Citations

ABSTRACT In our efforts to enhance sensitivity to PARP inhibitors, we identified clofarabine (CLF) as a potential therapy for drug-resistant ovarian cancer and nuclear trafficking of Cathepsin L (CTSL) as a treatment- responsive biomarker. Using PARP inhibitor-sensitive and -resistant OC cell lines, ex vivo cultures of patient-derived ovarian ascites (OVA), primary ovarian tumors, and xenografts (PDX), we found that CLF monotherapy induces nuclear CTSL (nCTSL) in CLF-responsive cells (CLF-r) and sensitizes them to PARP inhibitors olaparib and rucaparib. In CLF non-responsive cells (CLF-nr), a combination of CLF with olaparib is necessary for nCTSL trafficking and synergy. CLF+olaparib synergy was observed in 47% of CLF-r and 24% of CLF-nr OVA samples. Drug-induced nCTSL is crucial for DNA damage response, including cell cycle arrest and apoptosis. Knockdown of CTSL in both CLF-r and CLF-nr cells conferred resistance to the CLF+olaparib combination, emphasizing nCTSL’s role in the DNA damage response pathway (DDR). Mechanistically, CLF facilitates CTSL nuclear import via KPNB1 in CLF-r cells. In CLF-nr cells, both olaparib and CLF are needed to facilitate CTSL nuclear import. Additionally, CLF downregulates the nuclear export protein CRM1 (XPO1) in both cohorts. Interestingly, CLF does not downregulate CRM1 in a subset of OVAs (29%), and they were classified as CLF-resistant (CLF- Res). In these samples, inhibiting CRM1 with KPT8602 restored synergy between CLF and PARP inhibitors. In vivo, CLF-r and CLF-nr PDX models exhibited enhanced DDR, reduced tumor burden, and prolonged survival with the CLF+olaparib combination. These findings suggest the CLF+olaparib combination is a promising therapeutic strategy for drug-resistant OC by inducing DDR through CTSL nuclear localization.

Shear wave elasticity imaging is a non-invasive imaging modality that characterizes the mechanical properties of soft tissue, such as the shear wave speed or shear modulus. Present time-domain methods for shear wave parameter estimation divide the propagation distance by the propagation time to obtain an estimate of the shear wave speed. However, soft tissues are viscoelastic, and the shear viscosity frequently produces large errors in the estimated shear wave speed. To address this problem, a simplified time-domain model for shear wave parameter estimation in viscoelastic media is applied to simulated three-dimensional (3D) shear waves in a viscoelastic medium, where these 3D simulations require high performance computing to evaluate an approximate time-domain Green’s function solution of Navier’s equation that employs a Kelvin-Voigt rheological model. Parameters for the time-domain model are determined from an optimization procedure, then the shear wave speed is estimated from estimated time delays that account for the shear viscosity. Estimates of the shear wave speed are shown at the focal depth and in a two-dimensional region for various parameter combinations. The simplified time-domain viscoelastic model consistently yields smaller errors for the shear wave speed than cross-correlations while simultaneously providing estimates of the shear viscosity.

In soft tissue, the attenuation of shear waves satisfies a power law. However, the values of power law exponents for shear waves in various soft tissues remain unknown due to windowing artifacts that limit the effectiveness of present methods that are based on two-dimensional fast Fourier transforms. To solve this problem, a time-domain signal processing approach is proposed. Robust shear wave parameter estimates are obtained by minimizing the least-squares error between measured time-domain shear wave data and stable probability density functions that describe the solution to a closely related fractional-order diffusion equation. Assessments are performed with measured shear wave data collected from ex vivo pig liver using a Verasonics system with an L7-4 linear array transducer. Power law exponents are obtained from measured shear wave data at the focal depth between 1.2 and 13.9 mm from the center of the push beam. The mean estimated power law exponent for these locations is 0.74, and the standard deviation is 0.05. The results suggest that fractional calculus models that support power law exponents less than one are needed for shear waves in pig liver.

BACKGROUND: During orthotopic liver transplantation, allograft reperfusion is a dynamic point in the operation and often requires vasoactive medications and blood transfusions. Normothermic machine perfusion (NMP) of liver allografts has emerged to increase the number of transplantable organs and may have utility during donation after circulatory death (DCD) liver transplantation in reducing transfusion burden and vasoactive medication requirements. METHODS: This is a single-center retrospective study involving 226 DCD liver transplant recipients who received an allograft transported with NMP (DCD-NMP group) or with static cold storage (DCD-SCS group). Veno-venous bypass was not used in any patients. Infusion doses of norepinephrine, epinephrine, and vasopressin as well as bolus doses of vasoactive medications during reperfusion were recorded. Blood component therapy was recorded according to phase of liver transplantation and during the first 24 hours postprocedure. RESULTS: A total of 103 recipients in the DCD-NMP group and 123 patients in the DCD-SCS group were included. Post-reperfusion syndrome (PRS) incidence was reduced in the DCD-NMP group compared to the DCD-SCS group (10.7% [95% confidence interval, CI, 5.5%–18.3%] vs 42.3% [95% CI, 33.4%–51.5%]; P < .001). During the reperfusion period, patients in the DCD-SCS group required increased bolus doses of epinephrine and vasopressin compared to the DCD-NMP group (24.6 vs 7.5 µg; P < .001) and (5.4 vs 2.4 units; P < .001), respectively. The DCD-SCS group received a higher infusion dose of epinephrine during anhepatic phase, at reperfusion, and up to 90 minutes after reperfusion. In the postreperfusion period, there were significant increases in the transfusion of red blood cells (RBCs; 5.3 vs 3.7 units; P = .006), fresh frozen plasma (FFP; 3.4 vs 1.9 units; P < .001), cryoprecipitate (2.7 vs 1.8 pooled units; P = .015) and platelets (0.9 vs 0.4 units; P = .008) in the DCD-SCS group compared to the DCD-NMP group. During the first 24 hours postprocedure, transfusion of RBCs, FFP, and cryoprecipitate in the DCD-SCS group was increased compared to the DCD-NMP group ([2.6 vs 1.7 units; P = .028], [1.6 vs 0.8 units; P < .001], [1.5 vs 0.9 pooled units; P = .031]) respectively. Administration of tranexamic acid was more frequent in the DCD-SCS group during the post-reperfusion period compared to the DCD-NMP group (13% [95% CI, 5.7%–17.4%] vs 3.9% [95% CI, 1.1%–9.6% 95%]; P = .018). CONCLUSIONS: In DCD liver transplantation, use of NMP was associated with reduced incidence of PRS and decreased vasopressor and inotrope requirements at the time of allograft reperfusion compared to using SCS. Additionally, NMP was associated with reduced transfusion of all blood product components as well as antifibrinolytic agent administration in the post-reperfusion period. Reduced transfusion burden in the DCD-NMP group also occurred during the first 24 hours posttransplant.

