Neuroprotective Effects of Curcumin in Neurodegenerative Diseases.

Curcumin, a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, is now considered a candidate drug for the treatment of neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and prion disease, due to its potent anti-inflammatory, antioxidant potential, anticancerous, immunomodulatory, neuroprotective, antiproliferative, and antibacterial activities. Traditionally, curcumin has been used for medicinal and dietary purposes in Asia, India, and China. However, low water solubility, poor stability in the blood, high rate of metabolism, limited bioavailability, and little capability to cross the blood-brain barrier (BBB) have limited the clinical application of curcumin, despite the important pharmacological activities of this drug. A variety of nanocarriers, including liposomes, micelles, dendrimers, cubosome nanoparticles, polymer nanoparticles, and solid lipid nanoparticles have been developed with great success to effectively deliver the active drug to brain cells. Functionalization on the surface of nanoparticles with brain-specific ligands makes them target-specific, which should significantly improve bioavailability and reduce harmful effects. The aim of this review is to summarize the studies on curcumin and/or nanoparticles containing curcumin in the most common neurodegenerative diseases, highlighting the high neuroprotective potential of this nutraceutical.

Limosilactobacillus reuteri DSM 17938 relieves inflammation, endoplasmic reticulum stress, and autophagy in hippocampus of western diet-fed rats by modulation of systemic inflammation.

The consumption of western diets, high in fats and sugars, is a crucial contributor to brain molecular alterations, cognitive dysfunction and neurodegenerative diseases. Therefore, a mandatory challenge is the individuation of strategies capable of preventing diet-induced impairment of brain physiology. A promising strategy might consist in the administration of probiotics that are known to influence brain function via the gut-brain axis. In this study, we explored whether Limosilactobacillus reuteri DSM 17938 (L. reuteri)-based approach can counteract diet-induced neuroinflammation, endoplasmic reticulum stress (ERS), and autophagy in hippocampus, an area involved in learning and memory, in rat fed a high fat and fructose diet. The western diet induced a microbiota reshaping, but L. reuteri neither modulated this change, nor the plasma levels of short-chain fatty acids. Interestingly, pro-inflammatory signaling pathway activation (increased NFkB phosphorylation, raised amounts of toll-like receptor-4, tumor necrosis factor-alpha, interleukin-6, GFAP, and Haptoglobin), as well as activation of ERS (increased PERK and eif2α phosphorylation, higher C/EBP-homologous protein amounts) and autophagy (increased beclin, P62-sequestosome-1, and LC3 II) was revealed in hippocampus of western diet fed rats. All these hippocampal alterations were prevented by L. reuteri administration, showing for the first time a neuroprotective role of this specific probiotic strain, mainly attributable to its ability to regulate western diet-induced metabolic endotoxemia and systemic inflammation, as decreased levels of lipopolysaccharide, plasma cytokines, and adipokines were also found. Therapeutic strategies based on the use of L. reuteri DSM17938 could be beneficial in reversing metabolic syndrome-mediated brain dysfunction and cognitive decline.

Can plants build their niche through modulation of soil microbial activities linked with nitrogen cycling? A test with Arabidopsis thaliana.

In natural systems, different plant species have been shown to modulate specific nitrogen (N) cycling processes so as to meet their N demand, thereby potentially influencing their own niche. This phenomenon might go beyond plant interactions with symbiotic microorganisms and affect the much less explored plant interactions with free-living microorganisms involved in soil N cycling, such as nitrifiers and denitrifiers. Here, we investigated variability in the modulation of soil nitrifying and denitrifying enzyme activities (NEA and DEA, respectively), and their ratio (NEA : DEA), across 193 Arabidopsis thaliana accessions. We studied the genetic and environmental determinants of such plant-soil interactions, and effects on plant biomass production in the next generation. We found that NEA, DEA, and NEA : DEA varied c. 30-, 15- and 60-fold, respectively, among A. thaliana genotypes and were related to genes linked with stress response, flowering, and nitrate nutrition, as well as to soil parameters at the geographic origin of the analysed genotypes. Moreover, plant-mediated N cycling activities correlated with the aboveground biomass of next-generation plants in home vs away nonautoclaved soil, suggesting a transgenerational impact of soil biotic conditioning on plant performance. Altogether, these findings suggest that nutrient-based plant niche construction may be much more widespread than previously thought.

