Dextran-based nanoparticles with 5-FU-conjugated polymethacrylate segments for drug delivery: Synthesis of amphiphilic graft copolymers by mechanochemical solid-state polymerization and characterization.

Dextran (Dx) is a biodegradable and biocompatible polysaccharide, thus promising as a drug delivery carrier for tumor therapy. Herein, we applied mechanical energy to a high molecular weight Dx to control its molecular weight and simultaneously generate mechanoradicals. The solid-state polymerization of methacrylate- or methacrylamide derivatives initiated with Dx mechanoradicals showed polymer conversion of >95 %, yielding Dx-based graft copolymers with molecular weights of approximately 30,000 g mol-1. The Dx-based graft copolymers with hydrophobic segments formed nanoparticles with a particle size of 25-35 nm in an aqueous solution. The anti-pancreatic tumor drug 5-fluorouracil (5-FU) was covalently conjugated onto the hydrophobic segments of the amphiphilic Dx, and the nanoparticles were also prepared. The drug release profile from 5-FU-conjugated nanoparticles corresponded well to the Korsmeyer-Peppas model applied to drug release from matrix substrates, and was also immensely predicted by the Logistic and Gompertz curves. The 5-FU-conjugated nanoparticles showed cytotoxicity against the pancreatic adenocarcinoma cell lines (BxPC-3) that were not significantly inferior to the 5-FU positive group. Furthermore, the fluorescein-labeled nanoparticles internalized into BxPC-3 within 6 h and actively migrated into the cytosol. These results suggest that Dx-based graft copolymers with hydrophobic segments might be used to enhance therapeutic activity.

Case Report: A Very Low Birth Weight Female Infant With Congenital Bilateral Periventricular Leukomalacia, Born to a Mother With Coronavirus Disease 2019.

A 26-year-old primipara woman with COVID-19 performed an emergency Cesarean section due to further hypoxemia at 28 weeks 5/7 days gestation. The female neonate was born weighing 1,347 gram with an Apgar score of four at 1 min, three at 5 min, and eight at 10 min. RT-PCR from nasopharyngeal swabs for COVID-19 were performed at birth, 24 h, and 48 h after birth, all of which were negative. On head ultrasound bilateral cystic lesions were found in the anterior horn of the lateral ventricles at birth. A brain magnetic resonance imaging (MRI) test at 56 days of life (corrected 36 weeks and 6/7 days) revealed cystic lesions with T1 low signal, T2 high signal, and T2 Flair high signal around the anterior horn of the lateral ventricle and We diagnose it as Grade 2 periventricular leukomalacia (PVL). She was discharged on day 64 of life, with no abnormality on exam. While the majority of neonates born to women with COVID-19 during pregnancy have favorable outcome, we report a case of a neonate with Grade 2 periventricular leukomalacia and this should prompt clinicians to monitor fetal cerebral function and structure shortly after birth.

PET/MRI is useful for early detection of pelvic insufficiency fractures after radiotherapy for cervical cancer.

Radiotherapy (RT) is used to manage cervical cancer, and pelvic insufficiency fracture (PIF) is known as a late complication of RT. The present study identified risk factors for PIF after radiotherapy for cervical cancer, and investigated its incidence rate. It also considered the usefulness of positron emission tomography/magnetic resonance imaging (PET/MRI) in PIF diagnosis. A total of 149 patients with cervical cancer who received definitive or adjuvant RT with/without concurrent chemotherapy between January 2013 and December 2018 were investigated in the present study and followed up for more than one month after RT at Kobe University Hospital. The median follow-up period was 32 months (range, 1-87 months), and the median age of all patients was 66 years (age range, 34-90 years). Computed tomography (CT), MRI, PET/CT or PET/MRI were used for image examination. Among the 149 patients, 31 (20.8%) developed PIF. The median age of these patients was 69 years (age range, 44-87 years). Univariate analysis using the log-rank test demonstrated that age (≥60 years) was significantly associated with PIF. The median maximum standardized uptake value of PIF sites on PET/CT was 4.32 (range, 3.04-4.81), and that on PET/MRI was 3.97 (range, 1.21-5.96) (P=0.162). Notably, the detection time of PIF by PET/MRI was significantly earlier compared with PET/CT (P<0.05). The incidence of PIF after RT for cervical cancer was 20.8%, and age was significantly associated with risk factors for such fractures. Taken together, these results suggest that PET/MRI, which offers the advantage of decreased radiation exposure to the patient, is useful for diagnosing PIF and can detect it earlier than PET/CT imaging.

A Case of Significant Response to Olaparib in a Patient with Primary Peritoneal Carcinosarcoma Diagnosed by Laparoscopic Surgery.

