Brazilian national production of active pharmaceutical ingredients: regulatory and strategic framework.

Active Pharmaceutical Ingredient (API) is any component of the final pharmaceutical product that serves as the active ingredient. The goal of the API Manufacturing is to produce APIs that are competitively priced and meet the quality standards with the least possible impact on the environment. The global API market is expected to experience massive growth in the coming years reaching the size of USD 355.94 billion. The global Pharmaceutical Industry is facing a new scenario in 2023 after responding to the COVID-19 pandemic. In this new panorama, rethinking the pharmaceutical production and market is necessary. Despite Brazil's prominence in terms of worldwide pharmaceutical spending, only 5% of the APIs required by local pharmaceutical companies are produced domestically. Therefore, Brazil is an untapped field for APIs' manufacturing and faces a scenario of health vulnerability associated with the reliance on foreign API imports to ensure the viability of national Pharmaceutical Production and Services. Huge investments are required to boost the growth of the API Manufacturing sector. Herein is presented a critical analysis of the current regulatory and strategic status of Brazilian national production and/or acquisition of APIs, which represent the key starting materials for the Pharmaceutical Industry.

Patient-Derived Multiple Myeloma 3D Models for Personalized Medicine-Are We There Yet?

Despite the wide variety of existing therapies, multiple myeloma (MM) remains a disease with dismal prognosis. Choosing the right treatment for each patient remains one of the major challenges. A new approach being explored is the use of ex vivo models for personalized medicine. Two-dimensional culture or animal models often fail to predict clinical outcomes. Three-dimensional ex vivo models using patients' bone marrow (BM) cells may better reproduce the complexity and heterogeneity of the BM microenvironment. Here, we review the strengths and limitations of currently existing patient-derived ex vivo three-dimensional MM models. We analyze their biochemical and biophysical properties, molecular and cellular characteristics, as well as their potential for drug testing and identification of disease biomarkers. Furthermore, we discuss the remaining challenges and give some insight on how to achieve a more biomimetic and accurate MM BM model. Overall, there is still a need for standardized culture methods and refined readout techniques. Including both myeloma and other cells of the BM microenvironment in a simple and reproducible three-dimensional scaffold is the key to faithfully mapping and examining the relationship between these players in MM. This will allow a patient-personalized profile, providing a powerful tool for clinical and research applications.

In situ evaluation of desensitizing toothpastes for protecting against erosive tooth wear and its characterization.

OBJECTIVE: This five-phase, single-blind, crossover in situ trial evaluated the effects of desensitizing or anti-erosive toothpastes on dentin erosive wear and tubule occlusion. MATERIALS AND METHODS: Some characteristics such as relative dentin abrasivity (RDA), viscosity (V), cytotoxicity, and fluoride and calcium (Ca) availability of the toothpastes were also tested. Samples were positioned on removable intraoral appliances from 15 volunteers (n=4), according to the groups, C-control (0 ppm fluoride), F-sodium monofluorophosphate (MFP), A-MFP and arginine+calcium carbonate, CSP-calcium sodium phosphosilicate, and CS-MFP and calcium silicate+sodium phosphate. Erosion-abrasion cycling was performed (1% citric acid, 2min, 6×/day; toothbrushing, 5s, 2×/day). Surface loss (SL) was evaluated by optical profilometry. Environmental scanning electron microscopy images (ESEM) counted the number of open dentin tubules (ODTs). Data were statistically analyzed (α=0.05). RESULTS: There were no significant differences in SL among groups (p=0.468). The ODT for CSP, CS, and A groups were significantly lower than the control. CSP and CS presented significantly less ODT than F, but they did not significantly differ from A. F and CS were more abrasive than all the other toothpastes; CSP was more abrasive than A, and C was the least abrasive. CSP presented higher V (p<0.05). All toothpastes presented lower cell viability than the control without toothpaste exposure. F and A presented significantly higher values of F- (p<0.05). All fluoride toothpastes had similar amount of Ca, differing from the control (p<0.05). CONCLUSION: Although the toothpastes caused similar degree of erosive wear, CSP and CS were able to occlude the dentin tubules. CLINICAL RELEVANCE: Desensitizing toothpastes containing calcium, sodium, phosphate, and silicate could be a suitable option for treating dentin hypersensitivity.

Charcoal-based dentifrices: Effect on color stability and surface wear of resin composites.

