The male slings: an effective and safe alternative surgical treatment to the artificial urinary sphincter for male stress urinary incontinence?-a narrative review.

Background and Objective: The ideal candidate for a male sling (MS) should have a mild to moderate degree of stress urinary incontinence (SUI). This narrative review article evaluates the current MS devices in the commercial market and examines the role of MS as an effective and safe alternative treatment option for male SUI. Methods: The available literature on MS was reviewed and relevant clinical studies pertaining to each MS were summarised with emphasis on device design and technology as well as specific surgical findings relating to clinical outcomes. Key Content and Findings: Over the past two decades, there have been considerable scientific advances in MS design and technology, and MS is an attractive alternative for patients who might not require or want an artificial urinary sphincter. The modern MS can be classified as adjustable or non-adjustable types and is placed either through a retropubic or transobturator (TO) approach. Strict patient selection and counselling, selection of MS with proven clinical records, and safe surgical practice are paramount to ensure a high continence rate, good patient satisfaction, and low postoperative complications. Published data on various MS materials and devices showed reasonable clinical efficacy and safety outcomes, although many of these synthetic MS devices may not be available worldwide due to a lack of regulatory approval in many countries. While the ideal MS is probably yet to be developed, continued scientific advances in slings design, mesh technology, and more refined surgical techniques will improve the continence rate and deliver better safety records. Conclusions: As clinical data matures with longer-term outcomes coupled with advances in scientific designs and technology, the ability to have and select the optimal MS for a particular patient will come to fruition.

Systematic review and network meta-analysis of re-intervention rates of new surgical interventions for benign prostatic hyperplasia.

OBJECTIVE: To assess the re-intervention rates of new surgical benign prostatic hyperplasia (BPH) interventions, as the clinical durability of new surgical interventions for BPH is not widely known. METHODS: A critical review of new surgical BPH therapies namely 'UroLift®', 'Aquablation', 'Rezum', 'prostatic artery embolisation (PAE)' and 'temporary implantable nitinol device (iTIND)' was performed on PubMed, the Cochrane Library, and Embase databases between May 2010 and December 2022 according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. All relevant articles were reviewed, and the risk of bias was evaluated using the Cochrane risk assessment tool and Newcastle-Ottawa Scale. RESULTS: Of the 32 studies included, there were 10 randomised controlled trials and 22 prospective observational cohorts. A total of 2400 participants were studied with a median patient age of 66 years, a median prostate volume of 51.9 mL, and a median International Prostate Symptom Score of 22. The lowest re-intervention rate at 12 months was for Aquablation at 0.01%, followed by Rezum at 0.02%, iTIND at 0.03%, and PAE at 0.05%. Network meta-analysis (NMA) showed that the best-ranked treatment at 12 months was transurethral resection of the prostate (TURP), followed by Aquablation, iTIND, Rezum, and UroLift. Re-intervention rates with these new BPH interventions are comparable, although some interventions reported better outcomes than TURP in the shorter term. CONCLUSIONS: While this systematic review and NMA showed that the re-intervention rate with these new surgical BPH interventions appears to be comparable to TURP in the short term, further studies are required to directly compare these various BPH procedures.

Impact of the COVID-19 pandemic on delivery of prostate cancer care in Australia: An interrupted time series analysis.

The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.

A review of the objective cognitive function measurements in males receiving hormonal therapy for prostate cancer.

PURPOSE: Prostate cancer (PC) is more common in the older population and the use of hormonal therapy in PC can increase medical frailty and cognitive decline. This narrative review examines the impact of androgen deprivation therapies (ADTs) and next-generational hormonal therapies (NGHT) on cognitive function outcomes amongst patients with hormone-sensitive or castrate-resistant PC. MATERIALS AND METHODS: Six electronic databases were searched from January 2000 to June 2022 for quantitative studies to evaluate the impacts of hormonal therapies (ADT, combined androgen blockade, and NGHT) on cognitive functions in men with PC. RESULTS: Of the 36 studies identified, 20 studies reported no effect of hormonal therapies on any cognitive domain while 16 studies found possible declines in at least one domain. The domains assessed were highly variable and objective assessment measurements were not standardized or widely adopted. While the results have been inconsistent, a relationship between declining androgen levels and poorer performances in the visuospatial and visual memory domains has been highlighted. It was not possible to distinguish the degree of cognitive parameter changes between the populations of hormone-sensitive and castrate-resistant PC. CONCLUSIONS: While the exact impact of ADT and NGHT on cognitive function in men with PC remains controversial, appropriate care should be undertaken especially in older and frail individuals, specifically in those with progressive or established visuospatial or visual memory deficits.

