Explore the vast range of titles available.

Notch signaling is universally conserved in metazoans where it is important for a wide variety of both normal and abnormal physiology. All four mammalian Notch receptors are activated by a conserved mechanism that releases Notch intracellular domains (NICDs) from the plasma membrane to translocate to the nucleus. Once there, NICDs interact through highly conserved ankyrin domains to form head-to-head homodimers on Notch sensitive promoters and stimulate transcription. Due to the highly conserved nature of these Notch ankyrin domains in all four mammalian Notch proteins, we hypothesized that NICDs may also engage in heterodimerization. Our results reveal the presence of two NICD dimerization states that can both engage in homo and heterodimerization. Using a Co-IP approach, we show that all NICD’s can form non-transcriptionally active dimers and that the N4ICD appears to perform this function better than the other NICDs. Using a combination of ChIP analysis and transcriptional reporter assays, we also demonstrate the formation of transcriptionally active heterodimers that form on DNA. In particular, we demonstrate heterodimerization between the N2ICD and N4ICD and show that this heterodimer pair appears to exhibit differential activity on various Notch sensitive promoters. These results illustrate a new diversification of Notch signaling mechanisms which will help us better understand basic Notch function.

Background The field of laparoscopy has undergone several changes to improve the morbidity and cosmesis of laparoscopic surgery. The robotic single-site surgery is the inevitable hybridization of robotic technology with laparoendoscopic single-site surgery. Methods Perioperative information of 12 robotic single-site hysterectomies (R-SSH) were collected to evaluate the surgical feasibility and the possible influence of the body mass index (BMI) and the uterine weight on operative times. Results The mean operative time was 85 ± 33 min (range, 355 to 149 min), the mean docking time was 9 ± 3 min, and the mean console time was 76 ± 33 min. The mean blood loss was 80 ± 18 mL, and the median weight of resected uteri was 220 ± 45 g. No serious postoperative complications occurred. The CUSUM learning curve was observed to consist of two different phases: phase 1 (the initial 6 cases) and phase 2 (the last 6 cases) with significant reduction in operative and console time observed between the two phases. For BMI, no correlation was found with operative times, console times, and docking times, and no correlation was found between uterine weight and operative time. Conclusions This series, identifying two different phases of the learning curve and suggesting that the initial learning phase for the procedure can be achieved after six cases, confirms the feasibility and safety of a robotic approach for single-site hysterectomy. However, the limits of this study mainly rely on the limited casuistic and short follow-up, although the preliminary results appear promising. Larger series and prospective studies comparing R-SSH hysterectomy with standard robotic multiport hysterectomy are necessary to define properly the role of this innovative surgical technique.

The clinical consequences of toxoplasmosis are greatly dependent on the Toxoplasma gondii strain causing the infection. To better understand its epidemiology and design appropriate control strategies, it is important to determine the strain present in infected animals. Serotyping methods are based on the detection of antibodies that react against segments of antigenic proteins presenting strain-specific polymorphic variations, offering a cost-effective, sensitive, and non-invasive alternative to genotyping techniques. Herein, we evaluated the applicability of a panel of peptides previously characterized in mice and humans to serotype sheep and pigs. To this end, we used 51 serum samples from experimentally infected ewes (32 type II and 19 type III), 20 sheep samples from naturally infected sheep where the causative strain was genotyped (18 type II and 2 type III), and 40 serum samples from experimentally infected pigs (22 type II and 18 type III). Our ELISA test results showed that a combination of GRA peptide homologous pairs can discriminate infections caused by type II and III strains of T. gondii in sheep and pigs. Namely, the GRA3-I/III-43 vs . GRA3-II-43, GRA6-I/III-213 vs. GRA6-II-214 and GRA6-III-44 vs. GRA6-II-44 ratios showed a statistically significant predominance of the respective strain-type peptide in sheep, while in pigs, in addition to these three peptide pairs, GRA7-II-224 vs. GRA7-III-224 also showed promising results. Notably, the GRA6-44 pair, which was previously deemed inefficient in mice and humans, showed a high prediction capacity, especially in sheep. By contrast, GRA5-38 peptides failed to correctly predict the strain type in most sheep and pig samples, underpinning the notion that individual standardization is needed for each animal species. Finally, we recommend analyzing for each animal at least 2 samples taken at different time points to confirm the obtained results.

