Discovery of CDC42 Inhibitors with a Favorable Pharmacokinetic Profile and Anticancer In Vivo Efficacy.

We previously reported trisubstituted pyrimidine lead compounds, namely, ARN22089 and ARN25062, which block the interaction between CDC42 with its specific downstream effector, a PAK protein. This interaction is crucial for the progression of multiple tumor types. Such inhibitors showed anticancer efficacy in vivo. Here, we describe a second class of CDC42 inhibitors with favorable drug-like properties. Out of the 25 compounds here reported, compound 15 (ARN25499) stands out as the best lead compound with an improved pharmacokinetic profile, increased bioavailability, and efficacy in an in vivo PDX tumor mouse model. Our results indicate that these CDC42 inhibitors represent a promising chemical class toward the discovery of anticancer drugs, with ARN25499 as an additional lead candidate for preclinical development.

Par3/bazooka binds NICD and promotes notch signaling during Drosophila development.

The conserved bazooka (baz/par3) gene acts as a key regulator of asymmetrical cell divisions across the animal kingdom. Associated Par3/Baz-Par6-aPKC protein complexes are also well known for their role in the establishment of apical/basal cell polarity in epithelial cells. Here we define a novel, positive function of Baz/Par3 in the Notch pathway. Using Drosophila wing and eye development, we demonstrate that Baz is required for Notch signaling activity and optimal transcriptional activation of Notch target genes. Baz appears to act independently of aPKC in these contexts, as knockdown of aPKC does not cause Notch loss-of-function phenotypes. Using transgenic Notch constructs, our data positions Baz activity downstream of activating Notch cleavage steps and upstream of Su(H)/CSL transcription factor complex activity on Notch target genes. We demonstrate a biochemical interaction between NICD and Baz, suggesting that Baz is required for NICD activity before NICD binds to Su(H). Taken together, our data define a novel role of the polarity protein Baz/Par3, as a positive and direct regulator of Notch signaling through its interaction with NICD.

Wg/Wnt-signaling-induced nuclear translocation of ß-catenin is attenuated by a ß-catenin peptide through its interference with the IFT-A complex.

Wnt/Wingless (Wg) signaling is critical in development and disease, including cancer. Canonical Wnt signaling is mediated by ß-catenin/Armadillo (Arm in Drosophila) transducing signals to the nucleus, with IFT-A/Kinesin 2 complexes promoting nuclear translocation of ß-catenin/Arm. Here, we demonstrate that a conserved small N-terminal Arm34-87/ß-catenin peptide binds to IFT140, acting as a dominant interference tool to attenuate Wg/Wnt signaling in vivo. Arm34-87 expression antagonizes endogenous Wnt/Wg signaling, resulting in the reduction of its target expression. Arm34-87 inhibits Wg/Wnt signaling by interfering with nuclear translocation of endogenous Arm/ß-catenin, and this can be modulated by levels of wild-type ß-catenin or IFT140, with the Arm34-87 effect being enhanced or suppressed. Importantly, this mechanism is conserved in mammals with the equivalent ß-catenin24-79 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt signaling can be regulated by a defined N-terminal ß-catenin peptide and thus might serve as an entry point for therapeutic applications to attenuate Wnt/ß-catenin signaling.

Characterization of a chromatin-associated TCF7L1 complex in human embryonic stem cells.

Human embryonic stem cells (hESCs) resemble the pluripotent epiblast cells found in the early postimplantation human embryo and represent the "primed" state of pluripotency. One factor that helps primed pluripotent cells retain pluripotency and prepare genes for differentiation is the transcription factor TCF7L1, a member of a small family of proteins known as T cell factors/Lymphoid enhancer factors (TCF/LEF) that act as downstream components of the WNT signaling pathway. Transcriptional output of the WNT pathway is regulated, in part, by the activity of TCF/LEFs in conjunction with another component of the WNT pathway, ß-CATENIN. Because TCF7L1 plays an important role in regulating pluripotency, we began to characterize the protein complex associated with TCF7L1 when bound to chromatin in hESCs using rapid immunoprecipitation of endogenous proteins (RIME).  Data are available via ProteomeXchange with identifier PXD047582. These data identify known and new partners of TCF7L1 on chromatin and provide novel insights into how TCF7L1 and pluripotency itself might be regulated.

