Hematopoietic colony-stimulating factors in head and neck cancers: Recent advances and therapeutic challenges.

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.

Rehabilitation in primary care for an ageing population: a secondary analysis from a scoping review of rehabilitation delivery models.

BACKGROUND: The world population is ageing rapidly. Rehabilitation is one of the most effective health strategies for improving the health and functioning of older persons. An understanding of the current provision of rehabilitation services in primary care (PC) is needed to optimise access to rehabilitation for an ageing population. The objectives of this scoping review are a) to describe how rehabilitation services are currently offered in PC to older persons, and b) to explore age-related differences in the type of rehabilitation services provided. METHODS: We conducted a secondary analysis of a scoping review examining rehabilitation models for older persons, with a focus on PC. Medline and Embase (2015-2022) were searched to identify studies published in English on rehabilitation services for people aged 50 + . Two authors independently screened records and extracted data using the World Health Organization (WHO)'s operational framework, the Primary Health Care Systems (PRIMASYS) approach and the WHO paper on rehabilitation in PC. Data synthesis included quantitative and qualitative analysis. RESULTS: We synthesised data from 96 studies, 88.6% conducted in high-income countries (HICs), with 31,956 participants and identified five models for delivering rehabilitation to older persons in PC: community, home, telerehabilitation, outpatient and eldercare. Nurses, physiotherapists, and occupational therapists were the most common providers, with task-shifting reported in 15.6% of studies. The most common interventions were assessment of functioning, rehabilitation coordination, therapeutic exercise, psychological interventions, and self-management education. Environmental adaptations and assistive technology were rarely reported. CONCLUSIONS: We described how rehabilitation services are currently provided in PC and explored age-related differences in the type of rehabilitation services received. PC can play a key role in assessing functioning and coordinating the rehabilitation process and is also well-placed to deliver rehabilitation interventions. By understanding models of rehabilitation service delivery in PC, stakeholders can work towards developing more comprehensive and accessible services that meet the diverse needs of an ageing population. Our findings, which highlight the role of rehabilitation in healthy ageing, are a valuable resource for informing policy, practice and future research in the context of the United Nations Decade of Healthy Ageing, the Rehab2030 initiative and the recently adopted WHA resolution on strengthening rehabilitation in health systems, but the conclusions can only be applied to HICs and more studies are needed that reflect the reality in low- and middle-income countries.

Oral manifestations of graft-versus-host disease in patients submitted to allogeneic hematopoietic stem cell transplantation: the experience of a Brazilian Cancer Center.

PURPOSE: Graft-versus-host disease (GVHD) is an important complication of allogeneic hematopoietic stem cell transplantation (AHCT) that affects several organs, including the mouth. OBJECTIVES: The aim of the present study was to describe the prevalence and clinical manifestations of oral GVHD, to determine the time interval from AHCT to the onset of oral GVHD manifestations, to identify predictive factors of oral GVHD, and to evaluate the survival rates of patients diagnosed with oral GVHD. METHODS: Medical records of 147 patients who underwent AHCT between January 2010 and January 2015 were reviewed for clinical features and the statistical establishment of risk factors. RESULTS: Of the 147 patients in the study, 99 (67.3%) developed GVHD. The skin was the most affected site (45.6%), followed by the gastrointestinal tract (27.9%) and oral cavity (17.7%). The mean post-AHCT oral GVHD development time was 229 days. Among patients with oral GVHD, pain was the main complaint (96.2%) followed by xerostomia (65.4%). The most common oral manifestations were ulcers (53.8%) followed by striae-associated ulcers (19.2%), mostly affecting the buccal mucosa and tongue. Seventy-three patients (48.6%) died within 20 months of receiving AHCT. Cox regression analysis indicated that patients who received myeloablative conditioning regimen had higher survival rate than those who underwent a reduced-intensity conditioning regimen (RR = 0.541; 95% CI, 0.334-0.878; p = 0.03). CONCLUSION: The mouth was the third most common GVHD-affected site. Pain, xerostomia, and ulcers with or without striae were the main clinical manifestations of GVHD observed in our study cohort. Reduced-intensity conditioning regimen showed significant relationship with mortality risk.

Novel Regioisomeric Analogues of Naphthyl-N-Acylhydrazone Derivatives and Their Anti-Inflammatory Effects.