Symptomatic scrotal-inguino-retroperitoneal lymphocele in a kidney transplant patient-to drain but how to drain?

Scrotal-inguino-retroperitoneal (SIR) lymphocele is a rare complication following kidney transplant. This entity is characterized by a tract originating in the retroperitoneal space, through the inguinal canal and scrotum following lymph hydrodissection. Systematic review investigating SIR lymphocele yielded cases with open fenestration of the sac into the peritoneum as treatment. We described a case report of a male in his 60s with a functioning kidney transplant and SIR lymphocele, which was successfully managed in the short term with percutaneous drainage of the collection. However, the collection recurred and computed tomography scan showed a multiloculated collection that prompted surgical management. Intraoperatively, the encapsulated fluid-filled tract was excised and a drain was placed, which was removed 48 h later. The patient wore a hernia belt for 6 weeks as support. He had no recurrence of his lymphocele following serial reviews for 9 months now.

Aortic valve leaflet disruption techniques in transcatheter aortic valve replacement.

With continued technological advancement and technical improvement of transcatheter aortic valve replacement (TAVR), it has become a desirable treatment option for aortic valve stenosis. Its minimally invasive approach compared to surgical aortic valve replacement offers the treatment to a broader patient population, mainly non-surgical candidates. A feared complication of TAVR is the occlusion of coronary artery ostium by the native aortic valve leaflet due to its displacement by the expanded transcatheter valve. Bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) is a technique developed to mitigate this risk by creating a lengthwise laceration of the left and/or right aortic valve leaflets prior to TAVR. Patient outcomes following TAVR with BASILICA have been promising. Meticulous preoperative examination, patient selection, and hemodynamic management are imperative. With continued refinement, BASILICA may further expand the application of TAVR to patients at high risk for coronary occlusion associated with the procedure.

Can malleable penile prosthesis implantation improve voiding dysfunction in men with concurrent erectile dysfunction and buried penis?

PURPOSE: A buried penis causes voiding dysfunction and limits penetrative sexual intercourse. This pilot study evaluates the urinary outcomes in men with buried penis following insertion of malleable penile implants. MATERIALS AND METHODS: Men with buried penis and co-existing urinary problems and erectile dysfunction underwent malleable penile prosthesis implantation were reviewed in a prospective ethics approved database. Patient demographics, flow rate (Qmax), International Prostate Symptom Score (IPSS), Patient Global Impression of Improvement (PGI-I) score, International Index of Erectile Function (IIEF)-5 score, Sexual Encounter Profile (SEP) and overall satisfaction score (on a 5-point scale) were recorded. RESULTS: A total of 12 men (age 55 to 72 years) were reviewed, and the average gain in penile length post-implant, as measured from the pubis to the tip of the glans penis, was 6.8 (3 to 8) cm. There was a significant improvement in IIEF-5 score (8.2 vs. 22.5; p=0.029) post-implant, and more than half of patients were able to resume normal sexual intercourse and positive SEP-2 and SEP-4 were reported in 9 (75%) and 8 (67%) patients. There were no significant intraoperative or postoperative complication. Significant improvement in Qmax (8.4 ml/s vs. 18.6 ml/s; p=0.042) and IPSS (24.5±5.5 vs 15.5±3.5; p=0.038) were observed. More than two-thirds (83%) reported PGI-I score at 1 or 2, while 9 (75%) patients scored a 5/5 in overall satisfaction rate. CONCLUSIONS: Malleable penile implants increases penile length and improves urinary function in a highly select group of men with a buried penis and erectile dysfunction.

Use of the Hypotension Prediction Index During Cardiac Surgery.