Effect of ambient air pollution on hospital admission for respiratory diseases in Hanoi children during 2007-2019.

Air pollution poses a threat to children's respiratory health. This study aims to quantify the association between short-term air pollution exposure and respiratory hospital admissions among children in Hanoi, Vietnam, and estimate the population-attributable burden using local data. A case-crossover analysis was conducted based on the individual records where each case is their own control. The health data was obtained from 13 hospitals in Hanoi and air pollution data was collected from four monitoring stations from 2007 to 2019. We used conditional logistic regression to estimate Percentage Change (PC) and 95% Confidence Interval (CI) in odd of hospital admissions per 10 µg/m3 increase in daily average particulate matter (e.g. PM1, PM2.5, PM10), Sulfur Dioxide (SO2), Nitrogen Dioxide (NO2), 8-h maximum Ozone and per 1000 µg/m3 increase in daily mean of Carbon Monoxide (CO). We also calculated the number and fraction of admissions attributed to air pollution in Hanoi by using the coefficient at lag 0. A 10 µg/m3 increase in the concentration of PM10, PM2.5, PM1, SO2, NO2, O3 8-h maximum and 1000 µg/m3 increase in CO concentration was associated with 0.6%, 1.2%, 1.4%, 0.8%, 1.6%, 0.3%, and 1.7% increase in odd of admission for all respiratory diseases among children under 16 years at lag 0-2. All PM metrics and NO2 are associated with childhood admission for pneumonia and bronchitis. Admissions due to asthma and upper respiratory diseases are related to increments in NO2 and CO. For attributable cases, PM2.5 concentrations in Hanoi exceeding the World Health Organization Air Quality Guidelines accounted for 1619 respiratory hospital admissions in Hanoi children in 2019. Our findings show that air pollution has a detrimental impact on the respiratory health of Hanoi children and there will be important health benefits from improved air quality management planning to reduce air pollution in Vietnam.

The complex relationship of Wnt-signaling pathways and cilia.

Wnt family proteins are secreted glycolipoproteins that signal through multitude of signal transduction pathways. The Wnt-pathways are conserved and critical in all metazoans. They are essential for embryonic development, organogenesis and homeostasis, and associated with many diseases when defective or deregulated. Wnt signaling pathways comprise the canonical Wnt pathway, best known for its stabilization of ß-catenin and associated nuclear ß-catenin activity in gene regulation, and several non-canonical signaling branches. Wnt-Planar Cell Polarity (PCP) signaling has received the most attention among the non-canonical Wnt pathways. The relationship of cilia to Wnt-signaling is complex. While it was suggested that canonical Wnt signaling requires cilia this notion was always challenged by results suggesting the opposite. Recent developments provide insight and clarification to the relationship of Wnt signaling pathways and cilia. First, it has been now demonstrated that while ciliary proteins, in particular the IFT-A complex, are required for canonical Wnt/ß-catenin signaling, the cilium as a structure is not. In contrast, recent work has defined a diverged canonical signaling branch (not affecting ß-catenin) to be required for ciliary biogenesis and cilia function. Furthermore, the non-canonical Wnt-PCP pathway does not affect cilia biogenesis per se, but it regulates the position of cilia within cells in many cell types, possibly in all cells where it is active, with cilia being placed near the side of the cell that has the Frizzled-Dishevelled complex. This Wnt/PCP feature is conserved with both centrioles and basal bodies/cilia being positioned accordingly, and it is also used to align mitotic spindles within the Wnt-PCP polarization axis. It also coordinates the alignment of cilia in multiciliated cells. This article addresses these new insights and different links and relationships between cilia and Wnt signaling.

HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver.

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the Clock gene alters the circadian oscillation of P2- (but not P1-)HNF4α RNA, revealing a complex feedback loop between the HNF4α isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure of the Hnf4a gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

ABERRANT METHYLATION OF CANCER-RELATED GENES IN VIETNAMESE BREAST CANCER PATIENTS: ASSOCIATIONS WITH CLINICOPATHOLOGICAL FEATURES.