Phthalazine Sulfonamide Derivatives as Carbonic Anhydrase Inhibitors. Synthesis, Biological and in silico Evaluation.

Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.

Climbing anxiety scale (CAS-20): Preliminary development and validation.

Anxiety has been the primary focus of emotion research in sport psychology. Most of the existing anxiety measures focus on the competition related anxiety. Little is known about the way in which anxiety affects athletic outcomes in extreme sports. We contribute to the literature on anxiety in extreme sports by: (1) developing and providing a preliminary validation for a novel, theoretically anchored sport climbing inventory, Climbing Anxiety Scale (CAS-20), among an international sample of rock-climbers (N = 153); and (2) providing preliminary evidence on its factorial and criterion-related validity. Our investigation includes two phases. The first phase (6 clinical and sport psychology experts) included the development and expert review of a climbing specific anxiety scale. The second phase (N = 153) offers preliminary evidence pertaining to the measure's reliability, factorial, convergent and criterion related validity. Factorial validity was investigated by deploying a series of confirmatory factorial analyses. Convergent and discriminatory validity were examined by comparing the scale's associations with a general anxiety measure, a sport anxiety measure, as well as climbing self-efficacy. Criterion-related validity was estimated by examining its relationship with rock-climbing performance. We contribute to the general domain of sport and athletic research by developing a sport-specific anxiety measure, investigating whether and how anxiety comes into play in rock-climbing, a high-risk sport. This scale can be used for assessing anxiety in climbing and monitoring the impact of an interventions designed to reduce these symptoms.

Q3 lab-on-chip real-time PCR for the diagnosis of Leishmania infantum infection in dogs.

Leishmaniasis is a vector-borne disease caused by many Leishmania spp. which infect humans and other mammalian hosts. Leishmania infantum is the main agent of canine leishmaniasis (CanL) whose diagnosis is usually confirmed by serological and molecular tests. This study aimed to evaluate the clinical and analytical sensitivities of a lab-on-chip (LOC) real-time PCR applied on the portable Q3-Plus V2 platform (Q3 qPCR) in the detection of L. infantum. The Q3 qPCR performance was assessed by comparing the quantification cycle (Cq) values with those obtained using the qPCR run on a CFX96 Real-Time System (CFX96 qPCR). A total of 173 DNA samples (extracted from bone marrow, lymph node, blood, buffy coat, conjunctival swab, and skin) as well as 93 non-extracted samples (NES) (bone marrow, lymph node, blood, and buffy coat) collected from dogs were tested with both systems. Serial dilutions of each representative DNA and NES sample were used to assess the analytical sensitivity of the Q3 qPCR system. Overlapping Cq values were obtained with the Q3 qPCR and CFX96 qPCR, both using DNA extracted from L. infantum promastigotes (limit of detection, <1 promastigote per milliliter) and from biological samples as well as with NES. However, the Q3 qPCR system showed a higher sensitivity in detecting L. infantum in NES as compared with the CFX96 qPCR. Our data indicate that the Q3 qPCR system could be a reliable tool for detecting L. infantum DNA in biological samples, bypassing the DNA extraction step, which represents an advance in the point-of-care diagnostic of CanL.

Phytochemicals Involved in Mitigating Silent Toxicity Induced by Heavy Metals.

Heavy metals (HMs) are natural elements present in the Earth's crust, characterised by a high atomic mass and a density more than five times higher than water. Despite their origin from natural sources, extensive usage and processing of raw materials and their presence as silent poisons in our daily products and diets have drastically altered their biochemical balance, making them a threat to the environment and human health. Particularly, the food chain polluted with toxic metals represents a crucial route of human exposure. Therefore, the impact of HMs on human health has become a matter of concern because of the severe chronic effects induced by their excessive levels in the human body. Chelation therapy is an approved valid treatment for HM poisoning; however, despite the efficacy demonstrated by chelating agents, various dramatic side effects may occur. Numerous data demonstrate that dietary components and phytoantioxidants play a significant role in preventing or reducing the damage induced by HMs. This review summarises the role of various phytochemicals, plant and herbal extracts or probiotics in promoting human health by mitigating the toxic effects of different HMs.

The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation.