OBJECTIVE: The hypotension prediction index (HPI) is a novel parameter developed by Edwards Lifesciences (Irvine, CA) that is obtained through an algorithm based on arterial pressure waveform characteristics. Past studies have demonstrated its accuracy in predicting hypotensive events in noncardiac surgeries. The authors aimed to evaluate the use of the HPI in cardiac surgeries requiring cardiopulmonary bypass (CPB). DESIGN: Prospective cohort feasibility study. SETTING: Single university medical center. PARTICIPANTS: Sequential adult patients undergoing elective cardiac surgeries requiring CPB between October 1, 2018, and December 31, 2018. INTERVENTIONS: HPI monitor was connected to the patient's arterial pressure transducer. Anesthesiologists and surgeons were blinded to the monitor output. MEASUREMENTS AND MAIN RESULTS: HPI values and hypotensive events were recorded before and after CPB. The primary outcomes were the area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, and specificity of HPI predicting hypotension. The AUC, sensitivity, and specificity for HPI lead time to hypotension five minutes before the event were 0.90 (95% confidence interval [CI]: 0.853-0.949), 84% (95% CI: 77.7-90.5), and 84% (95% CI: 70.9-96.8), respectively. Ten minutes before the event AUC, sensitivity, and specificity for HPI lead time to hypotension were 0.83 (95% CI: 0.750-0.905), 79% (95% CI: 69.8-88.1), and 74% (95% CI: 58.8-89.6), respectively. Fifteen minutes before the hypotensive event AUC, sensitivity, and specificity for HPI lead time to hypotension were 0.83 (95% CI: 0.746-0.911), 79% (95% CI: 68.4-89.0), and 74% (95% CI: 58.8-89.6), respectively. CONCLUSION: HPI predicted hypotensive episodes during cardiac surgeries with a high degree of sensitivity and specificity.

Transanal total mesorectal excision the Gold Coast experience: learning curve and comparison to traditional technique.

BACKGROUND: Laparoscopic and open techniques in rectal cancer are well-published, however, technical challenges remain for mid to low rectal cancer resections in the narrow pelvis. Transanal total mesorectal excision (taTME) has been pioneered to potentially circumvent these challenges. The aims of this study were to evaluate the learning curve associated with our first cases of taTME as well as compare outcomes to that of conventionally performed rectal resections. METHODS: This was a single-centre retrospective study with data collated from all elective resections by the colorectal unit from 2015 to 2017. Primary outcome was completeness of total mesorectal excision and secondary outcomes were intra- and post-operative morbidity and mortality. RESULTS: A total of 43 patients were identified. Of which, 20 underwent taTME. Mesorectal completeness was obtained in only 47.4% in the taTME group compared to 78.3% in the anterior resection group (p = 0.115). 5.9% of patients in our taTME group had positive circumferential resection margin compared to nil in the anterior resection. Conversion rates were greater in the taTME group (15% versus 0%; 0.028). Operative time, length of stay and clavien IV and V complications were greater in the taTME group. CONCLUSION: This study highlights the difficulty in introducing a novel technique given the learning curve. Our results would expect to improve with increased caseload.

Do Illuminated Foot Pedals Improve the Speed and Accuracy of Pedal Activation During Endoscopic Procedures?

PURPOSE: Endourologic procedures such as percutaneous nephrolithotomy (PCNL) employ the use of foot pedals in low-light operating room (OR) settings. These pedals can be especially difficult to locate or distinguish when several pedals are present during a single operation. Improper instrument activation in the OR has led to serious complications ranging from unintentional electrocautery to patient burns and even an intraoperative explosion. This study evaluates the impact of color-coded illumination on speed and efficiency of foot pedal activation. MATERIALS AND METHODS: During a simulated PCNL procedure, the foot pedals for a C-arm, laser, and ultrasonic lithotripter (USL) were placed in random positions. Ten participants performed pedal activation in a randomized sequence. Objective outcomes included time to instrument activation, number of attempted pedal presses, number of incomplete pedal presses, and number of incorrect pedal presses. Subjective preferences for pedal illumination were also determined. Data were analyzed using Mann-Whitney U, Wilcoxon signed-rank, and Chi-square tests with p < 0.05 indicating statistical significance. RESULTS: Illuminated foot pedals were associated with decreases in the average activation time for all instruments collectively (3.95 seconds vs 6.49 seconds; p = 0.017) and individually (C-arm: 3.07 seconds vs 4.21 seconds; p = 0.006; laser: 13.04 seconds vs 15.18 seconds; p < 0.001; USL: 3.28 seconds vs 4.91 seconds; p < 0.001) compared with nonilluminated pedals. Illuminated pedals were associated with fewer attempted pedal presses (33.5 vs 39.5; p = 0.007) and incomplete pedal presses (1.5 vs 8.5; p = 0.002). The number of incorrect pedal presses decreased with illumination, but this did not reach statistical significance (0 vs 0.5; p = 0.08). Participants reported that illumination simplified pedal activation and recommended its use (p < 0.01). CONCLUSION: Color-coded illumination improved the speed and efficiency of foot pedal activation during simulated PCNL. Participants subjectively preferred using illuminated foot pedals for endourologic procedures and felt that they improved safety and efficiency.

