Heat Treatment as a Safe-Handling Procedure for Rift Valley Fever Virus.

Rift Valley Fever virus (RVFV) is a mosquito-borne virus with high pathogenic potential in ruminants and humans. Due to its high potential for spreading, it is considered a priority pathogen, and it is included in the Bluepoint list of the World Health Organization (WHO). Given the high pathogenic potential of the virus, it is crucial to develop a rapid heat-mediated inactivation protocol to create a safer working environment, particularly in medical facilities that lack a biosafety level 3 laboratory required for direct handling of RVFV.

Digital Applications for Videoterminal-Associated Dry Eye Disease.

Dry eye disease (DED) has become increasingly prevalent in the digital era, largely due to prolonged screen exposure. The excessive use of digital devices contributes to inappropriate blink frequency and dynamics, leading to ocular surface dryness and discomfort. Additionally, digital screen use has broader implications for systemic health, including visual strain, headaches, and disrupted circadian rhythms caused by blue light exposure.

Topical insulin used alone or in combination with drug-depository contact lens for refractory cases of neurotrophic keratopathy.

Purpose: To report the clinical outcomes achieved in refractory cases of neurotrophic keratopathy (NK) through the utilization of insulin eye drops alone or in conjunction with a drug-depository contact lens (DDCL).

Observations: This multicentric prospective open-label uncontrolled case series included consecutive patients with NK refractory to conventional treatment. Insulin eye drops (1 unit/mL) were prescribed 4 times/day in all cases, and a Therapeutic Hyper-CL™ soft contact lens (EyeYon Medical, Ness Ziona, Israel), designed to act as a drug reservoir, was applied in selected patients.

Long-COVID autonomic syndrome in working age and work ability impairment.

Long-COVID19 has been recently associated with long-sick leave and unemployment. The autonomic nervous system functioning may be also affected by SARS-CoV-2, leading to a chronic autonomic syndrome. This latter remains widely unrecognized in clinical practice.

ATF6 supports lysosomal function in tumor cells to enable ER stress-activated macroautophagy and CMA: impact on mutant TP53 expression.

The inhibition of the unfolded protein response (UPR), which usually protects cancer cells from stress, may be exploited to potentiate the cytotoxic effect of drugs inducing ER stress. However, in this study, we found that ER stress and UPR activation by thapsigargin or tunicamycin promoted the lysosomal degradation of mutant (MUT) TP53 and that the inhibition of the UPR sensor ATF6, but not of ERN1/IRE1 or EIF2AK3/PERK, counteracted such an effect. ATF6 activation was indeed required to sustain the function of lysosomes, enabling the execution of chaperone-mediated autophagy (CMA) as well as of macroautophagy, processes involved in the degradation of MUT TP53 in stressed cancer cells.

Camellin-Calossi Formula for Intraocular Lens Power Calculation in Patients With Previous Myopic Laser Vision Correction.

Purpose: To assess the performance of the Camellin-Calossi formula in eyes with prior myopic laser vision correction.

Methods: This was a retrospective case series. Patients included had a history of uncomplicated myopic laser vision correction and cataract surgery.

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression.

Recent studies have shown that thyrocytes are permissive to HHV-6A infection and that the virus may contribute to the pathogenesis of autoimmune thyroiditis. Thyroid autoimmune diseases increase the risk of papillary cancer, which is not surprising considering that chronic inflammation activates pathways that are also pro-oncogenic. Moreover, in this condition, cell proliferation is stimulated as an attempt to repair tissue damage caused by the inflammatory process.

The inhibition of IRE1alpha/XBP1 axis prevents EBV-driven lymphomagenesis in NSG mice.

The novelty of this study lies in the fact that it shows that IRE1 alpha endoribonuclease inhibition by 4μ8C was able to counteract Epstein-Barr virus-driven lymphomagenesis in NOD SCID gamma mice and prevent B-cell immortalization unveiling that this drug may be a promising therapeutic approach to reduce the risk of post-transplant lymphoproliferative disorders (PTLD) onset in immune-deficient patients. This hypothesis is further supported by the fact that 4μ8C impaired the survival of PTLD-like cells derived from mice, meaning that it could be helpful also in the case in which there is the possibility that these malignancies have begun to arise.

Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1.

PD-L1 is an immune checkpoint inhibitor, whose surface expression may be exploited by cancer cells to escape T cell-mediated immune recognition. PD-L1 expression and nuclear localization can be affected by epigenetic modifications, such as acetylation. In this study, we showed that VPA, a class I/IIa HDAC inhibitor, upregulated PD-L1 expression on the surface of pancreatic cancer cells.

NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells.

NFE2L2 and STAT3 are key pro-survival molecules, and thus, their targeting may represent a promising anti-cancer strategy. In this study, we found that a positive feedback loop occurred between them and provided evidence that their concomitant inhibition efficiently impaired the survival of PEL cells, a rare, aggressive B cell lymphoma associated with the gammaherpesvirus KSHV and often also EBV. At the molecular level, we found that NFE2L2 and STAT3 converged in the regulation of several pro-survival molecules and in the activation of processes essential for the adaption of lymphoma cells to stress.

Surgical Tips for Aesthetic Lower Lid Blepharoplasty: Prevention of Round Eye.

Unlabelled: In the present study, we highlight surgical tips based on our experience in lower eyelid blepharoplasty. These have been shown to be crucial in the prevention of several complications, specifically lateral lower-lid displacement.