BACKGROUND: When homeostasis is disturbed it can result in a pathological event named inflammation. The main drugs used in the treatment consist of non-steroidal and steroidal anti-inflammatory drugs. However, the side effects remain an obstacle during the treatments. In this study, we aimed to evaluate three new regioisomers analogues of naphthyl-N-acylhydrazone derivatives. METHODS: Acute models of inflammation in vivo (formalin-induced licking and carrageenan-induced inflammation) as well as in vitro were used to evaluate the effects of LASSBio-2039, LASSBio-2040, and LASSBio-2041. RESULTS: All three substances (at 1, 10 or 30 µmol/kg) presented significant effects in the in vivo model reducing leukocyte migration, nitric oxide (NO) and interleukin-1ß production. It was observed that only LASSBio-2039 significantly reduced cell migration in vitro. None of the LASSBios affected inducible nitric oxide synthase activity nor presented nitric oxide (NO) scavenger effect. No toxic effect was observed, either in vivo or in vitro. The new regioisomers analogues of naphthyl-N-acylhydrazone derivatives presented significant anti-inflammatory activity, suggesting LASSBio-2039 has a direct effect in leukocytes migratory capacity. CONCLUSIONS: Taken together, the data indicate that these substances present promising effects for the development of a prototype for new drugs.

Endometriosis: A Disease with Few Direct Treatment Options.

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues inside and outside the pelvic cavity. The evolution of the disease can lead to infertility in addition to high treatment costs. Currently, available medications are only effective in treating endometriosis-related pain; however, it is not a targeted treatment. The objective of this work is to review the characteristics of the disease, the diagnostic means and treatments available, as well as to discuss new therapeutic options.

Langerhans cell histiocytosis in the oral and maxillofacial region: An update.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by abnormal proliferation and infiltration of histiocytic cells. METHODS: This review focused on the main aspects associated with LCH. RESULTS: LCH can involve single or multiple organs and systems, with bone and skin being the most commonly affected sites. Regarding skeletal manifestations, the jawbones are involved in about 20%-30% of all cases. Such lesions may present as unilocular or multilocular images mainly affecting the posterior mandible. Oral soft tissue lesions may also occur, with the gingiva and hard palate being the most frequently affected sites. CONCLUSION: The diagnosis and management of LCH are challenging, requiring a multidisciplinary approach, with dentists playing a central role since oral manifestations can be the first sign of the condition.

A Histopathological Study Reveals New Insights Into Responses of Chestnut (Castanea spp.) to Root Infection by Phytophthora cinnamomi.

The European chestnut (Castanea sativa) is threatened by the hemibiotrophic oomycete Phytophthora cinnamomi, the causal agent of ink disease. Chestnut species have different susceptibility levels to P. cinnamomi, with the Asian species (C. crenata; C. mollissima) exhibiting the highest level of resistance. A histological approach was used to study the responses exhibited by susceptible and resistant chestnut genotypes by characterizing the early stages of P. cinnamomi infection and the cellular responses it induces in roots. C. sativa (susceptible) and C. crenata (resistant) plantlets were inoculated with a P. cinnamomi virulent isolate with a zoospore suspension or by direct contact with mycelia agar pieces. Root samples were collected at 0.5, 3.5, 24, 48, and 72 h after inoculation (hai) for microscopic observations. Penetration was observed in both species at 0.5 and 3.5 hai with mycelium and zoospore inoculations, respectively. In both inoculation methods, following penetration into the rhizodermis, P. cinnamomi hyphae grew inter- and intracellularly through the cortex and into the vascular cylinder. C. crenata cells displayed a delay in the pattern of infection by having fewer cell layers colonized compared with C. sativa. At 72 hai, the collapse of the first layers of C. sativa cortical cells was observed, indicating the beginning of necrotrophy. C. crenata was able to respond more efficiently to P. cinnamomi than C. sativa by restricting the pathogen's growth area through the early activation of resistance responses such as callose deposition around some intracellular hyphae, hypersensitive response-like cell death, cell wall thickening, and accumulation of phenolic-like compounds.

Benzo[f]indole-4,9-dione Derivatives Effectively Inhibit the Growth of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor clinical outcome, and currently no effective targeted therapies are available. Indole compounds have been shown to have potential antitumor activity against various cancer cells. In the present study, we found that new four benzo[f]indole-4,9-dione derivatives reduce TNBC cell viability by reactive oxygen species (ROS) accumulation stress in vitro. Further analyses showed that LACBio1, LACBio2, LACBio3 and LACBio4 exert cytotoxic effects on MDA-MB 231 cancer cell line by inducing the intrinsic apoptosis pathway, activating caspase 9 and Bax/Bcl-2 pathway in vitro. These results provide evidence that these new four benzo[f]indole-4,9-dione derivatives could be potential therapeutic agents against TNBC by promoting ROS stress-mediated apoptosis through intrinsic-pathway caspase activation.

Characterization of ßN-Octadecanoyl-5-hydroxytryptamide Anti-Inflammatory Effect.