BACKGROUND: Epigenetic alteration is one of the most common molecular changes identified in the progression of breast cancer (BC). AIM: To study the frequency and relation between methylation of BRCA1, MLH1, MGMT, GSTP1, APC, RASSF1A, p16, WIF, and EGFR and the clinicopathological features in Vietnamese BC patients. MATERIALS AND METHODS: Methylation-specific polymerase chain reaction (MS-PCR) and SPSS 20.0 software were utilized in order to identify methylated frequency as well as evaluate its relationship with the patient's clinical features. RESULTS: In 162 BC cases, the methylation rates of the selected genes were 53.7%, 22.8%, 38.9%, 34.6%, 29.0%, 46.3%, 20.4%, 18.5%, and 28.4% respectively. In 32 cases of benign breast diseases (BBD) - 12.5%, 15.6%, 6.3%, 3.1%, 12.5%, 21.9%, 3.1%, 15.6% and 3.1%. BC samples displayed higher BRCA1, MGMT, GSTP1, APC, RASSF1A, WIF1, and p16 methylation levels than BBD samples (p < 0.001). Hypermethylation of BRCA1, GSTP1, and RASSF1A was predominant in the invasive ductal carcinoma, while hypermethylation of BRCA1, GSTP1, RASSF1A, WIF-1, and p16 was found to significantly correlate with lymph node metastasis (p < 0.05). Hypermethylation of BRCA1, MGMT, and GSTP1 was more common in stage III (p < 0.05) than in stages I/II, whereas MLH1 methylation was predominant in stage I and APC methylation was less common in stage III (p = 0.03). In addition, methylation of RASSF1A and EGFR was more frequent in younger patients (p < 0.01) than in elder patients. CONCLUSION: These data suggest that a gene panel (BRCA1/MGMT/GSTP1) can be used to support the diagnosis and screening of Vietnamese patients' BC with a sensitivity of 70%, and a specificity of 85%.

Wg/Wnt-signaling induced nuclear translocation of ß-catenin is attenuated by a ß-catenin peptide through its interaction with IFT-A in development and cancer cells.

Wnt/Wingless (Wg) signaling is critical for many developmental patterning processes and linked to diseases, including cancer. Canonical Wnt-signaling is mediated by ß-catenin, Armadillo/Arm in Drosophila transducing signal activation to a nuclear response. The IFT-A/Kinesin-2 complex is required to promote the nuclear translocation of ß-catenin/Arm. Here, we define a small conserved N-terminal Arm/ß-catenin (Arm 34-87 ) peptide, which binds IFT140, as a dominant interference tool to attenuate Wg/Wnt-signaling in vivo . Expression of Arm 34-87 is sufficient to antagonize endogenous Wnt/Wg-signaling activation resulting in marked reduction of Wg-signaling target gene expression. This effect is modulated by endogenous levels of Arm and IFT140, with the Arm 34-87 effect being enhanced or suppressed, respectively. Arm 34-87 thus inhibits Wg/Wnt-signaling by interfering with the nuclear translocation of endogenous Arm/ß-catenin. Importantly, this mechanism is conserved in mammals with the equivalent ß-catenin 34-87 peptide blocking nuclear translocation and pathway activation, including in cancer cells. Our work indicates that Wnt-signaling can be regulated by a defined N-terminal peptide of Arm/ß-catenin, and thus this might serve as an entry point for potential therapeutic applications to attenuate Wnt/ß-catenin signaling.

Design, Synthesis, In Vitro and In Vivo Characterization of CDC42 GTPase Interaction Inhibitors for the Treatment of Cancer.