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

NG2 Molecule Expression in Acute Lymphoblastic Leukemia B Cells: A Flow-Cytometric Marker for the Rapid Identification of KMT2A Gene Rearrangements.

Background: B-lineage acute lymphoblastic leukemias (B-ALL) harboring rearrangements of the histone lysine [K]-Methyltransferase 2A (KMT2A) gene on chromosome 11q23 (KMT2A-r) represent a category with dismal prognosis. The prompt identification of these cases represents an urgent clinical need. Considering the correlation between rat neuron glial-antigen 2 (NG2) chondroitin-sulfate-proteoglycan molecule expression and KMT2A-r, we aimed to identify an optimized cytofluorimetric diagnostic panel to predict the presence of KMT2A-r. Materials and Methods: We evaluated 88 NG2+ B-ALL cases identified with an NG2 positivity threshold >10% from a cohort of 1382 newly diagnosed B-ALLs referred to the Division of Hematology of 'Sapienza' University of Rome. Results: Eighty-five of 88 (96.6%) NG2+ B-ALLs harbored KMT2A-r and were mainly pro-B ALL (77/85; 91%). Only 2 B-ALLs with KMT2A-r showed NG2 expression below 10%, probably due to the steroid therapy administered prior to cytofluorimetric analysis.Compared to KMT2A-r-cases, KMT2A r+ B-ALLs showed a higher blast percentage, significantly higher mean fluorescence intensity (MFI) of CD45, CD38, and CD58, and significantly lower MFI of CD34, CD22, TdT, and CD123.The study confirmed differences in CD45, CD34, CD22, and TdT MFI within the same immunologic EGIL group (European Group for the immunological classification of leukemias), indicating no influence of the B-ALLs EGIL subtype on the KMT2A-r+ B-ALLs immunophenotype. Conclusions: Our data demonstrate the association between NG2 and KMT2A-r in B-ALLs identify a distinctive immunophenotypic pattern, useful for rapid identification in diagnostic routines of these subtypes of B-ALLs with a poor prognosis that benefits from a specific therapeutic approach.

Development of an indirect ELISA for the serodiagnosis of canine infection by Onchocerca lupi.

Onchocerca lupi is a zoonotic filarioid parasite of dogs and cats with widespread distribution. A specific non-invasive diagnostic assay for the detection of O. lupi infections remains unavailable. This study aimed to assess the accuracy, specificity, and sensitivity of an ELISA test designed using nine peptides from two O. lupi proteins. Sera (n = 54) collected from O. lupi infected dogs from endemic areas (Portugal and USA), alongside sera from dogs positive for Dirofilaria immitis, D. repens, Cercopithifilaria bainae, and Acanthocheilonema reconditum (n = 53) from a non-endemic area for O. lupi, as well as from helminth-free dogs (n = 60), were tested. The checkerboard titration method was applied for the optimization of peptide concentrations and conjugate anti-dog dilutions. Sensitivity, specificity, and optimal cut-off values were calculated using ROC curve analysis. All peptides reacted against sera of O. lupi, with no correlation between optic density (OD) values and microfilariae (mfs) loads. Sensitivity and specificity values ranging from 85.45 to 100%, and 88.89% to 100%, respectively, were recorded for all peptides examined, with 100% specificity and sensitivity observed for peptides 40_3, 40_5, 130_3, 120_3 and 40_1, 130_5, respectively. The maximum cut-off value was observed for peptides 40_5 (0.765) and 40_3 (0.708). Testing of sera from dogs positive for other filarioids resulted in lower OD values (up to 1.565) for peptides 40_3 and 40_5 when compared with O. lupi (up to 2.929). The availability of this assay will be of value in epidemiological studies of canine O. lupi infection in both endemic and non-endemic areas, and in assessing the risk for zoonotic transmission.

The Ongoing Impact of COVID-19 on Pediatric Obesity.

In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO.

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

A Comprehensive Review on the State of the Art of Breast Cancers in Italy.