BACKGROUND: N-octadecanoyl-5-hydroxytryptamide (C18-5HT) is an amide that can be obtained by the coupling of serotonin and octadecanoic acid. This study aims to characterize the in vivo and in vitro anti-inflammatory activity of C18-5HT. METHODS: A subcutaneous air pouch model (SAP) was used. The exudates were collected from SAP after carrageenan injection to assess cell migration and inflammatory mediators production. RAW 264.7 cells were used for in vitro assays. RESULTS: C18-5HT significantly inhibited leukocyte migration into the SAP as well as nitric oxide (NO) and cytokines production and protein extravasation. We also observed an reduction in some cytokines and an increase in IL-10 production. Assays conducted with RAW 264.7 cells indicated that C18-5HT inhibited NO and cytokine produced. CONCLUSIONS: Taken together, our data suggest that C18-5HT presents a significant effect in different cell types (leukocytes collected from exudate, mainly polumorphonuclear leukocytes and cell culture macrophages) and is a promising compound for further studies for the development of a new anti-inflammatory drug.

Therapeutic Effects of Anti-Inflammatory N-Acylhydrazones in the Resolution of Experimental Colitis.

Inflammatory bowel diseases are caused by inflammation of the gastrointestinal tract, which may or may not have a specific cause or pathogen. They affect millions of people around the world and there are still few effective treatments. The aim of this work is to investigate the anti-inflammatory effect of the IKK-ß inhibitor LASSBio-1524 and its three analogs, LASSBio-1760, LASSBio-1763, and LASSBio-1764, on mediator production and expression of inflammatory enzymes using experimental animal models of intestinal inflammatory diseases. Colitis was performed using two different models, which mimic Crohn disease (induced by dinitrobenzene acid) and ulcerative colitis (induced by sodium dextran sulfate) in mice. In both models, a therapeutic protocol with a daily dose of 1, 3, or 30 µmol/kg was performed. LASSBio-1524 and its three analogs reduced the secretion of tumor necrosis factor-α, IL-1ß, IL-6, IL-12, and IFN-γ and increased secretion of IL-10, protecting gastrointestinal homeostasis. All compounds reduced macro- and microscopic colonic damage caused by experimental colitis and p38 mitogen-activated protein kinase expression in the colon, as well as leukocytosis and anemia resulting from the disease. Our data may suggest LASSBio-1524 and its analogs (LASSBio-1760, LASSBio-1763, and LASSBio-1764) as promising candidates for new prototypes designed to treat inflammatory bowel diseases. SIGNIFICANCE STATEMENT: Three new N-acylhydrazones were synthetized as analogs of LASSBio-1524. All new substances were evaluated in dextran sulfate- and dinitrobenzene acid-induced colitis, with LASSBio-1760, LASSBio-1762, and LASSBio-1763 presenting a significant effect in both models of colitis without toxic effects. The new substances could be considered as a new prototype for the development of new anti-inflammatory treatments of colitis.

A multiplex RT-PCR method to detect papaya meleira virus complex in adult pre-flowering plants.

Papaya sticky disease (PSD), which can destroy orchards, was first attributed to papaya meleira virus (PMeV). However, the discovery of papaya meleira virus 2 (PMeV2) associated with PSD plants impose the need to detect this viral complex. We developed a multiplex RT-PCR (mPCR) technique capable of detecting two viruses in a single assay from pre-flowering plant samples, which is a useful tool for early diagnosis of PSD. We also determined the limit of detection (LOD) using asymmetric plasmid dilutions of both PMeV and PMeV2, which revealed that a higher titer of one virus prevents detection of the other. Thus, this technique is an alternative method for detecting PMeV and PMeV2 in a single reaction.

Battle of Three: The Curious Case of Papaya Sticky Disease.

Among the most serious problems in papaya production are the viruses associated with papaya ringspot and papaya sticky disease (PSD). PSD concerns producers worldwide because its symptoms are extremely aggressive and appear only after flowering. As no resistant cultivar is available, several disease management strategies have been used in affected countries, such as the use of healthy seeds, exclusion of the pathogen, and roguing. In the 1990s, a dsRNA virus, papaya meleira virus (PMeV), was identified in Brazil as the causal agent of PSD. However, in 2016 a second virus, papaya meleira virus 2 (PMeV2), with an ssRNA genome, was also identified in PSD plants. Only PMeV is detected in asymptomatic plants, whereas all symptomatic plants contain both viral RNAs separately packaged in particles formed by the PMeV capsid protein. PSD also affects papaya plants in Mexico, Ecuador, and Australia. PMeV2-like viruses have been identified in the affected plants, but the partner virus(es) in these countries are still unknown. In Brazil, PMeV and PMeV2 reside in laticifers that promote spontaneous latex exudation, resulting in the affected papaya fruit's sticky appearance. Genes modulated in plants affected by PSD include those involved in reactive oxygen species and salicylic acid signaling, proteasomal degradation, and photosynthesis, which are key plant defenses against PMeV complex infection. However, the complete activation of the defense response is impaired by the expression of negative effectors modulated by the virus. This review presents a summary of the current knowledge of the Carica papaya-PMeV complex interaction and management strategies.