CDC42 GTPases (RHOJ, CDC42, and RHOQ) are overexpressed in multiple tumor types and activate pathways critical for tumor growth, angiogenesis, and metastasis. Recently, we reported the discovery of a novel lead compound, ARN22089, which blocks the interaction of CDC42 GTPases with specific downstream effectors. ARN22089 blocks tumor growth in BRAF mutant mouse melanoma models and patient-derived xenografts (PDXs) in vivo. ARN22089 also inhibits tumor angiogenesis in three-dimensional vascularized microtumor models in vitro. Notably, ARN22089 belongs to a novel class of trisubstituted pyrimidines. Based on these results, we describe an extensive structure-activity relationship of ∼30 compounds centered on ARN22089. We discovered and optimized two novel inhibitors (27, ARN25062, and 28, ARN24928), which are optimal back-up/follow-up leads with favorable drug-like properties and in vivo efficacy in PDX tumors. These findings further demonstrate the potential of this class of CDC42/RHOJ inhibitors for cancer treatment, with lead candidates ready for advanced preclinical studies.

Patient-Reported Mental Health Outcomes After Single-Digit Non-thumb Traumatic Amputation in Adults.

Background: Though traumatic digital amputations are common, outcomes data are scarce. The FRANCHISE study clarified functional outcomes after digital amputation, but little information is available regarding mental health outcomes. The aims of this study were to document patient-reported mental health outcomes after traumatic digital amputation, elucidate the relationship between mental health and functional outcomes, and determine which patient/injury attributes conferred risk of unfavorable mental health outcomes. Methods: This was a descriptive, retrospective study of 77 patients with history of single digit, non-thumb traumatic amputation. Eligible patients completed Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity, Pain Interference, Anger, Anxiety, and Depression computer adaptive tests, and a short questionnaire recorded handedness, demographics, and worker's compensation status. Results: Correlation across the 3 PROMIS mental health domains (Anger, Anxiety, Depression) was uniformly strong and statistically significant. Correlation between the PROMIS mental health and functional (Upper Extremity and Pain Interference) scores was statistically significant but much weaker. Multivariable analysis revealed younger age and a worker's compensation claim had independent statistically significant predictive value for worse PROMIS Anger, Anxiety, and Depression scores. Female sex was also found to independently predict PROMIS Anxiety. Conclusions: By identifying patients at increased risk for feelings of anger, anxiety, and depression after digital amputation, anticipatory counseling can be provided. Anger, anxiety, and depression are very likely to coexist in the same patient; when responding to a patient who exhibits 1 element of this triad, the surgeon should be aware that the other 2 elements are likely to be present, even if not obvious.

Notch-dependent Abl signaling regulates cell motility during ommatidial rotation in Drosophila.

A collective cell motility event that occurs during Drosophila eye development, ommatidial rotation (OR), serves as a paradigm for signaling-pathway-regulated directed movement of cell clusters. OR is instructed by the EGFR and Notch pathways and Frizzled/planar cell polarity (Fz/PCP) signaling, all of which are associated with photoreceptor R3 and R4 specification. Here, we show that Abl kinase negatively regulates OR through its activity in the R3/R4 pair. Abl is localized to apical junctional regions in R4, but not in R3, during OR, and this apical localization requires Notch signaling. We demonstrate that Abl and Notch interact genetically during OR, and Abl co-immunoprecipitates in complexes with Notch in eye discs. Perturbations of Abl interfere with adherens junctional organization of ommatidial preclusters, which mediate the OR process. Together, our data suggest that Abl kinase acts directly downstream of Notch in R4 to fine-tune OR via its effect on adherens junctions.

Combined pectoralis and rectus abdominis flaps are associated with improved outcomes in sternal reconstruction.

