Role of fibroblast growth factor receptor 2 in kidney mesenchyme

Conditional deletion of murine fibroblast growth factor receptors (Fgfrs) 1 and 2 in metanephric mesenchyme leads to renal agenesis with unbranched ureteric buds; however, there are occasionally two buds per nephric duct. Our goal was to determine whether conditional deletion of Fgfr1 or Fgfr2 alone resulted in multiple ureteric bud induction sites. Although deletion of Fgfr1 alone results in no abnormalities, loss of Fgfr2 often leads to multiple ureteric buds and anomalies including renal aplasia, misshaped kidneys, partially duplicated kidneys, duplicated ureters, and obstructed hydroureter. Deletion of Fgfr2 did not change expression domains of glial cell line-derived neurotrophic factor (GDNF), Robo2, bone morphogenetic protein 4, or Sprouty1, all of which regulate ureteric bud induction. Cultured Fgfr2 mutant nephric ducts were also not more sensitive to exogenous GDNF than controls. Whole mount in situ hybridization revealed that in mutant embryos, Fgfr2 was deleted from stromal cells around the nephric duct and ureteric bud base, which correlates well with the ureteric bud induction abnormalities. Thus, Fgfr2 is critical in ensuring that there is a single ureteric bud from the nephric duct. The plethora of later stage defects in Fgfr2 conditional knockouts is reminiscent of many human cases of genetic urogenital anomalies.     

Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo

Objectives

Uterine serous carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associated with USC in approximately 30–35% of cases. The objective of this study was to determine the sensitivity of a panel of primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo.

Methods

HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro. Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo.

Results

HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean ± SEM IC₅₀: 0.011 μM ± 0.0008 vs. 0.312 μM ± 0.0456 p < 0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p = 0.0019).

Conclusions

Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.     

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

Tobacco smoke and red/processed meats are well-known risk factors for colorectal cancer (CRC). Most research has focused on studies of normal colon biopsies in epidemiologic studies or treatment of CRC cell lines in vitro. These studies are often constrained by challenges with accuracy of self-report data or, in the case of CRC cell lines, small sample sizes and lack of relationship to normal tissue at risk. In an attempt to address some of these limitations, we performed a 24-hour treatment of a representative carcinogens cocktail in 37 independent organoid lines derived from normal colon biopsies. Machine learning algorithms were applied to bulk RNA-sequencing and revealed cellular composition changes in colon organoids. We identified 738 differentially expressed genes in response to carcinogens exposure. Network analysis identified significantly different modules of co-expression, that included genes related to MSI-H tumor biology, and genes previously implicated in CRC through genome-wide association studies. Our study helps to better define the molecular effects of representative carcinogens from smoking and red/processed meat in normal colon epithelial cells and in the etiology of the MSI-H subtype of CRC, and suggests an overlap between molecular mechanisms involved in inherited and environmental CRC risk.     

Socioeconomic support to improve initiation of tuberculosis preventive therapy and increase tuberculosis treatment success in Peru: a household-randomised,controlled evaluation

Background

For the first time in the modern era of tuberculosis control, the WHO's End TB strategy specifically integrates socioeconomic support for people affected by tuberculosis with existing biomedical interventions. However, there is little evidence of the impact of this approach on tuberculosis outcomes. We designed and implemented one of the world's first tuberculosis-specific socioeconomic support interventions, assessed its impact on tuberculosis prevention measures and treatment success, and refined the support for use in the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent Tuberculosis (CRESIPT) project.

Acquisition of new medical devices among the persistently critically ill: A retrospective cohort study in the Veterans Affairs

Patients who develop persistent critical illness remain in the ICU predominately because they develop new late-onset organ failure(s), which may render them at risk of acquiring a new medical device. The epidemiology and short-term outcomes of patients with persistent critical illness who acquire a new medical device are unknown.We retrospectively studied a cohort admitted to the Veterans Affairs (VA) ICUs from 2014 to 2019. Persistent critical illness was defined as an ICU length of stay of at least 14 days. Receipt of new devices was defined as acquisition of a new tracheostomy, feeding tube (including gastrostomy and jejunostomy tubes), implantable cardiac device, or ostomy. Logistic regression models were fit to identify patient factors associated with the acquisition of each new medical device. Among hospitalized survivors, 90-day posthospitalization discharge location and mortality were identified.From 2014 to 2019, there were 13,184 ICU hospitalizations in the VA which developed persistent critical illness. In total, 30.4% of patients (N = 3998/13,184) acquired at least 1 medical device during their persistent critical illness period. Patients with an initial higher severity of illness and prolonged hospital stay preICU admission had higher odds of acquiring each medical device. Among patients who survived their hospitalization, discharge location and mortality did not significantly differ among those who acquired a new medical device as compared to those who did not.Less than one-third of patients with persistent critical illness acquire a new medical device and no significant difference in short-term outcomes was identified. Future work is needed to understand if the acquisition of new medical devices is contributing to the development of persistent critical illness.     