The aim of this work was to identify causes of abortion through laboratory investigations in sheep flocks in Uruguay. One hundred cases of abortion, comprising 58 fetuses, 36 fetuses with their placentas, and 6 placentas were investigated in 2015–2021. Cases were subjected to gross and microscopic pathologic examinations, and microbiological and serological testing for the identification of causes of abortion, including protozoal, bacterial, and viral pathogens. An etiologic diagnosis was determined in 46 (46%) cases, including 33 (33%) cases caused by infectious pathogens, as determined by the detection of a pathogen along with the identification of fetoplacental lesions attributable to the detected pathogen. Twenty-seven cases (27%) were caused by Toxoplasma gondii , 5 (5%) by Campylobacter fetus subspecies fetus , and 1 (1%) by an unidentified species of Campylobacter . Fourteen cases (14%) had inflammatory and/or necrotizing fetoplacental lesions compatible with an infectious etiology. Although the cause for these lesions was not clearly identified, T. gondii was detected in 4 of these cases, opportunistic bacteria ( Bacillus licheniformis, Streptococcus sp.) were isolated in 2 cases, and bovine viral diarrhea virus 1 subtype i (BVDV-1i) was detected in another. Campylobacter jejuni was identified in 1 (1%) severely autolyzed, mummified fetus. BVDV-2b was identified incidentally in one fetus with an etiologic diagnosis of toxoplasmosis. Microscopic agglutination test revealed antibodies against ≥1 Leptospira serovars in 15/63 (23.8%) fetuses; however, Leptospira was not identified by a combination of qPCR, culture, fluorescent antibody testing nor immunohistochemistry. Neospora caninum, Chlamydia abortus, Chlamydia pecorum, Coxiella burnetii and border disease virus were not detected in any of the analyzed cases. Death was attributed to dystocia in 13 (13%) fetuses delivered by 8 sheep, mostly from one highly prolific flock. Congenital malformations including inferior prognathism, a focal hepatic cyst, and enterohepatic agenesis were identified in one fetus each, the latter being the only one considered incompatible with postnatal life. Toxoplasmosis, campylobacteriosis and dystocia were the main identified causes of fetal losses. Despite the relatively low overall success rate in establishing an etiologic diagnosis, a systematic laboratory workup in cases of abortion is of value to identify their causes and enables zoonotic pathogens surveillance.

The aim of this paper was to assess hypersensitivity reactions in 69 patients who received carboplatin (CBDCA) retreatment for recurrent ovarian cancer. Hypersensitivity reactions developed in 15 (21.7%) patients and occurred during the second cycle of retreatment in 13 (86.7%) of them. Reactions consisted of skin rash, flushing, itching, or abdominal cramping in eight (53.3%) and severe respiratory or cardiovascular events in seven patients (46.7%). One patient had a chest pain, without any other symptoms suggestive of hypersensitivity, followed by cardiac arrest unresponsive to standard resuscitative measures. All the other cases promptly recovered from symptoms. Logistic regression analysis showed that allergy history and CBDCA retreatment interval (interval time between the last cycle of first-line chemotherapy and CBDCA retreatment) were independent predictive variables for the risk of hypersensitivity, whereas patient age, first-line chemotherapy, total CBDCA dose given during first-line treatment, recurrence treated with CBDCA (first versus other), and CBDCA regimen at recurrence had no predictive value. Hypersensitivity reaction rate was higher in patients with CBDCA retreatment interval longer than 23.4 months compared to those with a shorter interval (36.3% versus 8.3%, P= 0.0132). Nine patients were subsequently treated with cisplatin, and two (22.2%) still developed allergic reactions. In conclusion, hypersensitivity reactions to CBDCA retreatment can occur in approximately one fifth of the cases, and a CBDCA retreatment interval longer than 2 years appears to be the strongest predictive variable for the development of allergic reactions.

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.

The aim of the present study was to evaluate the effectiveness of hyaluronic acid (HA) in the prevention of acute and late vaginal toxicities after high-dose-rate (HDR) vaginal brachytherapy (BT). Between January 2011 and January 2015, we retrospectively analyzed 126 patients with endometrial cancer who underwent extrafascial hysterectomy with or without lymphadenectomy and adjuvant HDR-vaginal BT +/- adjuvant chemotherapy. The total dose prescription was 21 Gy in 3 fractions (one fraction for week). Vaginal ovules containing 5 mg of HA were given for whole duration of vaginal BT and for the two following weeks. Acute and late toxicities were evaluated according to CTCAE vs 4.02. According to the revised FIGO 2009 classification, most tumors were in stage IA (30.9%) and in stage IB (57.9%). Thirty-three patients (26.2%) received adjuvant chemotherapy before vaginal BT. Five-year disease-free survival (DFS) and five-year overall survival (OS) were 88% and 93%, respectively. The most common grade 1-2 acute toxicities were vaginal inflammation (18 patients, 14.3%) and dyspareunia (7 patients, 5.5%). Two patients (1.6%) had more than one toxicity. Late toxicity occurred in 20 patients (15.9%). Grade 1-2 late toxicities were fibrosis (14 patients, 11.1%) and telangiectasias (7 patients, 5.5%). Six patients (4.8%) had more than one late toxicity. No grade 3 or higher acute or late toxicities were observed. These results appear to suggest that the local therapy with HA is of clinical benefit for intermediate risk endometrial cancer patients who receive adjuvant HDR-vaginal BT after surgery. A randomized trial comparing HA treatment vs. no local treatment in this clinical setting is warranted to further evaluate the efficacy of HA in preventing vaginal BT-related vaginal toxicity.

The Pursuit of Racial and Ethnic Equality in American Public Schools: Mendez, Brown, and Beyond edited by Kristi L. Bowman is reviewed.