Androgens play an important role in prostate cancer development and progression. Androgen action is mediated through the androgen receptor (AR), a ligand-dependent DNA-binding transcription factor. AR is arguably the most important target for prostate cancer treatment. Current USA Food and Drug Administration (FDA)-approved AR inhibitors target the ligand-binding domain (LBD) and have exhibited efficacy in prostate cancer patients, particularly when used in combination with androgen deprivation therapy. Unfortunately, patients treated with the currently approved AR-targeting agents develop resistance and relapse with castration-resistant prostate cancer (CRPC). The major mechanism leading to CRPC involves reactivation of AR signaling mainly through AR gene amplification, mutation, and/or splice variants. To effectively inhibit the reactivated AR signaling, new approaches to target AR are being actively explored. These new approaches include novel small molecule inhibitors targeting various domains of AR and agents that can degrade AR. The present review provides a summary of the existing FDA-approved AR antagonists and the current development of some of the AR targeting agents.
Humans ; Male ; Androgen Receptor Antagonists/therapeutic use* ; Receptors, Androgen/metabolism* ; Prostatic Neoplasms/drug therapy* ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Signal Transduction/drug effects*

Objective: Traditional open discectomy has long been the standard treatment for lumbar disc herniation, but minimally invasive endoscopic approaches are increasingly being adopted. However, comprehensive comparative analyses of these techniques in terms of clinical outcomes remain limited. This study aimed to compare the short-term clinical outcomes of endoscopic versus open single-level lumbar discectomy, with the hypothesis that the endoscopic approach reduces postoperative complications within 1 month of surgery. Methods: This retrospective cohort study used data from the MARINER database, covering January 2017 to October 2022. Adult patients aged 18 to 74 years who underwent single-level lumbar discectomy were included. A total of 243,684 patients were identified (1,470 endoscopic and 242,214 open surgical procedures). A 1:3 propensity score matching was performed based on age, sex, Charlson Comorbidity Index, and selected comorbidities, yielding a balanced cohort of 5,640 patients (1,416 endoscopic; 4,224 open). Results: After matching, the demographic and comorbidity profiles of the 2 groups were well balanced. The endoscopic group demonstrated significantly lower rates of surgical site infections (0.35% vs. 0.95%, p<0.05; odds ratio [OR], 2.69; 95% confidence interval [CI], 1.06–6.85), surgical complications (0.71% vs. 1.52%, p<0.05; OR, 2.16; 95% CI, 1.11–4.17), and 30-day readmissions (2.47% vs. 7.65%, p<0.05; OR, 3.09; 95% CI, 2.19–4.36). Kaplan-Meier survival analysis over 18 months revealed no significant difference in the probability of subsequent lumbar fusion between groups (log-rank test p=0.8). Conclusion Endoscopic single-level lumbar discectomy is associated with fewer short-term complications compared with open surgery. These findings support the consideration of endoscopic techniques as a lower-risk alternative for appropriately selected patients. Further studies are needed to evaluate long-term outcomes.

Complex structural variants(CSVs)are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.How-ever,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery com-pared with simple structural variants.Here,we systematically analyzed the multi-breakpoint con-nection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70％,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.

The syndrome of the trephined is a neurologic phenomenon that manifests as sudden decline in cognition, behavior, and sensorimotor function due to loss of intracranial domain. This scenario typically occurs in the setting of large craniectomy defects, resulting from trauma, infection, and/or oncologic extirpation. Cranioplasty has been shown to reverse these symptoms by normalizing cerebral hemodynamics and metabolism. However, successful reconstruction may be difficult in patients with complex and/or hostile calvarial defects. We present the case of a 48-year-old male with a large cranial bone defect, who failed autologous cranioplasty secondary to infection, and developed rapid neurologic deterioration leading to a near-vegetative state. Following debridement and antibiotic therapy, delayed cranioplasty was accomplished using a polyetheretherketone (PEEK) implant with free chimeric latissimus dorsi/serratus anterior myocutaneous flap transfer for vascularized resurfacing. Significant improvements in cognition and motor skill were noted in the early postoperative period. At 6-month follow-up, the patient had regained the ability to speak, ambulate and self-feed—correlating with evidence of cerebral/ventricular re-expansion on computed tomography. Based on our findings, we advocate delayed alloplastic implantation with total vascularized soft tissue coverage as a viable alternative for reconstructing extensive, hostile calvarial defects in patients with the syndrome of the trephined.
Cognition ; Craniocerebral Trauma ; Debridement ; Follow-Up Studies ; Free Tissue Flaps ; Hemodynamics ; Humans ; Male ; Metabolism ; Middle Aged ; Motor Skills ; Myocutaneous Flap ; Neurologic Manifestations ; Postoperative Period ; Reconstructive Surgical Procedures