Is Hysterectomy Necessary for Laparoscopic Pelvic Floor Repair? A Prospective Study

Study ObjectiveTo evaluate whether the addition of hysterectomy to laparoscopic pelvic floor repair has any impact on the short-term (perioperative) or long-term (prolapse outcome) effects of the surgery.DesignA controlled prospective trial (Canadian Task Force classification II–1).SettingPrivate and public hospitals affiliated with a single institution.PatientsA total of 64 patients with uterovaginal prolapse pelvic organ prolapse quantification system stage 2 to 4 had consent for laparoscopic pelvic floor repair from January 2005 through January 2006 (32 patients in each treatment arm). Patients self-selected to undergo hysterectomy in addition to their surgery.InterventionsPatients were divided into group A (laparoscopic pelvic floor repair with hysterectomy) or group B (laparoscopic pelvic floor repair alone). All patients had laparoscopic pelvic floor repair in at least 1 compartment, whereas 52 patients had global pelvic floor prolapse requiring multicompartment repair. Burch colposuspension and/or additional vaginal procedures were performed at the discretion of the surgeon in each case.Measurements and Main ResultsSymptoms of prolapse and pelvic organ prolapse quantification system assessments were collected preoperatively, perioperatively, and at 6 weeks, 12 months, and 24 months postoperatively. Validated mental and physical health questionnaires (Short-Form Health Survey) were also completed at baseline, 6 weeks, and 12 months. No demographic differences occurred between the groups. Time of surgery was greater in group A (+35 minutes), as was estimated blood loss and inpatient stay, although the latter 2 results had no clinically significant impact. No difference between groups was detected in the rate of de novo postoperative symptoms. At 12 months, 4 (12.9%) patients in group A had recurrent prolapse as did 6 (21.4%) patients in group B. At 24 months these figures were 6 (22.2%) and 6 (21.4%), respectively. These differences were not statistically significant (p = .500 at 12 months and .746 at 24 months). In the group not having hysterectomy, 4 (14.3%) of 28 patients had cervical elongation or level-1 prolapse by the 12-month assessment.ConclusionThe addition of total laparoscopic hysterectomy to laparoscopic pelvic floor repair adds approximately 35 minutes to surgical time with no difference in the rate of perioperative or postoperative complications or prolapse outcome. Leaving the uterus in situ, however, is associated with a risk of cervical elongation potentially requiring further surgery. Laparoscopic pelvic floor repair is successful in 80% of patients at 2 years.     

In vitro maturation of baboon oocytes retrieved at the time of cesarean section

Objective: To investigate the feasibility of oocyte retrieval at the time of cesarean delivery and the potential of such oocytes to undergo nuclear maturation in vitro using a baboon model and an established culture system.

Design: Randomized, controlled animal study.

Setting: Research foundation and university research laboratory.

Animal(s): Mature pregnant baboons.

Intervention(s): In vitro culture of aspirated oocytes with or without epidermal growth factor (EGF).

Main Outcome Measure(s): Oocyte yield, germinal vesicle breakdown, polar body extrusion.

Result(s): A total of 246 oocytes were retrieved (mean, 35; range, 14–67). Eighty-seven oocytes (35%) underwent germinal vesicle breakdown and 72 oocytes (29%) extruded a polar body. A χ² analysis revealed no significant effect of EGF on outcome parameters. No effect of gestational age or maternal age on oocyte yield or development was observed.

Conclusion(s): A sizeable proportion of oocytes obtained from puerperal primates exhibited the capacity to undergo nuclear maturation in vitro.     

An Innovative Approach to Airway Foreign Body Management in an Extremely Premature Neonate

This case report is a retrospective review of a challenging though ultimately successful removal of an airway foreign body in a 2-day-old premature female born at 23 weeks and 4 days gestation. A segment of a 5-F surfactant catheter was cut and accidentally dislodged in the distal airway within the lumen of the patient's endotracheal tube. Ultimately, visualization was obtained using a 1.6-mm KARL STORZ sialoendoscope, and retrieval was performed using sialoendoscopy forceps passed via the working channel of the sialoendoscope while maintaining ventilation. This case represents an innovative approach to complex airway foreign body management utilizing sialoendoscopy instruments. Laryngoscope, 130:1236–1238, 2020