BACKGROUND: Mortality increases nearly 5-fold in the approximately 5% of patients who develop sternal wound complications after cardiothoracic surgery. Flap-based reconstruction can improve outcomes by providing well-vascularized soft tissue for potential space obliteration, antibiotic delivery, and wound coverage; however, reoperation and readmission rates remain high. This study used the high case volume at a tertiary referral center and a diverse range of reconstructive approaches to compare various types of flap reconstruction. Combined (pectoralis and rectus abdominis) flap reconstruction is hypothesized to decrease sternal wound complication-related adverse outcomes. METHODS: A retrospective cohort study of consecutive adult patients treated for cardiothoracic surgery sternal wound complications between 2008 and 2018 was performed. Patient demographics, comorbidities, wound characteristics, surgical parameters, and perioperative data were collected. Multivariable regression modeling with stepwise forward selection was used to characterize predictive factors for sternal wound-related readmissions and reoperations. RESULTS: In total, 215 patients were assessed for sternal wound reconstruction. Patient mortality at 1 year was 12.4%. Flap selection was significantly associated with sternal wound-related readmissions (P = .017) and reoperations (P = .014). Multivariate regression demonstrated rectus abdominis flap reconstruction independently predicted increased readmissions (odds ratio 3.4, P = .008) and reoperations (odds ratio 2.9, P = .038). Combined pectoralis and rectus abdominis flap reconstruction independently predicted decreased readmissions overall (odds ratio 0.4, P = .031) and in the deep sternal wound subgroup (odds ratio 0.1, P = .033). CONCLUSION: Although few factors can be modified in this complex highly comorbid population with a challenging and rare surgical problem, consideration of a more surgically aggressive multiflap reconstructive approach may be justified to improve outcomes.

National Trends and Outcomes in Adolescents Undergoing Bariatric Surgery.

BACKGROUND: In the US, obesity continues to be a severe health issue now affecting adolescents. Bariatric surgery remains the most effective treatment for obesity, but use among adolescents remains low. The objective of this study was to identify current national trends in bariatric surgery among adolescents. STUDY DESIGN: Using the Nationwide Inpatient Sample database, adolescents aged 9 to 19 with a diagnosis of morbid obesity who underwent a laparoscopic gastric bypass (Roux-en-Y gastric bypass) or laparoscopic sleeve gastrectomy (SG) between 2015 and 2018 were identified. Demographics, comorbidities, and in-hospital complications were collected. National estimates were calculated. The trend of annual number of operations was determined by Kruskal-Wallis rank test. RESULTS: Between 2015 and 2018, 1,203 adolescents were identified, resulting in a nationwide estimate of 4,807 bariatric cases. The number of bariatric operations increased annually from 1,360 in 2015 to 1,740 operations in 2018 (p = 0.0771). The majority of patients were female (76%), 17 to 19 years old (84.1%), and White (47.9%). Most patients underwent SG (82.0%). Black and Hispanic patients comprised 40.2% of the cohort. Significant comorbidities included diabetes, dyslipidemia, nonalcoholic fatty liver disease, hypertension, and sleep apnea. The average length of stay decreased from 2.12 days to 1.64 days. There were no in-hospital mortalities, and complications were less than 1%. CONCLUSIONS: With the increasing prevalence of obesity among adolescents in the US, bariatric surgery increased over time but was performed less in patients younger than 16 years of age and racial minorities. Bariatric surgery among adolescents remains safe, with extremely low complication rates and zero in-hospital mortality.

Characterization of Host-Pathogen-Device Interactions in Pseudomonas aeruginosa Infection of Breast Implants.

BACKGROUND: Pseudomonas aeruginosa accounts for 7 to 22 percent of breast implant-associated infections, which can result in reconstructive failures and explantation. Investigating host-pathogen-device interactions in mice and patient samples will improve the understanding of colonization mechanisms, for targeted treatments and clinical guidelines. METHODS: Mice with and without implants were infected with PAO1 laboratory strain or BIP2 or BIP16 clinical strains and killed at 1 day or 7 days after infection to evaluate for colonization of implants and underlying tissues by means of colony-forming unit enumeration. Immunostaining was performed on mouse implants, human tissue expanders colonized by BIP2, and acellular dermal matrix colonized by BIP16. RESULTS: Colonization of tissues and smooth implants by P. aeruginosa was strain-dependent: at 1 day after infection, all strains acutely infected tissues with and without implants with colonization levels reflecting growth rates of individual strains. At 7 days after infection, PAO1 caused colonization of approximately 10 5 colony-forming units/100 mg of tissue but required implant presence, whereas in mice infected with BIP2/BIP16, colony-forming units were below the limit of detection with or without implants. Immunofluorescence staining of mouse implants, however, demonstrated continued presence of BIP2 and BIP16. Staining showed co-localization of all strains with fibrinogen, collagen I, and collagen III on mouse and human samples. CONCLUSIONS: The trajectory of P. aeruginosa in breast implant-associated infections was strain-dependent, and strains could exhibit acute symptomatic or chronic asymptomatic colonization. With strains causing clinical symptoms, the presence of an implant significantly worsened infection. For asymptomatic colonizers, further studies investigating their long-term impacts, especially during periods of immunosuppression in hosts, are needed.

