Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Mirogabalin Decreases Pain-like Behaviours and Improves Opioid and Ketamine Antinociception in a Mouse Model of Neuropathic Pain

Neuropathic pain remains a difficult clinical challenge due to its diverse aetiology and complex pathomechanisms, which are yet to be fully understood. Despite the variety of available therapies, many patients suffer from ineffective pain relief; hence, the search for more efficacious treatments continues. The new gabapentinoid, mirogabalin has recently been approved for clinical use. Although its main mechanism of action occurs at the α2σ-1 and α2σ-2 subunits of calcium channels and is well documented, how the drug affects the disturbed neuropathic interactions at the spinal cord level has not been clarified, which is crucial information from a clinical perspective. The findings of our study suggest that several indirect mechanisms may be responsible for the beneficial analgesic effect of mirogabalin. This is the first study to report that mirogabalin enhances the mRNA expression of spinal antinociceptive factors, such as IL-10 and IL-18BP, and reduces the concentration of the pronociceptive substance P. Importantly, mirogabalin improves the morphine-, buprenorphine-, oxycodone-, and ketamine-induced antinociceptive effects in a neuropathic pain model. Our findings support the hypothesis that enhancing opioid and ketamine analgesia by combining these drugs with mirogabalin may represent a new strategy for the effective pharmacotherapy of neuropathic pain.

Emerging Molecular Markers Towards Potential Diagnostic Panels for Lupus

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease which can affect various tissues and organs, posing significant challenges for clinical diagnosis and treatment. The etiology of SLE is highly complex with contributions from environmental factors, stochastic factors as well as genetic susceptibility. The current criteria for diagnosing SLE is based primarily on a combination of clinical presentations and traditional lab testing. However, these tests have suboptimal sensitivity and specificity. They are unable to indicate disease cause or guide physicians in decision-making for treatment. Therefore, there is an urgent need to develop a more accurate and robust tool for effective clinical management and drug development in lupus patients. It is fortunate that the emerging Omics have empowered scientists in the discovery and identification of potential novel biomarkers of SLE, especially the markers from blood, urine, cerebrospinal fluids (CSF), and other bodily fluids. However, many of these markers have not been carefully validated for clinical use. In addition, it is apparent that individual biomarkers lack sensitivity or specificity. This review summarizes the sensitivity, specificity and diagnostic value of emerging biomarkers from recent studies, and discusses the potential of these markers in the development of biomarker panel based diagnostics or disease monitoring system in SLE.

In vitro activity of cefepime-taniborbactam against carbapenemase producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain

Novel β-lactam-β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB, formerly cefepime/VNRX-5133) and comparator agents against carbapenemase-producing Enterobacterales (n=247) and carbapenem-resistant Pseudomonas spp. (n=170) clinical isolates prospectively collected from different clinical origin in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MIC FTB ≤8/4 mg/L) and Pseudomonas populations (67.1% MIC FTB ≤8/4 mg/L). MIC FTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC- Klebsiella pneumoniae , 1 VIM- Enterobacter cloacae , 1 IMP- E. cloacae and 1 NDM- Escherichia coli ) and in 56/170 (32.9%) Pseudomonas spp., 19 of them carbapenemase producers (15 VIM, 2 GES, 1 GES+VIM, 1 GES+KPC). Against the Enterobacterales isolates with meropenem MIC>2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2% and 93.5% MIC FTB ≤8/4 mg/L, respectively) whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4% and 12.9%; meropenem-vaborbactam, 85.0% and 64.5%; imipenem-relebactam, 76.6% and 9.7%; ceftolozane-tazobactam, 1.9% and 0%; piperacillin-tazobactam, 0% and 0%, respectively). Among the meropenem-resistant Pseudomonas spp. isolates (163/170, MIC>2 mg/L), activity of FTB against serine-β-lactamase (35/163) and MBL producers (43/163) was 88.6% and 65.1%, respectively, whereas the susceptibility of comparators was: ceftazidime-avibactam, 88.5% and 16.0%; meropenem-vaborbactam, 8.5% and 7.0%; imipenem-relebactam, 2.9% and 2.3%; ceftolozane-tazobactam, 0% and 2.3%; and piperacillin-tazobactam, 0% and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.

Melatonin and cardiovascular disease: from mechanisms of action to potential clinical use (literature review)

Cardiovascular disease remains the most relevant public health problem. Most cardiovascular diseases are associated with an atherosclerosis, the development of which is associated with inflammation and endothelial dysfunction. Melatonin is a neurohormone that is synthesized mainly in the pineal gland and plays a central role in the regulation of sleep and some other body cyclic processes. For a long time, melatonin was perceived as a substance that is effective in the treatment of circadian cycle impairments. At the same time, a large number of studies have accumulated recently that demonstrate a wider range of its biological effects, including anti-inflammatory, antioxidant, antihypertensive and, possibly, hypolipidemic. The review includes current data from experimental and clinical studies demonstrating the cardioprotective effects of melatonin in atherosclerosis, myocardial ischemia, and heart failure.

Follicular Helper T-Cell-Based Classification of Endometrial Cancer Promotes Precise Checkpoint Immunotherapy and Provides Prognostic Stratification

Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan–Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper–like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.