In Vitro Sonothrombolysis Enhancement by Transiently Stable Microbubbles Produced by a Flow-Focusing Microfluidic Device.

Therapeutic approaches that enhance thrombolysis by combining recombinant tissue plasminogen activator (rtPA), ultrasound, and/or microbubbles (MBs) are known as sonothrombolysis techniques. To date, sonothrombolysis approaches have primarily utilized commercially available MB formulations (or derivatives thereof) with diameters in the range 1-4 µm and circulation lifetimes between 5 and 15 min. The present study evaluated the in vitro sonothrombolysis efficacy of large diameter MBs (d MB ≥ 10 µm) with much shorter lifetimes that were produced on demand and in close proximity to the blood clot using a flow-focusing microfluidic device. MBs with a N2 gas core and a non-crosslinked bovine serum albumin shell were produced with diameters between 10 and 20 µm at rates between 50 and 950 × 103 per second. Use of these large MBs resulted in approximately 4.0-8.8 fold increases in thrombolysis rates compared to a clinical rtPA dose and approximately 2.1-4.2 fold increases in thrombolysis rates compared to sonothrombolysis techniques using conventional MBs. The results of this study indicate that the large diameter microbubbles with transient stability are capable of significantly enhanced in vitro sonothrombolysis rates when delivered directly to the clot immediately following production by a flow focusing microfluidic device placed essentially in situ adjacent to the clot.

Battle against RNA oxidation: molecular mechanisms for reducing oxidized RNA to protect cells.

Oxidation is probably the most common type of damage that occurs in cellular RNA. Oxidized RNA may be dysfunctional and is implicated in the pathogenesis of age-related human diseases. Cellular mechanisms controlling oxidized RNA have begun to be revealed. Currently, a number of ribonucleases and RNA-binding proteins have been shown to reduce oxidized RNA and to protect cells under oxidative stress. Although information about how these factors work is still very limited, we suggest several mechanisms that can be used to minimize oxidized RNA in various organisms.

Comparing ERCC1 protein expression, mRNA levels, and genotype in squamous cell carcinomas of the head and neck treated with concurrent chemoradiation stratified by HPV status.

BACKGROUND: Previous studies examining excision repair cross-complementation group 1 (ERCC1) in squamous cell carcinoma of the head and neck (SCCHN) have not compared methods of ERCC1 testing nor been stratified by human papillomavirus (HPV) status. METHODS: ERCC1 protein expression, mRNA, and genotype were retrospectively evaluated from pretreatment biopsies in 55 patients with SCCHN treated with chemoradiation. RESULTS: In all, 50% of patients had high ERCC1 protein expression, 28.2% had low mRNA levels, and genotype frequencies were C/C = 17.1%, C/T = 43.9%, and T/T = 39.0%. No correlations were found among protein expression, mRNA, or genotype. With a median follow-up of 54 months, the 5-year overall survival was 57.7%. After adjusting for known prognostic factors, ERCC1 protein level and genotype resulted in hazard ratios indicating an increased risk of death of 4.4-fold (p = .004) and 4.2-fold (p = .044), respectively. An exploratory analysis suggested a differential prognostic effect in HPV-negative SCCHN. CONCLUSIONS: ERCC1 protein expression using the FL297 antibody warrants further study as a potential prognostic marker in SCCHN.

Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03.

PURPOSE: To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial. PATIENTS AND METHODS: We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS). RESULTS: LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile. CONCLUSION: AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.

Low allele frequency of MLH1 D132H in American colorectal and endometrial cancer patients.

