of patients (38 patients, 62%) were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Five (8%) patients received adjuvant chemotherapy. Sixteen patients (26%) relapsed with a median time to relapse of 5.5 years (0.7-8.1 years). Half of the recurrences (eight patients, 50%) occurred after five years of diagnosis. Five-year overall survival and disease-free survival (DFS) were 93% and 84%, respectively. Factors associated with a high risk of recurrence were the presence of ascites (p=0.000) and elevated preoperative CA 125 level (p=0.048). The overall survival was significantly influenced by the menopausal status (premenopausal 100% vs. postmenopausal 84%; p=0.02), preoperative CA 125 (normal 100% vs. elevated 64%; p=0.005), ascites (present 33% vs. absent 100%; p=0.000), and age (<55 years 100% vs. ≥ 55 years 77%; p= 0.002). CONCLUSION:  This study confirms a good outcome for patients with AOGCT. They require long-term follow-up as late recurrences can occur many years post definitive therapy. The presence of ascites and elevated preoperative CA 125 levels were associated with a higher risk of recurrence and poor prognosis. Outcomes appear unaffected by fertility-sparing surgery or adjuvant chemotherapy.

Outcomes of Patients with Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil beyond the Second Line: A Multicenter Retrospective Study from Saudi Arabia.

Background: The outcome of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) beyond the second-line has not been studied in Saudi Arabia. Therefore, this multicenter retrospective analysis was conducted to evaluate the efficacy of FTD/TPI. Methods: This multicenter retrospective analysis included five centers in Saudi Arabia. FTD/TPI was administered to all the patients beyond the oxaliplatin- and irinotecan-based chemotherapy regimens. The electronic medical records were reviewed, and progression-free survival (PFS) and overall survival (OS) were determined. Results: The study included 100 patients with a mean age of 55.4 ± 11.8 years. The overall response to FTD/TPI was 4%. The median PFS was 4 months (95% confidence interval (CI) 3.487-4.513), and the median OS was 11 months (95% CI, 9.226-12.771). In a Cox regression analysis of the independent predictors for PFS, advanced stage of the disease (P = 0.037; HR, 2.614; and CI, 1.102-7.524), presence of lymph node metastasis (P = 0.018; HR, 3.664; and 95% CI, 1.187-8.650), and >2 metastatic sites (P = 0.020; HR, 1.723; and 95% CI, 1.089-2.727) were independent factors predicting disease progression. The Cox regression analysis confirmed that age ≥ 55 years (P = 0.046; HR, 1.667; and 95%, 1.097-3.100), advanced disease stage (P = 0.044; HR, 1.283; and 95% CI, 1.035-2.940), prior use of adjuvant chemotherapy (P = 0.037; HR, 0.892; and 95% CI, 0.481-0.994), liver metastasis (P = 0.025; HR, 2.015; and 95% CI, 1.091-3.720), >2 metastatic sites (P = 0.038; HR, 1.248; and 95% CI, 1.036-1.846), development of neutropenia after receiving first cycle of FTD/TPI (P = 0.042; HR, 1.505; and 95% CI, 1.064-2.167), and increased number of FTD/TPI cycles (P = 0.002; HR, 0.769; and 95% CI, 0.664-0.891) were independent variables for OS. Conclusion: Treatment with FTD/TPI is feasible and effective in daily clinical practice in Saudi Arabian patients. The risk of progression increased with advanced disease stage, lymph node metastasis, bone metastasis, and metastasis to >2 sites. Age ≥ 55 years, advanced disease stage, liver metastasis, metastasis to >2 sites, neutropenia after the first cycle of FTD/TPI, and increased number of FTD/TPI cycles were independent factors predicting mortality.

Spatial Distribution, Contamination Levels, and Health Risk Assessment of Potentially Toxic Elements in Household Dust in Cairo City, Egypt.

Urban areas' pollution, which is owing to rapid urbanization and industrialization, is one of the most critical issues in densely populated cities such as Cairo. The concentrations and the spatial distribution of fourteen potentially toxic elements (PTEs) in household dust were investigated in Cairo City, Egypt. PTE exposure and human health risk were assessed using the USEPA's exposure model and guidelines. The levels of As, Cd, Cr, Cu, Hg, Mo, Ni, Pb, and Zn surpassed the background values. Contamination factor index revealed that contamination levels are in the sequence Cd > Hg > Zn > Pb > Cu > As > Mo > Ni > Cr > Co > V > Mn > Fe > Al. The degree of contamination ranges from considerably to very high pollution. Elevated PTE concentrations in Cairo's household dust may be due to heavy traffic emissions and industrial activities. The calculated noncarcinogenic risk for adults falls within the safe limit, while those for children exceed that limit in some sites. Cairo residents are at cancer risk owing to prolonged exposure to the indoor dust in their homes. A quick and targeted plan must be implemented to mitigate these risks.

