An active machine learning discovery platform for membrane-disrupting and pore-forming peptides.

Membrane-disrupting and pore-forming peptides (PFPs) play a substantial role in bionanotechnology and can determine the life and death of cells. The control of chemical and ion transport through cell membranes is essential to maintaining concentration gradients. Likewise, the delivery of drugs and intracellular proteins aided by pore-forming agents is of interest in treating malfunctioning cells. Known PFPs tend to be up to 50 residues in length, which is commensurate with the thickness of a lipid bilayer. Accordingly, few short PFPs are known. Here we show that the discovery of PFPs can be accelerated via an active machine learning approach. The approach identified 71 potential PFPs from the 25.6 billion octapeptide sequence space; 13 sequences were tested experimentally, and all were found to have the predicted membrane-disrupting ability, with 1 forming highly stable pores. Experimental verification of the predicted pore-forming ability demonstrated that a range of short peptides can form pores in membranes, while the positioning and characteristics of residues that favour pore-forming behaviour were identified. This approach identified more ultrashort (8-residues, unmodified, non-cyclic) PFPs than previously known. We anticipate our findings and methodology will be useful in discovering new pore-forming and membrane-disrupting peptides for a range of applications from nanoreactors to therapeutics.

Socio-Environmental Conditions Associated with Geospatial Clusters of Urothelial Carcinoma: A Multi-Institutional Analysis.

PURPOSE: The interaction between sources of industrial byproducts and environmental pollutants (IBP/EP) and the prevalence of urothelial carcinoma (UC) in surrounding communities has been infrequently explored. The purpose of this research is to identify microregional UC hotspots and associated industrial and environmental risk factors. MATERIALS AND METHODS: We retrospectively queried a multi-institutional database for UC patients diagnosed between 2008 and 2018. Addresses were geocoded and used to perform hotspot analysis on the census block level. Demographic and clinicopathological characteristics, census data and proximity to sources of IBP/EP were compared between patients who did vs did not reside in a hotspot. Associations were tested using multilevel logistic regression models using 95% confidence intervals. RESULTS: A total of 5,080 patients met inclusion criteria and 148 (2.9%) were identified as living in 1 of 3 UC hotspots. In univariate analyses, race, tobacco and alcohol use, household income, IBP/EP exposure and proximity to traffic, industrial discharge and airports were significantly associated with UC hotspots. Multivariable analysis demonstrated that polycyclic aromatic hydrocarbon exposure (OR: 48.09, p ≤0.001) and proximity to high-density traffic (OR: >999, p ≤0.001) increased the odds of living in a hotspot. Patients living in a hotspot were significantly less likely to be white (OR: 0.06, p ≤0.001) or tobacco users (OR: 0.39, p=0.031) on multivariate analysis. CONCLUSIONS: Spatially related clusters of UC may be associated with locoregional environmental exposures rather than tobacco exposure and may also be correlated with socioeconomic disparities. Geospatial analysis can help to identify at-risk populations, offering the opportunity to better focus preventive and diagnostic interventions.

Incisional hernia after cystectomy: incidence, risk factors and anthropometric predisposition.

INTRODUCTION: Postoperative incisional hernias (PIH) are an established complication of abdominal surgery with rates after radical cystectomy (RC) poorly defined. The objective of this analysis is to compare rates and risk factors of PIH after open (ORC) and robotic-assisted (RARC) cystectomy at a tertiary-care referral center. MATERIALS AND METHODS: We performed a retrospective review of patients undergoing ORC and RARC from 2000-2015 with pre and postoperative cross-sectional imaging available. Images were evaluated for anthropometric measurements and presence of postoperative radiographic PIH (RPIH). Patient demographics, type of urinary diversion and postoperative hernia repair (PHR) were also assessed. RESULTS: Of the patients that met inclusion criteria (n = 469), the incidence of RPIH and PHR were 14.3% and 9.0%, respectively. Between ORC and RARC, analysis revealed no statistically significant differences in rates of RPIH (13.6% versus 20.3%, p = 0.152) or PHR (8.2% versus 12.5%, p = 0.214). Body mass index was associated with a slightly increased likelihood of RPIH on univariate analysis alone (OR 1.08, p = 0.008). Ileal conduit was associated with a decreased likelihood of RPIH (OR 0.42, p = 0.034) and PHR (OR 0.36, p = 0.023). Supraumbilical rectus diastasis width (RDW) was an independent predictor of both RPIH (OR 1.52, p = 0.023) and PHR (OR 1.43, p = 0.039) on multivariate analysis. CONCLUSIONS: Patients undergoing RC are at significant risk of RPIH and PHR regardless of surgical approach. Anthropomorphic factors and urinary diversion type appear to be associated with PIH risk. Further research is needed to understand how risks of PIH can be reduced in patients undergoing cystectomy.