Protein kinases and phosphatases signal by phosphorylation and dephosphorylation to precisely control the activities of their individual and common substrates for a coordinated cellular outcome. In many situations, a kinase/phosphatase complex signals dynamically in time and space through their reciprocal regulations and their cooperative actions on a substrate. This complex may be essential for malignant transformation and progression and can therefore be considered as a target for therapeutic intervention. p38 is a unique MAPK family member that contains a PDZ motif at its C-terminus and interacts with a PDZ domain-containing protein tyrosine phosphatase PTPH1. This PDZ-coupled binding is required for both PTPH1 dephosphorylation and inactivation of p38 and for p38 phosphorylation and activation of PTPH1. Moreover, the p38/PTPH1 complex can further regulate their substrates phosphorylation and dephosphorylation, which impacts Ras transformation, malignant growth and progression, and therapeutic response. This review will use the p38/PTPH1 signaling network as an example to discuss the potential of targeting the kinase/phosphatase signaling complex for development of novel targeted cancer therapy.

Several non-receptor tyrosine kinase (nRTK) members are expressed in neurons of mammalian brains. Among these neuron-enriched nRTKs, two Src family kinase members (Src and Fyn) are particularly abundant at synaptic sites and have been most extensively studied for their roles in the regulation of synaptic activity and plasticity. Increasing evidence shows that the synaptic subpool of nRTKs interacts with a number of local substrates, including glutamate receptors (both ionotropic and metabotropic glutamate receptors), postsynaptic scaffold proteins, presynaptic proteins, and synapse-enriched enzymes. By phosphorylating specific tyrosine residues in the intracellular domains of these synaptic proteins either constitutively or in an activity-dependent manner, nRTKs regulate these substrates in trafficking, surface expression, and function. Given the high sensitivity of nRTKs to changing synaptic input, nRTKs are considered to act as a critical regulator in the determination of the strength and efficacy of synaptic transmission.

Azoreductases are involved in the bioremediation by bacteria of azo dyes found in waste water. In the gut flora, they activate azo pro-drugs, which are used for treatment of inflammatory bowel disease, releasing the active component 5-aminosalycilic acid. The bacterium P. aeruginosa has three azoreductase genes, paAzoR1, paAzoR2 and paAzoR3, which as recombinant enzymes have been shown to have different substrate specificities. The mechanism of azoreduction relies upon tautomerisation of the substrate to the hydrazone form. We report here the characterization of the P. aeruginosa azoreductase enzymes, including determining their thermostability, cofactor preference and kinetic constants against a range of their favoured substrates. The expression levels of these enzymes during growth of P. aeruginosa are altered by the presence of azo substrates. It is shown that enzymes that were originally described as azoreductases, are likely to act as NADH quinone oxidoreductases. The low sequence identities observed among NAD(P)H quinone oxidoreductase and azoreductase enzymes suggests convergent evolution.
Benzoquinones ; metabolism ; Catalytic Domain ; Enzyme Stability ; Evolution, Molecular ; Flavins ; chemistry ; Hot Temperature ; Kinetics ; Mesalamine ; chemistry ; NAD ; metabolism ; NADH, NADPH Oxidoreductases ; chemistry ; NADP ; metabolism ; Osmolar Concentration ; Oxidation-Reduction ; Phenylhydrazines ; chemistry ; Phylogeny ; Protein Binding ; Pseudomonas aeruginosa ; enzymology ; Spectrophotometry, Ultraviolet