Outcomes and Prognostic Factors of Metastatic Gastric Cancer: A Single-Center Experience.

Background Gastric cancer (GC) carries a poor survival outcome despite the availability of many therapeutic agents active in treatment. In this study, we aimed to evaluate the survival outcomes of metastatic GC treatment from a single center in Saudi Arabia and identify possible prognostic factors. Methodology Data on patients diagnosed with metastatic GC between December 2009 and November 2013 were collected and analyzed. Results During this period, 41 patients were diagnosed with a median age at diagnosis of 52 years, and 56.1% of patients were males. Only four (9.2%) patients had human epidermal growth factor receptor 2 overexpression. Overall, 83% were treated with oxaliplatin-based chemotherapy. The median progression-free survival (PFS) and overall survival (OS) were 4.1 and 15.4 months, respectively. Female sex was an independent prognostic factor for better PFS and OS. Normal lymphocyte count was associated with improved PFS. Conclusions Our study highlights poor outcomes in patients with metastatic GC and the need for further research in this field.

High AUF1 level in stromal fibroblasts promotes carcinogenesis and chemoresistance and predicts unfavorable prognosis among locally advanced breast cancer patients.

BACKGROUND: Locally advanced breast cancer (LABC), the most aggressive form of the disease, is a serious threat for women's health worldwide. The AU-rich RNA-binding factor 1 (AUF1) promotes the formation of chemo-resistant breast cancer stem cells. Thereby, we investigated the power of AUF1 expression, in both cancer cells and their stromal fibroblasts, as predictive biomarker for LABC patients' clinical outcome following neoadjuvant treatment. METHODS: We have used immunohistochemistry to assess the level of AUF1 on formalin-fixed paraffin-embedded tissues. Immunoblotting was utilized to show the effect of AUF1 ectopic expression in breast stromal fibroblasts on the expression of various genes both in vitro and in orthotopic tumor xenografts. Cytotoxicity was evaluated using the WST1 assay, while a label-free real-time setting using the xCELLigence RTCA technology was utilized to assess the proliferative, migratory and invasive abilities of cells. RESULTS: We have shown that high AUF1 immunostaining (≥ 10%) in both cancer cells and their adjacent cancer-associated fibroblasts (CAFs) was significantly associated with higher tumor grade. Kaplan-Meier univariate analysis revealed a strong correlation between high AUF1 level in CAFs and poor patient's survival. This correlation was highly significant in patients with triple negative breast cancer, who showed poor disease-free survival (DFS) and overall survival (OS). High expression of AUF1 in CAFs was also associated with poor OS of ER+/Her2- patients. Similarly, AUF1-positive malignant cells tended to be associated with shorter DFS and OS of ER+/Her2+ patients. Interestingly, neoadjuvant therapy downregulated AUF1 to a level lower than 10% in malignant cells in a significant number of patients, which improved both DFS and OS. In addition, ectopic expression of AUF1 in breast fibroblasts activated these cells and enhanced their capacity to promote, in an IL-6-dependent manner, the epithelial-to-mesenchymal transition and stemness processes. Furthermore, these AUF1-expressing cells enhanced the chemoresistance of breast cancer cells and their growth in orthotopic tumor xenografts. CONCLUSIONS: The present findings show that the CAF-activating factor AUF1 has prognostic/predictive value for breast cancer patients and could represent a great therapeutic target in order to improve the precision of cancer treatment.

Capecitabine Monotherapy as Palliative Treatment for Patients with Recurrent/Metastatic Nasopharyngeal Cancer.

Background: Numerous chemotherapeutic agents have antitumor activity in recurrent/metastatic (R/M) nasopharyngeal cancer (NPC). Evidence of capecitabine's effectiveness as monotherapy is limited. Capecitabine tolerability in solid malignancies has ethnic and geographical variability. We investigated capecitabine's tolerability and identified potential prognostic factors for clinical outcomes in R/M NPC. Methods: A consecutive retrospective cohort of patients who received capecitabine as the first recurrence, second- or third-line monotherapy for metastatic NPC (2011-2019) was reviewed concerning patient characteristics, pathological features, treatment outcomes, and toxicity. Results: Fifty-one patients were eligible (median age at diagnosis: 42 [35.5-52.5] years). Most patients (78.4%) tolerated a standard oral dose of 1,250 mg/m2 capecitabine (2 weeks on/1 week off) in a 3-week cycle. The objective response rate was 49%, and the disease control rate was 66.7%, with a median response duration of 6.2 months. Hand-foot syndrome (HFS) was associated with a higher objective response rate (odds ratio, 5.1 [95% confidence interval: 1.18-21.98]; P = 0.02). The median follow-up duration was 17.8 (interquartile range: 7.8-30.4) months. The median (95% confidence interval) progression-free survival and overall survival were 6.6 (4.3-8.8) and 32.7 (25.9-39.5) months, respectively. HFS (P = 0.02), better performance status (P = 0.02), and absence of brain metastasis (P = 0.04) were associated with prolonged progression-free survival. Conclusion: Capecitabine monotherapy is effective and well-tolerated as a palliative treatment for R/M NPC. Despite the lower incidence of HFS in our patients, it remained a favorable prognostic factor for objective response and progression-free survival.