PURPOSE: Hereditary nonpolyposis colon cancer is caused by mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2. Classic MLH1 mutations cause an approximately 20-fold increase in colorectal cancer susceptibility. Recently, we identified a hypomorphic allele, MLH1 D132H , which impairs, but does not completely eliminate the function of MLH1 in tumor suppression. MLH1 D132H confers an approximately fivefold increase in colorectal cancer susceptibility and was first described in a cohort of Israeli colorectal cancer patients, with an estimated allele frequency of 1.3 percent. Because MLH1 D132H has only recently been described, the ethnic distribution of this risk allele is not well understood. This study was undertaken to determine both the frequencies of this risk allele in ethnic groups outside of Israel and whether families harboring this mutation have susceptibility to extracolonic cancers in the hereditary nonpolyposis colon cancer spectrum. METHODS: We genotyped two independent cohorts: 629 population-based colorectal cancer patients ascertained from clinics in Orange, Imperial, and San Diego Counties, and 515 endometrial cancer patients ascertained from gynecologic oncology clinics in the Midwestern United States. RESULTS: MLH1 D132H was not detected in either study cohort, which together totaled more than 1,100 American colorectal cancer and endometrial cancer patients. CONCLUSIONS: The MLH1 D132H risk variant has significantly lower allele frequency in American compared with Israeli cancer patients and, alone, is unlikely to explain significant amounts of American sporadic colorectal cancer or uterine cancer susceptibility. Genetic testing for the MLH1 D132H allele exclusively is therefore unlikely to be cost effective for genetic risk assessment in American population-based and clinic-based colorectal cancer and endometrial cancer patients.

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer.

Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2 and MSH6 mutations underlie high-penetrance CRC susceptibility in hereditary nonpolyposis colon cancer (HNPCC), we hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. We looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability (MSI) phenotype. Association studies identified a new MLH1 variant (415G-->C, resulting in the amino acid substitution D132H) in approximately 1.3% of Israeli individuals with CRC self-described as Jewish, Christian and Muslim. MLH1 415C confers clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually do not have the MSI defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-->C mutation. The new MLH1 variant confers a high risk of CRC and identifies a previously unrecognized mechanism in microsatellite-stable tumors. These studies suggest that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than previously assumed.

Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27(Kip1) protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19(ARF) tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19(ARF) 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)(9)-p19(ARF) 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.

Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development.

The forkhead box (Fox) f1 transcription factor is expressed in the mouse splanchnic (visceral) mesoderm, which contributes to development of the liver, gallbladder, lung, and intestinal tract. Pulmonary hemorrhage and peripheral microvascular defects were found in approximately half of the newborn Foxf1(+/-) mice, which expressed low levels of lung Foxf1 mRNA [low-Foxf1(+/-) mice]. Microvascular development was normal in the surviving newborn high-Foxf1(+/-) mice, which compensated for pulmonary Foxf1 haploinsufficiency and expressed wild-type Foxf1 levels. To identify expression of genes regulated by Foxf1, we used Affymetrix microarrays to determine embryonic lung RNAs influenced by Foxf1 haploinsufficiency. Embryonic Foxf1(+/-) lungs exhibited diminished expression of hepatocyte growth factor receptor c-Met, myosin VI, the transcription factors SP-3, BMI-1, ATF-2, and glucocorticoid receptor, and cell cycle inhibitors p53, p21(Cip1), retinoblastoma, and p107. Furthermore, Notch-2 signaling was decreased in embryonic Foxf1(+/-) lungs, as evidenced by significantly reduced levels of the Notch-2 receptor and the Notch-2 downstream target hairy enhancer of split-1. The severity of the Notch-2-signaling defect in 18-day postcoitus Foxf1(+/-) lungs correlated with Foxf1 mRNA levels. Disruption of pulmonary Notch-2 signaling continued in newborn low-Foxf1(+/-) mice, which died of lung hemorrhage and failed to compensate for Foxf1 haploinsufficiency. In contrast, in newborn high-Foxf1(+/-) lungs, Notch-2 signaling was restored to the level found in wild-type mice, which was associated with normal microvascular formation and survival. Foxf1 haploinsufficiency disrupted pulmonary expression of genes in the Notch-2-signaling pathway and resulted in abnormal development of lung microvasculature.