Citations

Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.

The objective is to create an automated knowledge extraction tool for cancer research that builds high-quality academic corpora for LLM fine-tuning while investigating its effectiveness in interleukin-6 and bladder cancer domains. To address the current gap in knowledge retrieval techniques for cancer research data collection, we propose KnowledgePipeline, a novel automated tool that incorporates diverse aspects of academic papers and metadata. Our tool integrates content, co-citations, and co-authorship networks to construct domain-specific academic corpora suitable for fine-tuning LLMs. We leverage two LLMs (GPTJ-6.7B and Galactica30B) trained on domain-specific question-answer pairs from the refined data. The system’s evaluation focuses on both the quality of extracted knowledge and the performance of fine-tuned models in open-ended question-answering tasks. We see that KnowledgePipeline offers a scalable, automated framework for domain-specific knowledge retrieval and fine-tuned applications in cancer research, advancing literature discovery and addressing critical biomedical challenges. It achieved high relevance scores of 68% for IL-6 and 74.5% for bladder cancer, with a fine-tuned Galactica-30B model demonstrating promising capabilities.

Background: The radiolunate joint is conventionally thought to be spared from radiocarpal osteoarthritis, but proximal lunate degenerative changes have been noted. An investigation of radiolunate arthrokinematics in ostensibly healthy wrists may improve understanding of posttraumatic and postoperative outcomes. We hypothesize that four-dimensional computed tomography (4DCT)-derived radiolunate arthrokinematics during motion will differ between wrists with type 1 and type 2 lunates. The clinical-translational relevance of this analysis is highlighted using a 4DCT case study of scaphoid excision with 4-corner arthrodesis (SEFCA). Methods: Four-dimensional computed tomography data were collected during flexion-extension and radioulnar deviation in 19 healthy wrists (mean [SD] age: 43.6 [11.7] years, 21.1% female) and 1 wrist 3 years after SEFCA (male, 52 years). Carpal osteokinematics and joint arthrokinematics were calculated to derive median radiolunate interosseous proximities at each 4DCT-captured timepoint. Results: Median radiolunate interosseous proximities during motion are well approximated by second-order regressions in uninjured wrists. In the arthrodesed wrist, closest proximities occurred at the extremes of motion except maximum radial deviation. Conclusions: This study quantifies a normative range of median radiolunate interosseous proximities during wrist motion. The normative 4DCT datasets provide a reference range for evaluating postoperative arthrokinematics, suggesting the clinical-translational potential of dynamic imaging. The case study highlights applications for patient-level postoperative evaluation, which can be expanded to other pathologies, surgeries, or conditions in the future.

This study aimed to determine if extended infusion (EI; over > 3 hr) beta-lactam therapy increased IV access requirements compared with traditional dosing (TD; over 30 min). Eighty-six adult ICU patients treated with TD anti-pseudomonal beta-lactams who underwent therapeutic drug monitoring (TDM) were included. Patients who transitioned from TD to EI after TDM (EI group) were matched 1:1 to patients who remained on TD. In the primary analysis, the median (interquartile range) total number of lumens in the 24 hours before TDM compared with the 48 hours after TDM were similar between groups (pre: TD 3 [2–5] vs. EI 4 [3–5]; p = 0.22 and post: TD 3 [2–4] vs. EI 4 [3–5]; p = 0.05). Delivery of beta-lactams via EI was not associated with a need for more IV access. Practical challenges such as access should not limit use of EI beta-lactams when indicated.