Reliability of Perforator-based UPM Flap for Coverage of Little Finger and Dorsal Hand Defect.

There are different approaches for reconstruction of little finger and dorsal hand defects. The ulnar parametacarpal flap, first introduced by Backhach et al in 1995, is considered a good option for reconstructing such defects. In this study, we elevated this flap on one perforator and applied it as a propeller flap. We then discussed the reliability of this flap and which perforator (the proximal or the distal one) is more reliable. METHODS: This study was carried out on 20 patients with different little finger and dorsal hand defects between June 2017 and March 2019. All defects were covered by perforator-based ulnar parametacarpal flaps. Ten flaps were based on the proximal perforator, whereas the other 10 were based on the distal perforator. RESULTS: With a period of follow-up ranging from 6 months to 1 year, all flaps that were raised on the proximal perforator survived completely, whereas two of 10 flaps raised on the distal perforator showed venous congestion and also one flap showed partial necrosis of the distal one-third due to ischemia. CONCLUSIONS: The perforator based ulnar parametacarpal flap is a reliable option for reconstruction of little finger and dorsal hand defects. It is more reliable when it is raised on the proximal perforator rather than on the distal one.

The Role of MAPK3/1 and AKT in the Acquisition of High Meiotic and Developmental Competence of Porcine Oocytes Cultured In Vitro in FLI Medium.

The developmental potential of porcine oocytes cultured in vitro was remarkably enhanced in a medium containing FGF2, LIF and IGF1 (FLI) when compared to a medium supplemented with gonadotropins and EGF (control). We analyzed the molecular background of the enhanced oocyte quality by comparing the time course of MAPK3/1 and AKT activation, and the expression of genes controlled by these kinases in cumulus-oocyte complexes (COCs) cultured in FLI and the control medium. The pattern of MAPK3/1 activation in COCs was very similar in both media, except for a robust increase in MAPK3/1 phosphorylation during the first hour of culture in the FLI medium. The COCs cultured in the FLI medium exhibited significantly higher activity of AKT than in the control medium from the beginning up to 16 h of culture; afterwards a deregulation of AKT activity occurred in the FLI medium, which was not observed in the control medium. The expression of cumulus cell genes controlled by both kinases was also modulated in the FLI medium, and in particular the genes related to cumulus-expansion, signaling, apoptosis, antioxidants, cell-to-cell communication, proliferation, and translation were significantly overexpressed. Collectively, these data indicate that both MAPK3/1 and AKT are implicated in the enhanced quality of oocytes cultured in FLI medium.

Trastuzumab, Pertuzumab, and Docetaxel as the First Line for HER-2-Positive Metastatic Breast Cancer among Arabs.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER-2) targeted therapy regimens can improve tumor response in HER-2-positive metastatic breast cancer (MBC), with overall survival benefits. OBJECTIVE: We evaluated the efficacy of dual HER-2 blockade combined with chemotherapy for HER-2-positive MBC patients as a first-line therapy in our patient population. PATIENTS AND METHODS: We identified 75 patients at King Faisal Specialist Hospital and Research Center that received trastuzumab, pertuzumab, and docetaxel as a first-line therapy in HER-2 positive MBC in 2013-2016. RESULTS: Median age at diagnosis was 45 years; 54.7% were estrogen receptor (ER)-positive. 10% of patients presented with only bone metastasis. The median follow-up time was 36 months with an objective response rate of 74.7% (complete response [CR] 18.7%; partial response [PR] 56%). The 5-year progression-free survival (PFS) and overall survival (OS) were 21% and 71.9% respectively, with a median PFS of 36 months (95% confidence interval [CI] 23.6-48.4). The 5-year OS for ER-negative and ER-positive patients was 93.9% and 59.4% respectively (p = 0.189); 23 patients experienced grade 1/2 toxicity and 2 patients had grade 3/4 toxicity. In terms of OS and PFS, the site of metastasis did not make any significant difference. CONCLUSIONS: First line pertuzumab, trastuzumab, and docetaxel for HER-2-positive MBC patients was found to be an effective and safe therapy in the Saudi population. This finding was consistent with the results seen in the CLEOPATRA trials.