Synthesis of 18O-labelled alcohols from unlabelled alcohols.

The synthesis of primary, secondary and tertiary 18O-enriched alcohols from readily available 16O-alcohols via a Mitsunobu esterification and hydrolysis is described. The method is further exemplified in the labelling of the active pharmaceutical ingredient, dropropizine and is shown to be tolerant of modern, separation friendly Mitsunobu reagents.

Nephroureterectomy vs. segmental ureterectomy of clinically localized, high-grade, urothelial carcinoma of the ureter: Practice patterns and outcomes.

BACKGROUND: Nephroureterectomy (NU) remains the gold-standard for upper-tract urothelial carcinoma (UTUC). However, nephron-sparing management (NSM), specifically segmental ureterectomy (SU) for urothelial tumors distal to the renal pelvis may offer decreased risk of renal insufficiency and equivalent cancer control. OBJECTIVES: To identify patient-specific and facility-related factors that are associated with the selection of SU vs. NU for patients with clinically localized, high-grade, ureteral UTUC. DESIGN, SETTING, PARTICIPANTS: We searched the National Cancer Database between 2004 and 2015 for patients with high-grade, clinically localized, primary ureteral UTUC managed by either NU or SU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate and multivariate analysis was performed to assess patient, disease-specific, facility and treatment-related factors associated with SU vs. NU. Since surgical approach was only indexed after 2010, separate multivariable logistic regressions were performed including and excluding surgical approach in order to capture patients treated between 2004 and 2009. Survival analysis utilized Kaplan-Meier methods and Cox proportional hazards regression. RESULTS AND LIMITATIONS: Multivariate analysis including surgical approach demonstrated that among other factors, higher clinical stage (P = 0.034), larger tumor size (P < 0.001), the addition of neoadjuvant chemotherapy (P = 0.002), and the utilization of minimally invasive surgery (P < 0.05) decreased the likelihood of patients receiving SU. In this same cohort, institutions with larger facility volumes (P = 0.038) and performing intraoperative lymph node dissection (P < 0.001) were associated with a higher probability of SU. Excluding surgical approach, once again more advanced clinical stage (P = 0.005), larger tumor size (P < 0.001), and neoadjuvant chemotherapy (P = 0.003) decreased the probability of patients receiving SU, while increasing age (P = 0.049) and intraoperative lymph node dissection (P < 0.001) were more closely associated with SU compared to NU. No differences were noted in pathological T stage (P > 0.05), 30-day readmission (P = 0.7), 30-day mortality (P = 0.09), and 90-day mortality (P = 0.157) on multivariate analysis between SU and NU. Additionally, no significant differences were seen in median overall survival between patients receiving SU or NU (53 vs. 50 months; P = 0.143). CONCLUSIONS: Comparable outcomes suggest segmental ureterectomy for high-grade ureteral UTUC is appropriate in well-selected patients. Practice patterns appear consistent with guideline recommendations (decreased tumor size and lower clinical stage favor SU), but treatment disparities may exist based on a multitude of patient, pathologic- and facility-related factors. Improved dissemination of knowledge regarding practice patterns and outcomes of SU for UTUC of the ureter has the potential to improve delivery of NSM in appropriate patients. PATIENT SUMMARY: In this study, we examined factors associated with different surgical procedures for cancer of the ureter. We found that smaller tumor sizes, a less advanced clinical stage, intraoperative lymph dissection higher facility volumes tended to favor kidney-sparing treatment, while survival outcomes appear comparable to renal extirpation.

Paraganglioma of the Spermatic Cord With Spinal Metastasis: A Case Report.

A 40-year-old male with presented to the clinic with the chief complaint of right inguinal pain radiating to his right testicle and right thigh with no history of trauma, fever, chills, dysuria, hematuria, or unprotected sexual activity. Physical exam revealed right testicular tenderness with no palpable abnormality of the bilateral testes or spermatic cords. Scrotal ultrasound was performed and was unremarkable for testicular or other intrascrotal pathology. Concurrently, chronic low back pain had prompted a lumbar CT to be performed, which was indeterminate, but subsequent lumbar MRI performed three months later revealed abnormal signals in the vertebral bodies of T12, L3, and L5, concerning for occult metastatic disease or multiple myeloma. PET-CT was performed revealing hypermetabolic lesions throughout the axial skeleton and, most notably, hypermetabolic lesions in the left inguinal and left upper scrotum. At this time, about 4 months after the original visit, physical exam revealed a palpable mobile mass in the left upper scrotum that was distinct from the left testicle, and another mass palpable near the left inguinal ring.