OBJECTIVE: To evaluate the effect of charcoal-based dentifrices on the color change (CC) and surface wear (SW) of resin composites. MATERIALS AND METHODS: Five dentifrices, including three toothpastes: Colgate total-12 (C12), Black is the new White (CPX), and Natural (NAT); and two powders: Carvvo (CVV) and Whitemax (WMX), were evaluated. Composite blocks (5x5x2mm- Z350 3 M/ESPE, shade A2) were subjected to 417 and 5004 brushing cycles. The CC (n = 7, CIEDE2000; ΔE00 ) was evaluated using a spectrophotometer. SW (n = 5) was assessed using profilometry. The dentifrice particles were characterized by scanning electron microscopy (SEM). RESULTS: In 417 brushing cycles, resin composite exhibited higher color change upon being exposed to NAT, CVV and WMC than to C12 (p ≤ 0.05). In 5004 brushing cycles, resin composite showed higher color change values when exposed to all dentifrices, except C12 (p ≤ 0.05). The powders promoted higher SW on resin composite than C12 in both evaluation times (p ≤ 0.05). In 417 cycles, WMX caused higher SW on composite than C12, CPX, and NAT (p ≤ 0.05). No significant different SW was found between powders and charcoal-based toothpastes after 5004 brushing cycles (p > 0.05). SEM showed larger particles for powder than for toothpaste dentifrices. CONCLUSION: Within the limitations of this study, both null hypotheses have been rejected. Resin composites exposed to charcoal-based dentifrices exhibited significantly (p ≤ 0.05) higher color change and surface wear than conventional toothpastes. CLINICAL SIGNIFICANCE: Color change and surface wear shown by charcoal dentifrices may compromise the longevity of restorations.

Kynurenine elevation correlates with T regulatory cells increase in acute Plasmodium vivax infection: A pilot study.

BACKGROUND: Disease-tolerance mechanisms limit infection severity by preventing tissue damage; however, the underlying mechanisms in human malaria are still unclear. Tryptophan (TRP), an essential amino acid, is catabolized into tolerogenic metabolites, kynurenines (KYN), by indoleamine 2,3-dioxygenase 1 (IDO1), which can induce Foxp3+ T regulatory cells (Tregs). In this study, we evaluated the relationship of these metabolites with Treg-mediated tolerance induction in acute malaria infections. METHODS: We performed a cross-sectional study that evaluated asymptomatic, symptomatic malaria patients and endemic control patient groups. We assessed plasmatic concentration of cytokines by ELISA. Plasmatic TRP and KYN levels were measured by HPLC. Peripheral T regulatory cells were measured and phenotyped by flow cytometry. RESULTS: The KYN/TRP ratio was significantly elevated in asymptomatic and symptomatic Plasmodium infection, compared to healthy controls. Also, Th1 and Th2 cytokines were elevated in the acute phase of malaria disease. IFN-γ increase in acute phase was positively correlated with the KYN/TRP ratio and KYN elevation was positively correlated with the increase of peripheral FoxP3+ T regulatory cells. CONCLUSIONS: Additional studies are needed not only to identify innate mechanisms that increase tryptophan catabolism but also the role of Tregs in controlling malaria-induced pathology and malaria tolerance by the host.

Effect of desensitizing toothpastes on dentin erosive wear and tubule occlusion. An in situ study.

PURPOSE: To evaluate the effect of desensitizing dentifrices on dentin wear and tubule occlusion using a three-phase, single blind, crossover in situ trial. METHODS: The dentifrices containing Arginine and calcium carbonate (1,450 ppmF) and Novamin, (~1,426 ppmF) were tested in two conditions: A: abrasion and B: erosion/abrasion. A dentifrice without desensitizing agents was used as control (1,450 ppmF). In each study phase, 10 volunteers used intra-oral appliances containing dentin specimens (pre-treated with EDTA, to simulate hypersensitive dentin), which were either submitted to erosion with a cola-like drink (pH 2.6), 4×/day (2 minutes), followed by toothbrushing, using electric toothbrushes, with standard pressure (2×/ day, 5 seconds), or toothbrushing only. Dentin surface loss (SL, in µm) was determined with optical profilometry at the 3rd and 5th days of cycling. Dentin surface was analyzed with environmental scanning electron microscopy (ESEM), post EDTA and post cycling, and the dentin tubules were counted using Image J software. Data were statistically analyzed (α= 0.05). RESULTS: For condition A and B, there were no significant differences in SL among toothpastes in both experimental times. There were also no significant differences between times within groups. For ESEM, in A, Toothpaste with Novamin was the only dentifrice that showed significantly less opened tubules post cycling than post EDTA. In B, Toothpaste with Novamin and control toothpaste presented less opened tubules post cycling. In conclusion, toothbrushing with the tested dentifrices promoted similar levels of dentin loss; however, for tubule occlusion, the toothpaste with Novamin was the only toothpaste effective for both conditions, abrasion and erosion/abrasion. CLINICAL SIGNIFICANCE: Ideally, desensitizing dentifrices should promote obliteration of the dentin tubules or nerve desensitization, without further contributing to the progression of dentin wear.