Methods: A series of bilateral lower-lid blepharoplasties were performed on 280 patients at Humanitas-Research-Hospital (Milan, Italy) between January 2016 and January 2020.

mTORC1/ERK1/2 Interplay Regulates Protein Synthesis and Survival in Acute Myeloid Leukemia Cell Lines.

mTOR is constitutively activated in acute myeloid leukemia (AML) cells, as indicated by the phosphorylation of its substrates, 4EBP1 and P70S6K. Here, we found that quercetin (Q) and rapamycin (Rap) inhibited P70S6K phosphorylation, partially dephosphorylated 4EBP1, and activated ERK1/2 in U937 and THP1, two leukemia cell lines. ERK1/2 inhibition by U0126 induced a stronger dephosphorylation of mTORC1 substrates and activated AKT.

NRF2 and STAT3: friends or foes in carcinogenesis?

NRF2 is a transcription factor that plays a pivotal role in carcinogenesis, also through the interaction with several pro-survival pathways. NRF2 controls the transcription of detoxification enzymes and a variety of other molecules impinging in several key biological processes. This perspective will focus on the complex interplay of NRF2 with STAT3, another transcription factor often aberrantly activated in cancer and driving tumorigenesis as well as immune suppression.

JQ-1/bortezomib combination strongly impairs MM and PEL survival by inhibiting c-Myc and mTOR despite the activation of prosurvival mechanisms.

Multiple myeloma (MM) and primary effusion lymphoma (PEL) are two aggressive hematologic cancers against which bortezomib and JQ-1, proteasome and bromodomain and extraterminal domain (BET) inhibitors, respectively, have been shown to have a certain success. However, the combination of both seems to be more promising than the single treatments against several cancers, including MM. Indeed, in the latter, proteasome inhibition upregulated nuclear respiratory factor 1 (NRF1), and such a prosurvival effect was counteracted by BET inhibitors.

c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway.

It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells.

Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP: A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas.

It is emerging that targeting the adaptive functions of Unfolded Protein Response (UPR) may represent a promising anti-cancer therapeutic approach. This is particularly relevant for B-cell lymphomas, characterized by a high level of constitutive stress due to high c-Myc expression. In this study, we found that IRE1α/XBP1 axis inhibition exerted a stronger cytotoxic effect compared to the inhibition of the other two UPR sensors, namely PERK and ATF6, in Burkitt lymphoma (BL) cells, in correlation with c-Myc downregulation.

ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress.

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments.

The impairment of DDR reduces XBP1s, further increasing DNA damage, and triggers autophagy via PERK/eIF2alpha in MM and IRE1alpha/JNK1/2 in PEL cells.

Cancer cells, particularly MM, that are highly secretory cells, and PEL cells that harbor KSHV, are characterized by high level of stress to which they adapt by activating DDR, UPR and autophagy. It is known that UPR sensors may affect DDR, but whether DDR manipulation influences UPR is less known. In this study, we found an intricate interplay between these responses.

Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells.

Multiple myeloma (MM) and primary effusion lymphoma (PEL) are aggressive hematological cancers, for which the search for new and more effective therapies is needed. Both cancers overexpress c-Myc and are highly dependent on this proto-oncogene for their survival. Although c-Myc inhibition has been shown to reduce PEL and MM survival, the underlying mechanisms leading to such an effect are not completely clarified.

The dysregulation of autophagy and ER stress induced by HHV-6A infection activates pro-inflammatory pathways and promotes the release of inflammatory cytokines and cathepsin S by CNS cells.

HHV-6A is a neurotropic herpesvirus able to infect several CNS cells including astrocytes and primary neurons. Here we found that HHV-6A infection of astrocytoma cells, by reducing autophagy, increased ROS and induced ER stress, promoting the release of inflammatory cytokines such as IL-6 and IL-1β and activating pathways such as STAT3, NF-kB and mTOR. Moreover, HHV-6A infection increased the production of CXCL13, a B lymphocyte attracting chemokine, whose recruitment in the CNS could further enhance neuroinflammation.

VPA and TSA Interrupt the Interplay between mutp53 and HSP70, Leading to CHK1 and RAD51 Down-Regulation and Sensitizing Pancreatic Cancer Cells to AZD2461 PARP Inhibitor.

HDAC inhibitors (HDACi) represent promising anti-cancer treatments, as the acetylation of histone and non-histone proteins is often dysregulated in cancer and contributes to cancer onset and progression. HDACi have been also reported to increase the cytotoxicity of DNA-damaging agents, such as radiation or cisplatin. In this study, we found that TSA and, even more effectively, VPA synergized with AZD2461, PARP1, 2 and 3 inhibitor (PARPi) to induce DNA damage and reduce pancreatic cancer cell survival.

p62/SQSTM1 promotes mitophagy and activates the NRF2-mediated antioxidant and anti-inflammatory response restraining EBV-driven B lymphocyte proliferation.

Reactive oxygen species (ROS) and DNA repair, respectively, promote and limit oncogenic transformation of B cells driven by Epstein-Barr virus (EBV). We have previously shown that EBV infection reduced autophagy in primary B lymphocytes and enhanced ROS and interleukin 6 (IL-6) release, promoting B-cell proliferation and immortalization. In this study, we explored the role of p62/SQSTM1, accumulated as a consequence of autophagy reduction in EBV-infected B lymphocytes, and found that it exerted a growth-suppressive effect in these cells.

New Insights into Curcumin- and Resveratrol-Mediated Anti-Cancer Effects.

Curcumin and resveratrol are bioactive natural compounds displaying anti-inflammatory, anti-oxidant and anti-cancer properties. In this study, we compared the cytotoxic effects of these molecules and the molecular mechanisms involved against Her-2/neu-positive breast and salivary cancer cell lines. We found that both curcumin and resveratrol were efficient in reducing cancer cell survival and that they differently affected autophagy, ROS and activation of the PI3K/AKT/mTOR pathway.