Primary peritoneal carcinosarcomas which arise from extragenital locations are extremely rare. Carinosarcomas contain both carcinomatous and sarcomatous elements and can be mainly detected in the female genital tract. We herein report a case of primary peritoneal carcinosarcoma diagnosed by laparoscopic surgery and treated with olaparib. A 62-year-old woman referred to our hospital due to abdominal distension. From imaging findings, we suspected advanced primary peritoneal carcinoma, and laparoscopic surgery was thereafter performed. The pathological diagnosis was carcinosarcoma, and the patient received chemotherapy with docetaxel and carboplatin. After three cycles of chemotherapy, the interval debulking surgery was attempted but resulted in suboptimal results. Because the bilateral ovaries were observed with a normal size and normal findings, we considered that the most likely diagnosis was primary peritoneal carcinosarcoma. After the additional chemotherapy and a 6-month observation period, the tumor relapsed. The patient received chemotherapy again, and the peritoneal carcinosarcoma was judged to be a platinum-sensitive tumor. Oral administration of olaparib was thus initiated. Although a dose reduction was needed due to anemia, olaparib was effective, and the patient could continue the drug for another 7 months. This is the first report of primary peritoneal carcinosarcoma treated with olaparib and shows that it could be a treatment option for platinum-sensitive tumors.

Risk factors for deep venous thrombosis in women with ovarian cancer.

We aim to clarify the incidence of deep venous thrombosis (DVT) before treatment in women with ovarian cancer and identify risk factors for DVT.In this prospective study, 110 women underwent venous ultrasonography before cancer treatment and D-dimer levels were measured. We investigated factors predicting DVT by logistic regression.DVT was detected in 25 of 110 women (22.7%) and pulmonary thromboembolism was coexisted in 2 women (1.8%). A total of 21 women (84.4%) with DVT were asymptomatic. D-dimer levels in women with DVT (median, 10.9; range, <0.5-98.2 µg/mL) were significantly higher than those in women without DVT (2.0; <0.5-60.8 µg/mL; P < .01). When 10.9 µg/mL was used as a cutoff value for D-dimer levels to predict DVT, specificity, sensitivity, and positive and negative predictive values were 92.9%, 52.0%, 68.4%, and 86.8%, respectively. The multivariate analysis demonstrated that D-dimer level (odds ratio [OR], 19.7; 95% confidence interval [CI], 5.89-76.76) and clear cell histology (OR, 7.1; 95% CI, 2.12-25.67) were independent factors predicting DVT.Asymptomatic DVT occurred with great frequency before treatment in patients with ovarian cancer. High D-dimer level and clear cell pathology is associated with a higher DVT risk.

Relaxin has anti-apoptotic effects on human trophoblast-derived HTR-8/SV neo cells.

The study was conducted to evaluate the effects of human relaxin on apoptosis in the human trophoblast derived HTR-8/SV neo cell line, which is a possible model of human extravillous trophoblasts (EVTs). HTR-8/SV neo cells, cultured in phenol red free RPMI1640 medium, were treated with different doses of human recombinant (rH2) relaxin in serum-deprived conditions. RT-PCR was used for evaluating relaxin receptor: RXFP1 and RXFP2 expression in HTR-8/SV neo cells. The cell death was examined by TUNEL assay. Furthermore, we investigated caspase-3, cleaved PARP and Bcl-2 expressions by Western blot analysis to recognize the translational effects of anti-apoptotic and pro-apoptotic proteins. RXFP1 and RXFP2 mRNA expression was observed in HTR-8/SV neo cells. Compared with untreated control cultures, treatment with rH2 relaxin, decreased TUNEL-positive rate in HTR-8/SV neo cells was observed. Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 and cleaved PARP, but in contrast increased Bcl-2 expression in those cells. These results suggest that rH2 relaxin has anti-apoptotic effects on HTR8/SV neo cells by decreasing pro-apoptotic caspase-3 and cleaved PARP expression and up-regulating anti-apoptotic Bcl-2 expression.

Recombinant H2 relaxin inhibits apoptosis and induces cell proliferation in cultured leiomyoma cells without affecting those in cultured normal myometrial cells.

OBJECTIVE: To evaluate the effects of human relaxin on proliferation and apoptosis in cultured human uterine leiomyoma cells and normal myometrial cells. DESIGN: In vitro experiment. SETTING: Research laboratory at Kobe University Graduate School of Medicine. PATIENT(S): Nine patients undergoing hysterectomy for uterine leiomyoma. INTERVENTION(S): Cultured leiomyoma cells and normal myometrial cells were treated with human recombinant (rH2) relaxin. MAIN OUTCOME MEASURE(S): Human relaxin receptor LGR7 expressions in cultured leiomyoma cells and myometrial cells were evaluated by immunocytochemical staining. Cell proliferation, proliferating cell nuclear antigen-positive rate, and TUNEL-positive rate were assessed by MTS assay, immunocytochemistry, and TUNEL assay, respectively. Caspase-3 expression was evaluated by Western blot analysis. RESULT(S): LGR7 expression was observed both in cultured human leiomyoma cells and myometrial cells. Compared with untreated control cultures, treatment with rH2 relaxin increased the number of viable cultured leiomyoma cells and the proliferating cell nuclear antigen-positive rate in those cells but not in myometrial cells. Moreover, treatment with rH2 relaxin decreased the TUNEL-positive rate in cultured leiomyoma cells but not in myometrial cells. Similarly, Western blot analysis revealed that treatment with rH2 relaxin decreased the expression of caspase-3 in cultured leiomyoma cells but not in myometrial cells. CONCLUSION(S): These results suggest that rH2 relaxin selectively inhibits apoptosis by down-regulating caspse-3 expression and induces proliferation in cultured human leiomyoma cells without affecting apoptosis or proliferation in normal myometrial cells.