Benefits of laser phototherapy on nerve repair.

Post-traumatic nerve repair represents a major challenge to health sciences. Although there have been great advances in the last few years, it is still necessary to find methods that can effectively enhance nerve regeneration. Laser therapy has been widely investigated as a potential method for nerve repair. Therefore, in this article, a review of the existing literature was undertaken with regard to the effects of low-power laser irradiation on the regeneration of traumatically/surgically injured nerves. The articles were selected using either electronic search engines or manual tracing of the references cited in key papers. In electronic searches, we used the key words as "paresthesia", "laser therapy", "low-power laser and nerve repair", and "laser therapy and nerve repair", considering case reports and clinical studies. According to the findings of the literature, laser therapy accelerates and improves the regeneration of the affected nerve tissues, but there are many conflicting results about laser therapy. This can be attributed to several variables such as wavelength, radiation dose, and type of radiation. All the early in vivo studies assessed in this research were effective in restoring sensitivity. Although these results indicate a potential benefit of the use of lasers on nerve repair, further double-blind controlled clinical trials should be conducted in order to standardize protocols for clinical application.

The effect of desensitizing dentifrices on dentin wear and tubule occlusion.

PURPOSE: To evaluate the effect of desensitizing dentifrices on dentin erosive wear, using a 5-day erosion-abrasion-remineralization cycling model. The effect of the dentifrices on dentin's tubule occlusion was also investigated. METHODS: 30 samples of root dentin were randomly divided into three groups (n = 10): (1) Colgate Total 12 Clean Mint (control, 1,450 ppm F); (2) Colgate Sensitive Pro-Relief (1,450 ppm F, Pro-Argin); and (3) Sensodyne Repair&Protect (1,450 ppm F, Novamin). Erosion was performed with a cola drink, for 5 minutes, 4x/day. Toothbrushing with the slurry dentifrices (1:2) was performed 2x/day, with electric toothbrushes, using standard pressure for 15 seconds. Surface loss (SL) was determined with optical profilometry at baseline and after the first, third and fifth days of cycling. Before treatment and in the end of the cycling, the amount of opened dentin tubules per area was evaluated in three randomly selected specimens from each group, by environmental scanning electron microscopy. The relative dentin abrasitivity (RDA) of the dentifrices was also measured. Data were statistically analyzed (α = 0.05). RESULTS: All the dentifrices showed a progressive increase in SL over time. However, no significant differences in SL among the dentifrices were observed at any time studied. Sensodyne Repair&Protect significantly reduced the number of opened dentin tubules when compared to the other groups. Colgate Total 12 Clean Mint showed the highest RDA, followed by Sensodyne Repair&Protect and then by Colgate Sensitive Pro-Relief. The desensitizing dentifrices tested produced a similar rate of erosive dentin wear to the conventional dentifrice; however, only Sensodyne Repair&Protect was able to promote tubule occlusion.

The beneficial effect of fluoxetine on behavioral and cognitive changes in chronic experimental Chagas disease unveils the role of serotonin fueling astrocyte infection by Trypanosoma cruzi.

BACKGROUND: In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD. METHODOLOGY/PRINCIPAL FINDINGS: In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells. CONCLUSION/SIGNIFICANCE: We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders.

Are Universal Adhesives Effective for Bonding to Zirconia in the Long Term?

Background: The bond capacity of universal adhesives should be comparable to a specific primer for zirconia. Thus, this study evaluated the bond strength to zirconia of four universal adhesives and a zirconia primer over long-term storage. Materials and Methods: The surfaces of 75 samples of zirconia were sandblasted with 50 µm aluminum oxide particles and then divided into groups (n = 15): G1 - Single Bond Universal (SBU); G2 - All Bond Universal; G3 - Peak Universal Bond; G4 - Ambar Universal (AU), and G5 - Z-Prime Plus (ZP). A cone of resin composite was constructed on the applied materials. The samples were submitted to a tensile bond strength test after 24 h using a universal testing machine. Then, the remaining materials were removed from the sample surfaces, and the surfaces were polished and sandblasted again as previously described to obtain the same groups. These new samples were stored in distilled water at 37°C for 12 months and then submitted to a tensile bond strength test. The data were analyzed by two-way analysis of variance and Tukey's test (α =0.05). Results: The material factor (P = 0.001) and the storage factor (P = 0.001) were significant, and the interaction was not significant (P = 0.117). According to Tukey's test, bond strength mean values (in MPa) followed by distinct letters were significantly different. After 24 h, G5 = 21.12 A, G1 = 20.55 A, G4 = 19.19 AB, G2 = 14.22 B, and G3 = 8.44 C. After 12 months, G1 = 7.37 A, G5 = 5.61 AB, G4 = 4.97 B, G2 = 3.32 C, and G3 = 1.93 D. After 12 months of storage, all groups' bond strength significantly decreased. Conclusions: SBU and AU had bond strengths comparable to ZP after 24 h. No material resisted water degradation.