Different strategies by distinct Wnt-signaling pathways in activating a nuclear transcriptional response.

The Wnt family of secreted glycolipo-proteins signals through multiple signal transduction pathways and is essential for embryonic development and organ development and homeostasis. The Wnt-pathways are conserved and critical in all metazoans. Wnt signaling pathways comprise the canonical Wnt/ß-catenin pathway and several non-canonical signaling branches, of which Wnt-Planar Cell Polarity (PCP) signaling and the Wnt/Calcium pathway have received the most attention and are best understood. nterestingly, all Wnt-pathways have a nuclear signaling branch and also can affect many cellular processes independent of its nuclear transcriptional regulation. Canonical Wnt/ß-catenin signaling is the most critical for a nuclear transcriptional response, in both development and disease, yet the mechanism(s) on how the "business end" of the pathway, ß-catenin, translocates to the nucleus to act as co-activator to the TCF/Lef transcription factor family still remains obscure. Here we discuss and compare the very different strategies on how the respective Wnt signaling pathways activate a nuclear transcriptional response. We also highlight some recent new insights into how ß-catenin is translocated to the nucleus via an IFT-A, Kinesin-2, and microtubule dependent mechanism and how this aspect of canonical Wnt-signaling uses ciliary proteins in a cilium independent manner, conserved between Drosophila and mammalian cells.

Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer.

CDC42 family GTPases (RHOJ, RHOQ, CDC42) are upregulated but rarely mutated in cancer and control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. Here, we use computer-aided drug design to discover a chemical entity (ARN22089) that has broad activity against a panel of cancer cell lines, inhibits S6 phosphorylation and MAPK activation, activates pro-inflammatory and apoptotic signaling, and blocks tumor growth and angiogenesis in 3D vascularized microtumor models (VMT) in vitro. Additionally, ARN22089 has a favorable pharmacokinetic profile and can inhibit the growth of BRAF mutant mouse melanomas and patient-derived xenografts in vivo. ARN22089 selectively blocks CDC42 effector interactions without affecting the binding between closely related GTPases and their downstream effectors. Taken together, we identify a class of therapeutic agents that influence tumor growth by modulating CDC42 signaling in both the tumor cell and its microenvironment.

Predictors of Digital Amputation in Diabetic Patients With Surgically Treated Finger Infections.

BACKGROUND: Diabetes is a well-established risk factor for severe digital infection, and patients are more likely to require digital amputation for adequate source control. This study aims to identify factors predictive of digital amputation compared with preservation in patients with diabetes who present with surgically treated finger infections. METHODS: Current Procedural Terminology (CPT) and International Classification of Diseases Versions 9 and 10 (ICD-9/10) databases from a single academic medical center were queried to identify patients with type 1 or type 2 diabetes mellitus who underwent surgical treatment in the operating room for treatment of a digital infection from 2010 to 2020. Electronic medical records were reviewed to obtain historical and acute clinical variables at the time of hospital presentation. Bivariate and multivariable regression were used to identify factors associated with amputation. RESULTS: In total, 145 patients (61 digital amputation, 84 digital preservation) met inclusion criteria for this retrospective cohort study. Mean hospital stay was 6 days, and the average patient underwent 2 operations. Multivariable analysis revealed that the presence of osteomyelitis, ipsilateral upper extremity dialysis fistula, end-stage renal disease, and vascular disease each had significant independent predictive value for amputation rather than digital preservation. CONCLUSIONS: Digital amputation is common in the setting of diabetic finger infection. The 4 variables found to independently predict the outcome of amputation can be understood as factors which decrease the likelihood of successful digital salvage and increase the potential consequence of ongoing uncontrolled infection. Further study should focus on clinical factors affecting surgical decision making and how the treatment rendered affects patient outcomes.