Acute pulmonary hemorrhage associated with metastatic testicular choriocarcinoma in a 46-year-old incarcerated male.

Pure testicular choriocarcinoma is a rare histological subtype of germ cell tumor (GCT) and typically presents with distant metastases and aggressive features leading to a generally poor prognosis. Unique to choriocarcinoma among GCT histological subtypes is the propensity of spontaneous hemorrhage into metastatic lesions. We report a case of pure testicular choriocarcinoma in a 46-year-old male with postoperative acute pulmonary hemorrhage secondary to tumor invasion of the lungs, and the subsequent management of his disease with a discussion of relevant literature.

Male-to-Female Gender Reassignment Surgery: An Institutional Analysis of Outcomes, Short-term Complications, and Risk Factors for 240 Patients Undergoing Penile-Inversion Vaginoplasty.

OBJECTIVE: To report outcomes, complications, and risk factors of a population cohort undergoing male-to-female gender affirmation surgery via penile-inversion vaginoplasty by a single surgeon at a large academic institution. As gender dysphoria awareness increases among the medical community, so does the population of patients seeking gender-affirmation surgery. MATERIALS AND METHODS: A prospectively maintained database of patients undergoing penile-inversion vaginoplasty was retrospectively queried for all available patients with at least 1 week of postoperative follow-up. Univariate and multivariate analyses were performed using Fisher's exact test and logistic regression, respectively, in order to evaluate relationship of risk factors to complications at 30, 60, and 90 days, as well as the likelihood of revision/reoperation. RESULTS: From November 2016 to April 2018, 240 penile-inversion vaginoplasties were performed. Median follow-up was 87 days. When accounting for competing risk factors, only noncompliance with postoperative dilation regimen and activity restriction was significantly associated with increased risk of complications or reoperation/revision. Overall incidence of reoperation/revision was 7.9% (n = 19). Reasons for reoperation included cosmesis (3.8%; n = 9), neovaginal stenosis (2.1%; n = 5), and wound dehiscence (0.8%; n = 2), with less than 0.5% (n = 1) reoperations for meatal stenosis, hematoma or rectovaginal fistula, respectively. Incidence of Clavien IIIa-b complications was 1.7% (n = 4). There were no Clavien IV-V complications. CONCLUSION: At short-term follow-up, gender-affirmation surgery is associated with low rates of reoperation and revision and few major complications when performed by an experienced, high-volume surgeon. Patient selection and compliance is imperative. Increased reporting among surgeons is necessary to continue to improve patient outcomes.

Use of administrative data for comparative effectiveness research in the treatment of non-prostate genitourinary malignancies.

Comparative effectiveness research (CER) is imperative for objective and balanced assessment of treatment outcomes. CER that uses administrative databases (AD-CER) affords unique opportunities for large scale data analyses that potentially transcend limitations of small institutional datasets. Prostate cancer has received much attention from the AD-CER research community, whereas non-prostate genitourinary malignancies are less well-studied. The objective of this article is to review the currently available AD-CER that has been published in the non-prostate genitourinary malignancies space.

Extraordinarily Large Renal Cell Carcinoma With Metasynchronous Neuroendocrine Tumor of the Ileocecal Valve: A Rare Presentation of Disease.

A 71-year-old female presented with a large, protuberant abdominal mass, and was found to have both a left renal mass and a biopsy-proven neuroendocrine tumor of the ileocecal valve. Ultimately, right hemicolectomy revealed a well-differentiated and low-grade neuroendocrine tumor of the ileocecal valve, whereas left radical nephrectomy revealed a 23 cm × 22 cm × 15 cm renal cell carcinoma, chromophobe-type (RCC-CT) weighing 3564 g. RCC-CT represents a small portion of diagnosed RCC, and generally portends a more favorable prognosis than other variants. Modern reports of renal tumors exceeding 20 cm are exceedingly rare. In spite of massive size, favorable histology may allow for surgical cure.

Metastatic Prostate Cancer Presenting as Lower Extremity Soft Tissue Mass: A Rare Case Presentation.

A 69-year-old homeless African American male with prostate cancer diagnosed 2 years prior presents a large mass in the right thigh. An evaluation of the patient revealed a prostate-specific antigen of 9362 ng/mL. Biopsy of the leg mass was performed and final pathology indicated metastatic adenocarcinoma of the prostate. Although metastatic prostate cancer presents most commonly in bone, lymph nodes, lungs, and liver, metastatic disease presenting as a soft tissue mass is extremely rare (Bubendorf et al, 2000; Molenaar et al, 1996; Ward and Bourken, 1984). The advent of screening with prostate-specific antigen has led to earlier diagnosis of lower-grade disease, yet underserved populations continue to present with aggressive and morbid disease (Winer et al, 2014).