Isothermal denaturation fluorimetry vs differential scanning fluorimetry as tools for screening of stabilizers for protein freeze-drying: Human phenylalanine hydroxylase as the case study.

The structural maintenance of therapeutic proteins during formulation and/or storage is a critical aspect, particularly for multi-domain and/or multimeric proteins which usually exhibit intrinsic structural dynamics leading to aggregation with concomitant loss-of-function. Protein freeze-drying is a widely used technique to preserve protein structure and function during storage. To minimize chemical/physical stresses occurring during this process, protein stabilizers are usually included, their effect being strongly dependent on the target protein. Therefore, they should be screened for on a time-consuming case-by-case basis. Herein, differential scanning fluorimetry (DSF) and isothermal denaturation fluorimetry (ITDF) were employed to screen, among different classes of freeze-drying additives, for the most effective stabilizer of the model protein human phenylalanine hydroxylase (hPAH). Correlation studies among retrieved DSF and ITDF parameters with recovered enzyme amount and activity indicated ITDF as the most appropriate screening method. Biochemical and biophysical characterization of hPAH freeze-dried with ITDF-selected stabilizers and a long-term storage study (12 months, 5 ± 3 °C) showed that the selected compounds prevented protein aggregation and preserved hPAH structural and functional properties throughout time storage. Our results provide a solid basis towards the choice of ITDF as a high-throughput screening step for the identification of protein freeze-drying protectors.

Review of Piezoelectrical Materials Potentially Useful for Peripheral Nerve Repair.

It has increasingly been recognized that electrical currents play a pivotal role in cell migration and tissue repair, in a process named "galvanotaxis". In this review, we summarize the current evidence supporting the potential benefits of electric stimulation (ES) in the physiology of peripheral nerve repair (PNR). Moreover, we discuss the potential of piezoelectric materials in this context. The use of these materials has deserved great attention, as the movement of the body or of the external environment can be used to power internally the electrical properties of devices used for providing ES or acting as sensory receptors in artificial skin (e-skin). The fact that organic materials sustain spontaneous degradation inside the body means their piezoelectric effect is limited in duration. In the case of PNR, this is not necessarily problematic, as ES is only required during the regeneration period. Arguably, piezoelectric materials have the potential to revolutionize PNR with new biomedical devices that range from scaffolds and nerve-guiding conduits to sensory or efferent components of e-skin. However, much remains to be learned regarding piezoelectric materials, their use in manufacturing of biomedical devices, and their sterilization process, to fine-tune their safe, effective, and predictable in vivo application.

Combining metal nanoclusters and carbon nanomaterials: Opportunities and challenges in advanced nanohybrids.

The development of functional materials with uniquely advanced properties lies at the core of nanoscience and nanotechnology. From the myriad possible combinations of organic and/or inorganic blocks, hybrids combining metal nanoclusters and carbon nanomaterials have emerged as highly attractive colloidal materials for imaging, sensing (optical and electrochemical) and catalysis, among other applications. While the metal nanoclusters provide extraordinary luminescent and electronic properties, the carbon nanomaterials (of zero, one or two dimensions) convey versatility, as well as unique interfacial, electronic, thermal, optical, and mechanical properties, which altogether can be put to use for the desired application. Herein, we present an overview of the field, for experts and non-experts, encompassing the basic properties of the building blocks, a systematic view of the chemical preparation routes and physicochemical properties of the hybrids, and a critical analysis of their ongoing and emerging applications. Challenges and opportunities, including directions towards green chemistry approaches, are also discussed.

Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study.