Summary: Pyogenic flexor tenosynovitis (PFT), also known as septic or suppurative flexor tenosynovitis, is a closed-space infection of the hand’s flexor tendon sheath that necessitates timely diagnosis and treatment. The treatment consists of antibiotic therapy often combined with prompt surgical treatment. The most common surgical approach is the closed irrigation technique, which involves inserting a 16-gauge angiocatheter in the proximal aspect of the flexor tendon sheath, leaving the distal end of the Brunner incision open during the irrigation process. However, this method has its own challenges, such as catheter bending and kinking, thereby obstructing the fluid irrigation process and prolonging the operative duration. Instead, we propose the use of a rigid plastic facial fat grafting cannula, which is coupled to a 50-mL syringe with 0.9% saline solution. The cannula is placed at the level of the A1 pulley, and irrigation is easily performed. This simplifies this process by maintaining adequate fluid outflow through the flexor tendon sheath.

BACKGROUND AND OBJECTIVES: Vertebral artery injury (VAI) because of traumatic subaxial cervical spine injury is a rare but potentially devastating condition as it could lead to stroke. The aim of this study was to examine the incidence, risk factors, outcomes, and radiographic predictors of VAI in patients surgically treated for subaxial cervical spine injuries at a tertiary care trauma center. METHODS: This is a retrospective population-based cohort study, including all patients surgically treated for traumatic subaxial cervical spine injuries at the study center between 2006 and 2018. Primary outcomes included mortality and morbidity after the injury. Propensity score matching, survival, univariable, and multivariable analyses were used to study the outcomes of interest. RESULTS: Traumatic VAI primarily occurred after high-energy traumas such as motor vehicle accidents and falls from heights. The median age was 64.4 years (47.4-69.1), and 69% were male. In the cohort of patients with subaxial cervical injury, 54% had a spinal cord injury (SCI). In the subgroup with VAI, the frequency of SCI was 66% and a concomitant SCI and VAI were associated with a more severe American Spinal Cord Injury Association Impairment Scale grade ( P = .015). However, after accounting for age, sex, and associated injuries, VAI did not affect postoperative complications, short- or long-term outcomes, or mortality rates. Facet joint dislocation was a unique radiographic predictor of VAI (odds ratio 3.8 [CI 1.42-10.7], P = .009). CONCLUSION: The findings suggest that clinical outcomes of patients with traumatic cervical spine injuries were not negatively affected by the presence of a VAI. Several radiographic factors were associated with VAI; however, only facet joint dislocation remained as an independent predictor of this injury.

Background/Objectives: Little information has been published on patients diagnosed with brain metastasis secondary to lung cancer. Correlating outcome patterns (hospice care, lost to follow-up, death before hospice care or treatment) and specific characteristics of treated and untreated patients may identify subsets of patients who may benefit from treatment. Methods: We evaluated data from the Kentucky Cancer Registry and identified 284 cases who were diagnosed with brain metastasis secondary to non-small cell lung cancer (NSCLC) between 1 August 2016, and 31 December 2019. We evaluated type and timing of treatment received, as well as focused on those patients who did not receive treatment. For those patients who did not receive treatment, various characteristics that may have impacted their decision or ability to undergo follow-up were also evaluated. This included social history, disease burden, as well as oncology treatment timelines. Lastly, due to the high smoking rate in Kentucky, we conducted an analysis of patient tobacco use. Results: Our results show that 61 cases (21.8%) never received treatment for lung cancer with brain metastasis. Further analysis of the non-treated cases demonstrated that 19 cases (31.1%) never met with an oncology team while in the hospital or after discharge; 14 of the 61 cases (23.0%) were too sick to receive treatment and died prior to having the option of treatment; and 47 of the 61 cases (77.0%) may have had the option of treatment but declined. Conclusions: Historically, patients with brain metastases have faced poor prognoses and limited treatment options. However, advancements in systemic chemoimmunotherapy and targeted therapies have introduced new treatment possibilities, offering improved symptom control and the potential for prolonged survival. This analysis is crucial for identifying potential barriers to care, optimizing resource allocation, and guiding future research.

Abstract Limbic predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is highly prevalent in late life and a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC). LATE‐NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE‐NC is associated with a more rapid course. With the emergence of anti‐amyloid therapeutics, discrimination of LATE‐NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co‐pathology with LATE‐NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE‐NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). Highlights Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE‐NC) is a common co‐pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease‐modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE‐NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.