Breast cancer (BC) currently represents one of the most prevalent cancers among women worldwide and the leading cause of cancer death among women, also negatively affecting the quality of life (QoL) in patients. Over the past two decades, BC research has led to extraordinary advances in our understanding of the disease, resulting in more effective treatments. However, its occurrence is still increasing. Several new treatments are now under development worldwide, but they are not devoid of wellknown side effects, and a great number of patients develop endocrine resistance. Nevertheless, the design and synthesis of more suitable strategies and new drugs to treat breast cancers, overcome resistance and side effects, and obtain better therapeutic outcomes are needed. In this review, we summarize the therapies and the clinical studies currently ongoing in Italy for the treatment of BCs, mainly HER2+ MBC, HER2-low MBC, and TNBC, focusing on the most recent ones, also in consideration of diverse facets, including some aspects related to QoL. Finally, some studies related to the usefulness of physical activity in BC will be cited.

The Role of the Anterior Thalamic Nuclei in the Genesis of Memory Disorders in Alzheimer's Disease: An Exploratory Study.

BACKGROUND: Increasing evidence is demonstrating that degeneration of specific thalamic nuclei, in addition to the hippocampus, may occur in Alzheimer's disease (AD) from the prodromal stage (mild cognitive impairment - MCI) and contribute to memory impairment. OBJECTIVE: Here, we evaluated the presence of macro and micro structural alterations at the level of the anterior thalamic nuclei (ATN) and medio-dorsal thalamic nuclei (MDTN) in AD and amnestic MCI (aMCI) and the possible relationship between such changes and the severity of memory impairment. METHODS: For this purpose, a sample of 50 patients with aMCI, 50 with AD, and 50 age- and education-matched healthy controls (HC) were submitted to a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a comprehensive neuropsychological assessment. RESULTS: At macro-structural level, both the ATN and MDTN were found significantly smaller in patients with aMCI and AD when compared to HC subjects. At micro-structural level, instead, diffusion alterations that significantly differentiated aMCI and AD patients from HC subjects were found only in the ATN, but not in the MDTN. Moreover, diffusion values of the ATN were significantly associated with poor episodic memory in the overall patients' group. CONCLUSIONS: These findings represent the first in vivo evidence of a relevant involvement of ATN in the AD-related neurodegeneration and memory profile and strengthen the importance to look beyond the hippocampus when considering neurological conditions characterized by memory decline.

CGRP Antagonism and Ketogenic Diet in the Treatment of Migraine.

The study of migraine is based on the complexity of the pathology, both at the pathophysiological and epidemiological levels. Although it affects more than a billion people worldwide, it is often underestimated and underreported by patients. Migraine must not be confused with a simple headache; it is a serious and disabling disease that causes considerable limitations in the daily life of afflicted people, including social, work, and emotional effects. Therefore, it causes a daily state of suffering and discomfort. It is important to point out that this pathology not only has a decisive impact on the quality of life of those who suffer from it but also on their families and, more generally, on society as a whole. The clinical picture of migraine is complex, with debilitating unilateral or bilateral head pain, and is often associated with characteristic symptoms such as nausea, vomiting, photophobia, and phonophobia. Hormonal, environmental, psychological, dietary, or other factors can trigger it. The present review focuses on the analysis of the physiopathological and pharmacological aspects of migraine, up to the correct dietary approach, with specific nutritional interventions aimed at modulating the symptoms. Based on the symptoms that the patient experiences, targeted and specific therapy is chosen to reduce the frequency and severity of migraine attacks. Specifically, the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine is analyzed, along with the drugs that effectively target the corresponding receptor. Particularly, CGRP receptor antagonists (gepants) are very effective drugs in the treatment of migraine, given their high diffusion in the brain. Moreover, following a ketogenic diet for only one or two months has been demonstrated to reduce migraine attacks. In this review, we highlight the diverse facets of migraine, from its physiopathological and pharmacological aspects to prevention and therapy.

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers.

Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4-CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.

Complexes of Ruthenium(II) as Promising Dual-Active Agents against Cancer and Viral Infections.

Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study as possible anticancer and antiviral agents. The two Ru(III) and Ru(II) complexes, namely, BOLD-100 and RAPTA-C, are presently being studied in a clinical trial and preclinical studies evaluation, respectively, as anticancer agents. Interestingly, BOLD-100 has also recently demonstrated antiviral activity against SARS-CoV-2, which is the virus responsible for the COVID-19 pandemic. Over the last years, much effort has been dedicated to discovering new dual anticancer-antiviral agents. Ru-based complexes could be very suitable in this respect. Thus, this review focuses on the most recent studies regarding newly synthesized Ru(II) complexes for use as anticancer and/or antiviral agents.