Abstract Objective We hypothesized that a set of immunohistochemistry (IHC) stains could be used to distinguish Burkitt lymphoma (BL), the quintessential B-cell lymphoma with a germinal center B-cell (GCB) dark zone (DZ) expression signature, from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). This might also be applicable to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 rearrangements (double-hit lymphomas [DHLs]) and triple-hit lymphomas (THLs). Methods A 5-marker IHC algorithm was designed from gene lists that distinguish physiologic DZ from light zone GCBs. Results In training and validation cohorts, we distinguished BL from DLBCL, NOS with high sensitivity and specificity. Because DHLs/THLs are enriched for the gene expression DZ signature (DZsig), we evaluated 19 DHLs/THLs and 4 HGBCLs, NOS. Most (83%) cases were IHC DZ. The NanoString DLBCL90 assay was performed on 34 cases to correlate IHC DZ results with the molecular DZsig. The IHC DZ call was significantly associated with the DZsig (P = .0011). The sensitivity and specificity of IHC to recognize DZsig+ cases among DLBCL, NOS and DHLs with BCL2 rearrangements/THLs were 91% and 100%, respectively. Conclusions The IHC DZ algorithm can support a diagnosis of BL and identifies MYC-BCL2 DHLs/THLs with a molecular DZsig.

Background: The authors present a novel microsurgical model to investigate ischemia-reperfusion (I/R) injury in composite tissue (muscle/skin) using a musculocutaneous flap. I/R was induced in a rodent biceps femoris musculocutaneous flap through collateral ligation and arteriovenous clamping. The authors hypothesized that I/R flaps would show greater tissue damage compared with sham. Methods: Male rats were randomized into I/R ( n = 10) and sham ( n = 9) groups. The I/R group underwent flap elevation, collateral ligation, 3 hours of arteriovenous clamping, followed by reperfusion. The sham group had flap elevation only. Perfusion was monitored using laser-speckle imaging, and flap discoloration was assessed with blinded skin ischemia necrosis scores. Serum and the composite tissue (skin/muscle) were analyzed for injury on postoperative days (PODs) 1 or 3. Results: Clamping reduced perfusion ( P = 0.00), whereas unclamping increased perfusion ( P <0.00). Over time, flaps exposed to I/R were more ischemic (estimate, 0.39; P = 0.02). At POD1, the injury group had higher serum creatine kinase ( P = 0.04) and potassium ( P = 0.00) than the sham group. The injury group had more muscle apoptosis (34.7% versus 5.2%; P = 0.03), myonecrosis (30.3% versus 14.1%; P = 0.04), and inflammation (13.7% versus 4.9%; P = 0.02) than the sham group; myonecrosis and inflammation persisted into POD3. Skin apoptosis and inflammation were similar. Conclusions: This model reliably reproduces I/R injury with a 3-hour ischemic period followed by early reperfusion. Animals subjected to the authors’ technique showed greater tissue damage than the sham group, with muscle being more vulnerable than skin. Serum showed peak muscle injury at 24 hours, and histologic analysis showed myonecrosis and inflammation through 72 hours. This suggests that less than 24 hours’ reperfusion (eg, critical window) may serve as the optimal time for possible intervention. Clinical Relevance Statement: I/R injury is a complex phenomenon affecting vascular composite tissues. The mitochondrial superoxide dismutase may be more specific for I/R injury. There may be a critical window within which to mitigate injury (<24 hours after reperfusion). The authors’ model helps investigate muscle/skin I/R injury.

Clonus is a disabling symptom of upper motor neuron dysfunction in patients with multiple sclerosis (MS). We report immediate termination of mechanically evoked clonus by epidural lumbosacral spinal cord stimulation (ES) in a 58-year-old man with secondary progressive MS. This observation was captured during training using video and skin surface electromyography of soleus muscle activity. ES immediately reduced mechanically evoked clonus duration and cycle count compared to trials without stimulation, as determined by a Kruskal–Wallis test ( p < 0.05, n = 2–3 trials), and reverted to baseline status when stimulation was off.

