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The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics., (© 2024. The Author(s).)

Introduction: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs., Methods: We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro , ex-vivo and in vivo ., Results: We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and in vivo ., Discussion: Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hossain, Ucar, Monticone, Ran, Majumder, Larter, Luu, Wyczechowska, Heidari, Xu, Shanthalingam, Matossian, Xi, Burow, Collins-Burow, Del Valle, Hicks, Zabaleta, Golde, Osborne and Miele.)

Background: The efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined., Methods: CB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students' t -test. A one-way or two-way ANOVA followed by Tukey's post-analysis was performed to analyze the in vivo efficacy study results., The Results: CB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone., Conclusion: our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.

A critical feature of cancer is the ability to induce immunosuppression and evade immune responses. Tumor-induced immunosuppression diminishes the effectiveness of endogenous immune responses and decreases the efficacy of cancer immunotherapy. In this study, we describe a new immunosuppressive pathway in which adenosine promotes Casitas B-lineage lymphoma b (Cbl-b)-mediated Notch1 degradation, causing suppression of CD8+ T-cells effector functions. Genetic knockout and pharmacological inhibition of Cbl-b prevents Notch1 degradation in response to adenosine and reactivates its signaling. Reactivation of Notch1 results in enhanced CD8+ T-cell effector functions, anti-cancer response and resistance to immunosuppression. Our work provides evidence that targeting the Cbl-b-Notch1 axis is a novel promising strategy for cancer immunotherapy., Competing Interests: Authors FC, SLt, DC, and CL were employed by company Nimbus Theraputics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Monticone, Huang, Csibi, Leit, Ciccone, Champhekar, Austin, Ucar, Hossain, Ibba, Boulares, Carpino, Xu, Majumder, Osborne, Loh and Miele.)

Notch is a key evolutionary conserved pathway, which has fascinated and engaged the work of investigators in an uncountable number of biological fields, from development of metazoans to immunotherapy for cancer. The study of Notch has greatly contributed to the understanding of cancer biology and a substantial effort has been spent in designing Notch-targeting therapies. Due to its broad involvement in cancer, targeting Notch would allow to virtually modulate any aspect of the disease. However, this means that Notch-based therapies must be highly specific to avoid off-target effects. This review will present the newest mechanistic and therapeutic advances in the Notch field and discuss the promises and challenges of this constantly evolving field.

Background: The morphologic capillary microscopy (capillaroscopy) pattern of acrocyanosis is characterized by hemorrhages, pericapillary edema, and widened capillaries. These findings can result in a difficult differential diagnosis with systemic sclerosis (SSc)., Objective: We sought to quantify the characteristics of the capillaroscopy pattern that distinguishes patients with acrocyanosis from patients with SSc and control subjects., Methods: A videomicroscope with fiberoptic illumination and personal computer-based image processing was used to measure capillary density, giant capillaries, loop width, and arterial and venous limbs in 10 patients with acrocyanosis, 10 patients with SSc, and 10 healthy control subjects., Results: Acrocyanotic patients differed in every quantitative parameter both from control subjects and patients with SSc. In particular, capillary density, which was reduced compared with that of control subjects, was much higher than that of patients with SSc: one giant capillary per finger was observed in 2 patients with acrocyanosis, whereas more than 2 giant capillaries per finger were observed in each patient with SSc., Conclusion: These differences may aid in making the distinction between the capillaroscopy patterns in acrocyanosis and SSc.

Various electrophysiological tests have been employed to reveal functional abnormalities at different levels of the visual system in insulin-dependent diabetic (IDDM) patients. The aim of our work was to assess, with a comprehensive neurophysiological protocol evaluating the retinal, macular and visual pathways functions, whether and when such electrophysiological abnormalities do appear in IDDM patients free of any fluorangiographic sign of retinopathy with various disease duration. Flash-electroretinogram (ERG), oscillatory potentials (OPs), pattern-electroretinogram (PERG), and visual evoked potentials (VEPs) in basal condition and after photostress were assessed in 12 control subjects (C) and 42 aged-matched IDDM patients without clinical retinopathy (DR-) divided, on the basis of the disease duration, into 4 groups (1-5, 6-10, 11-15, 16-20 years). In addition another age-matched group of IDDM patients with a background retinopathy (DR+; n = 12; duration of disease 18 +/- 49 years) was evaluated. In all IDDM DR-patients PERG and VEP were significantly impaired. In addition, groups 11-15 and 16-20 years displayed impaired OPs. All electrophysiological parameters were further impaired in DR+ patients. In conclusion, retinal, macular and visual pathways functions are differently impaired in IDDM (DR-) patients with different disease duration. Electrophysiological impairment starts in the nervous conduction of the visual pathways with an early involvement, goes on in the innermost retinal layers and in the macula and ends in the middle and outer retinal layers.