Multiple myeloma (MM) is a hematological malignancy of clonal antibody-secreting plasma cells (PCs). MM diagnosis and risk stratification rely on bone marrow (BM) biopsy, an invasive procedure prone to sample bias. Liquid biopsies, such as extracellular vesicles (EV) in peripheral blood (PB), hold promise as new minimally invasive tools. Real-world studies analyzing patient-derived EV proteome are rare. Here, we characterized a small EV protein content from PB and BM samples in a cohort of 102 monoclonal gammopathies patients routinely followed in the clinic and 223 PB and 111 BM samples were included. We investigated whether EV protein and particle concentration could predict an MM patient prognosis. We found that a high EV protein/particle ratio, or EV cargo >0.6 µg/108 particles, is related to poorer survival and immune dysfunction. These results were supported at the protein level by mass spectrometry. We report a set of PB EV-proteins (PDIA3, C4BPA, BTN1A1, and TNFSF13) with a new biomarker potential for myeloma patient outcomes. The high proteomic similarity between PB and BM matched pairs supports the use of circulating EV as a counterpart of the BM EV proteome. Overall, we found that the EV protein content is related to patient outcomes, such as survival, immune dysfunction, and possibly treatment response.

Multiple Myeloma-Derived Extracellular Vesicles Modulate the Bone Marrow Immune Microenvironment.

Multiple myeloma (MM), the third most frequent hematological cancer worldwide, is characterized by the proliferation of neoplastic plasma cells in the bone marrow (BM). One of the hallmarks of MM is a permissive BM microenvironment. Increasing evidence suggests that cell-to-cell communication between myeloma and immune cells via tumor cell-derived extracellular vesicles (EV) plays a key role in the pathogenesis of MM. Hence, we aimed to explore BM immune alterations induced by MM-derived EV. For this, we inoculated immunocompetent BALB/cByJ mice with a myeloma cell line, MOPC315.BM, inducing a MM phenotype. Upon tumor establishment, characterization of the BM microenvironment revealed the expression of both activation and suppressive markers by lymphocytes, such as granzyme B and PD-1, respectively. In addition, conditioning of the animals with MOPC315.BM-derived EV, before transplantation of the MOPC315.BM tumor cells, did not anticipate the disease phenotype. However, it induced features of suppression in the BM milieu, such as an increase in PD-1 expression by CD4+ T cells. Overall, our findings reveal the involvement of MOPC315.BM-derived EV protein content as promoters of immune niche remodeling, strengthening the importance of assessing the mechanisms by which MM may impact the immune microenvironment.

Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors.

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

Sickle cell anemia with perforated duodenal ulcer as a complication: when to suspect this rare entity?

Perforated duodenal peptic ulcers are often not considered when making a differential diagnosis of abdominal pain, especially in the context of sickle cell disease, and cases have not been frequently described in the literature. This study reports the case of a 14 year-old girl with sickle cell anemia complicated with duodenal ulcer perforation, focusing mainly on the imaging aspects. Abdominal CT should be considered as a method for this diagnosis and it requires the knowledge of this entity and its characteristic imaging findings.

Boosting Immunity against Multiple Myeloma.

Despite the improvement of patient's outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody-drug conjugates or bispecific antibodies broadened the possibility of improving patients' survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

The Immune Microenvironment in Multiple Myeloma: Friend or Foe?

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

Is prolonged bleaching more harmful to dental enamel than daily dietary and hygienic oral habits?

The ultrastructural and mechanical properties of enamel surface were evaluated after prolonged bleaching treatments with 10% carbamide peroxide in the presence or absence of orange juice (erosive challenge) and toothbrushing (abrasive challenge). In total, 145 incisor bovine teeth were used in this study. Twenty-five samples were prepared for the ultrastructural evaluations, and 120 samples were prepared for microhardness and roughness tests. These 120 samples were divided into eight experimental groups (n = 15): G1- artificial saliva; G2- abrasion; G3- erosion; G4- dental bleaching; G5- erosion + abrasion; G6- bleaching + abrasion; G7- bleaching + erosion; and G8- bleaching + erosion + abrasion. All groups were tested at T0 (before treatment), T1 (14 days), T2 (21 days), and T3 (28 days). Two-way analysis of variance for repeated measures and the post hoc Sidak tests (p ≤ 0.05) were used. The roughness evaluation demonstrated an increase in damage for all experimental groups with an increase in the time period. For microhardness, the groups exposed to artificial saliva (AS) and abrasive challenge did not show any differences at any time points, while the other groups showed a decrease in microhardness from T0 to T3. Ultrastructural evaluation showed different surface alterations in response to the treatments. Despite prolonged bleaching periods, the procedure caused lesser enamel surface alterations than exposure to orange juice alone or in combination with brushing.