Background: Cholestatic liver diseases, including primary sclerosing cholangitis, are characterized by biliary fibroinflammation. TGFβ-activated cholangiocytes release signals that recruit immune cells and activate myofibroblasts, promoting inflammation and extracellular matrix (ECM) deposition. TGFβ also regulates stearoyl-CoA desaturase (SCD), an enzyme involved in lipid signaling. Yet, the role of SCD or its inhibitor, Aramchol, in biliary fibroinflammation had not been studied. Methods and Results: Mdr2 -/- with established biliary fibrosis and 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) diet-fed mice were treated with Aramchol meglumine (12.5 mg/kg/day). Hepatic fibrosis was assessed by qPCR, Picrosirius red staining, immunofluorescence, and hydroxyproline content. Human H69 or murine large cholangiocyte cell lines stimulated with TGFβ, as well as PSC-derived cholangiocytes (PSC-C), were treated with Aramchol or SCD siRNA. RNA-seq, fibroinflammatory marker expression, peroxisome proliferator-activated receptor (PPAR) activity, and targeted fatty acid profiling were performed. Aramchol treatment significantly reduced hepatic ECM gene expression, inflammatory cytokines ( Il6 , Tnfa ), collagen content, and myofibroblast activation (aSMA staining) in both mouse models. In TGFβ-stimulated H69 cells, Aramchol suppressed hepatic fibrosis pathways and enhanced PPAR signaling. Aramchol also reduced the expression of fibrotic markers, myofibroblast-activating mediators ( VEGFA and PDGFB ), and IL6, mirroring the effects of SCD knockdown. In PSC-C, Aramchol significantly downregulated SCD, VEGFA and IL6 . Conversely, PPARα and -γ activity and fatty acid agonist, linoleic acid levels were increased in cholangiocyte cell lines. Conclusions: Aramchol attenuates and prevents biliary fibrosis in mouse models of cholestatic liver disease by inhibiting TGFβ-induced fibroinflammatory mediators and activating PPARa/γ in cholangiocytes. These findings, combined with its favorable clinical safety profile, support the potential of Aramchol as a therapeutic candidate for PSC.

Abstract Purpose It remains unclear whether increasing the frequency of administration of 0.01% atropine improves its effectiveness in slowing axial elongation or refractive progression. This study compared twice‐daily 0.01% atropine administration and traditional once‐nightly administration. Methods A hybrid design was adopted incorporating both retrospective and prospective elements, with participants observed for 1 year. The control group (received saline eye drops) and once‐daily 0.01% atropine group (Atropine‐1 group) were derived from two previous trials, while the twice‐daily 0.01% atropine group (Atropine‐2 group) was enrolled prospectively. A total of 163 participants were included in the intention‐to‐treat set, with 51, 70 and 42 participants in the control, Atropine‐1 and Atropine‐2 groups, respectively. The primary outcome was the change in axial length (AL), and the secondary outcome was the change in cycloplegic spherical equivalent refraction (SER). Results Compared with the control group (0.48 ± 0.22 mm), both Atropine‐1 (0.26 ± 0.17 mm) and Atropine‐2 (0.15 ± 0.18 mm) groups showed significantly reduced AL elongation ( p < 0.001). Notably, Atropine‐2 significantly improved slowing of AL elongation compared with Atropine‐1 ( p = 0.008). The result of the secondary outcome (adjusted SER change) was consistent. Atropine‐2 was significantly more effective in slowing SER progression (−0.15 ± 0.37 D) than Atropine‐1 (−0.41 ± 0.50 D) ( p = 0.02). Based on a multivariable model, age was identified as the key covariate to perform subgroup analyses. In the younger subgroup (8–10 years), AL elongation was significantly reduced in the Atropine‐2 group (0.16 ± 0.17 mm) compared with the Atropine‐1 group (0.36 ± 0.22 mm; p = 0.002). In the older subgroup (10–12 years), there was no significant difference in progression. Consistent results were observed in the sensitivity analyses based on the per‐protocol set. Conclusion Twice‐daily administration of 0.01% atropine was more effective than once daily in slowing AL elongation and SER progression in children 8 to 10 years of age. Further investigation with extended follow‐up is warranted to substantiate this finding.