Objective: To evaluate the influence of diabetic peripheral neuropathy on postural strategy., Research Design and Methods: Static posturography and nerve conduction velocity were performed in the following age-matched subjects: 10 IDDM patients with peripheral neuropathy, 23 IDDM patients without peripheral neuropathy, and 21 control subjects. All subjects with signs or symptoms of postural instability were excluded from the study. The following posturographic parameters were drawn: 1) velocity of body sway, expressed as mean velocity and average of the SDs, 2) VFY, the parameter derived from the velocity variance and the anteroposterior mean position of the body (this parameter monitors the postural strategy pursued by the subject), and 3) fast Fourier transformation on the x (FFTX) and y (FFTY) planes, spectral analysis of the frequencies of body oscillation on frontal (x) and anteroposterior (y) planes., Results: Mean velocity and its SD were higher in IDDM patients with peripheral neuropathy than in control subjects and IDDM patients without peripheral neuropathy (P < 0.001). VFY was increased in IDDM patients with peripheral neuropathy versus control subjects and IDDM patients without peripheral neuropathy (P < 0.01). A direct relationship was found between parameters of posturography and some parameters of nerve conduction tests., Conclusions: Diabetic patients with peripheral neuropathy demonstrate a shift from physiological ankle control to hip postural control as monitored by specific posturography analysis.

Objective: To evaluate the efficacy of manufactured shoes specially designed for diabetic patients (Podiabetes by Buratto Italy) to prevent relapses of foot ulcerations., Research Design and Methods: A prospective multicenter randomized follow-up study of patients with previous foot ulcerations was conducted. Patients were alternatively assigned to wear either their own shoes (control group, C; n = 36) or therapeutic shoes (Podiabetes group, P; n = 33). The number of ulcer relapses was recorded during 1-year follow-up., Results: Both C and P groups had similar risk factors for foot ulceration (i.e., previous foot ulceration, mean vibratory perception threshold > 25 mV). After 1 year, the foot ulcer relapses were significantly lower in P than in C (27.7 vs. 58.3%; P = 0.009; odds ratio 0.26 [0.2-1.54]). In a multiple regression analysis, the use of therapeutic shoes was negatively associated with foot ulcer relapses (coefficient of variation = -0.315; 95% confidence interval = -0.54 to -0.08; P = 0.009)., Conclusions: The use of specially designed shoes is effective in preventing relapses in diabetic patients with previous ulceration.

Objective: To evaluate the influence of peripheral neuropathy on body sway assessed by posturography., Research Design and Methods: The age-matched study subjects included 10 insulin-dependent diabetes mellitus (IDDM) patients with peripheral neuropathy (DN), 23 IDDM patients without peripheral neuropathy (D) according to the San Antonio Consensus Conference guidelines, and 21 control subjects (C). All subjects with symptoms and/or clinical signs of postural instability were excluded from the study., Results: The trace surface was significantly larger in the DN than in the C and D groups (P < 0.05), and the trace length was longer in the DN than in the C and D groups (P < 0.01). Mean velocity was faster in the DN than in the other two groups (P < 0.001). A direct relationship was found between the parameters of posturography and some parameters of the nerve conduction velocity., Conclusions: Diabetic patients with peripheral neuropathy demonstrate a relative deficit in their ability to maintain posture. Posturography allows an early disclosure of the failure of postural control.

Visual evoked potentials (VEPs) were assessed under basal conditions and after photostress in normal control subjects, in insulin-dependent diabetic patients with retinopathy (IDDPWR) and in insulin-dependent diabetic patients without retinopathy (IDDP). The VEPs recorded under basal conditions showed a P100 latency significantly higher in IDDP and IDDP-WR eyes than in control eyes and in IDDPWR than in IDDP eyes (P < 0.01). N75-P100 amplitude was significantly lower in IDDP and IDDPWR eyes than in control eyes (P < 0.01). No difference was recorded in the N75-P100 amplitudes between IDDP and IDDPWR eyes. In all eyes, the VEPs recorded after photostress showed an increase in latency and a decrease in amplitude. In both IDDPWR eyes and IDDP eyes VEPs recorded at 20, 40 and 60 s after photostress showed higher mean increments in P100 latency than in C control eyes, and IDDPWR eyes showed higher mean increments in P100 latency than IDDP eyes (IDDP vs control P < 0.01, IDDPWR vs control P < 0.01, IDDPWR vs IDDP P < 0.017). The mean reductions in amplitude observed at 20, 40 and 60 s after photostress in IDDP and IDDPWR eyes were lower than in control eyes (IDDP vs control P = 0.01, IDDPWR vs control P < 0.01, IDDPWR vs IDDP P < 0.01). VEPs were superimposable on the basal VEP (recovery time) at 73.9 s in control eyes, at 88.17 s in IDDP eyes and at 113.3 s in IDDPWR eyes. VEPs after photostress in IDDP patients with normal visual acuity and no fluorangiographic signs of retinopathy may show multiple modifications. This may indicate the presence of an early functional deficiency of the central retinal layers.

Autonomic neuropathy is a common complication of diabetes. In this study we evaluated autonomic neuropathy by determining somatostatin (S-14)-evoked acetylcholine (Ach) release from postsynaptic parasympathetic fibers in the atria of controls (C) and streptozotocin diabetic rats (STZ-D), with and without tetrodotoxin (TTX). The release induced by S-14 did not differ in C and STZ-D. TTX blocked S-14 induced Ach in C but failed in STZ-D. TTX resistance in STZ-D may be explained by variations of membrane potential in nerve fibers.

The Autobac MTS is a semiautomatic modular system for the screening of urine cultures and the execution of both antibiogram and MIC. The principle on which these tests are based is that of turbidimetry. In this note, the authors examine in detail the determination of MIC, that is based on utilisation of the regression lines equation. The method used by Autobac has a greater precision than the break-point method. This fact is mostly due to the possibility of standardizing inoculum. The authors conclude that, on the ground of their experience, the MIC method always some disagreement with the literature for the tested antibiotics (aminoglycosides).