Pharmacological Evaluation of Artemisia cina Crude CO2 Subcritical Extract after the Removal of Santonin by Means of High Speed Countercurrent Chromatography.

Artemisia species are highly important due to their economic significance as medicines, fodder and food. Artemisia cina is an endemic species to Kazakhstan. In folk medicine, water extract of A. cina was used in the treatment of bronchial asthma while the alcohol extract has larvicidal and antituberculosis activity. The most common and most extensively studied compound from this species is the terpenoid santonin. The toxicity of this compound occurs at the doses of 60 mg for children and 200 mg for adults causing among other issues xanthopsia, leading to blindness. Having this in mind, the main idea of this work was to remove santonin from the crude extract and to check if the santonin-free extract would still be of any pharmacological importance. A CO2 subcritical extract was chromatographed using high-speed countercurrent chromatography (HSCCC) for the removal of santonin. The santonin-free CO2 subcritical extract (SFCO2E) as well as the isolated compound pectolinarigenin, a flavonoid, were assessed for their pharmacological actions. From the results obtained we can safely suggest that HSCCC is an efficient methodology to completely remove santonin from the CO2 subcritical extract. It was also possible to observe promising antinociceptive and anti-inflammatory activities for both SFCO2E and pectolinarigenin at concentrations that can justify the production of a phytomedicine with this endemic plant from Kazakhstan.

Study on the Antinociceptive Activity and Mechanism of Action of Isolated Saponins from Siolmatra brasiliensis (Cogn.) Baill.

Infusions of roots of Siolmatra brasiliensis (Cogn.) Baill, ("taiuiá", "cipó-tauá") are used for toothache pain and ulcers. We aimed to study the antinociceptive effects and identify the possible mechanism of action of this plant and its isolated substances (cayaponoside A1, cayaponoside B4, cayaponoside D, and siolmatroside I). Hydroethanol extract (HE), ethyl acetate fraction (EtOAc), and isolated saponins were evaluated in chemical and thermal models of pain in mice. Animals were orally pretreated and evaluated in the capsaicin- or glutamate-induced licking and in the hot plate tests. The antinociceptive mechanism of action was evaluated using the hot plate test with the following pretreatments: Atropine (cholinergic antagonist), naloxone (opioid antagonist), or L-NAME (nitric oxide synthase inhibitor). All extracts and isolated saponins increased the area under the curve in the hot plate test. Tested substances induced a higher effect than the morphine-treated group. Our data suggest that stems of S. brasiliensis and their isolated substances present antinociceptive effects. Cholinergic and opioidergic pathways seem to be involved in their mechanism of action. Taken together our data corroborate the traditional use of the plant and expands the information regarding its use.

Transcriptome analysis provides insights into the delayed sticky disease symptoms in Carica papaya.

KEY MESSAGE: Global gene expression analysis indicates host stress responses, mainly those mediated by SA, associated to the tolerance to sticky disease symptoms at pre-flowering stage in Carica papaya. Carica papaya plants develop the papaya sticky disease (PSD) as a result of the combined infection of papaya meleira virus (PMeV) and papaya meleira virus 2 (PMeV2), or PMeV complex. PSD symptoms appear only after C. papaya flowers. To understand the mechanisms involved in this phenomenon, the global gene expression patterns of PMeV complex-infected C. papaya at pre-and post-flowering stages were assessed by RNA-Seq. The result was 633 and 88 differentially expressed genes at pre- and post-flowering stages, respectively. At pre-flowering stage, genes related to stress and transport were up-regulated while metabolism-related genes were down-regulated. It was observed that induction of several salicylic acid (SA)-activated genes, including PR1, PR2, PR5, WRKY transcription factors, ROS and callose genes, suggesting SA signaling involvement in the delayed symptoms. In fact, pre-flowering C. papaya treated with exogenous SA showed a tendency to decrease the PMeV and PMeV2 loads when compared to control plants. However, pre-flowering C. papaya also accumulated transcripts encoding a NPR1-inhibitor (NPR1-I/NIM1-I) candidate, genes coding for UDP-glucosyltransferases (UGTs) and several genes involved with ethylene pathway, known to be negative regulators of SA signaling. At post-flowering, when PSD symptoms appeared, the down-regulation of PR-1 encoding gene and the induction of BSMT1 and JA metabolism-related genes were observed. Hence, SA signaling likely operates at the pre-flowering stage of PMeV complex-infected C. papaya inhibiting the development of PSD symptoms, but the induction of its negative regulators prevents the full-scale and long-lasting tolerance.

Synthesis and pharmacological evaluation of novel isoquinoline N-sulphonylhydrazones designed as ROCK inhibitors.

In this study, we synthesized a new congener series of N-sulphonylhydrazones designed as candidate ROCK inhibitors using the molecular hybridization of the clinically approved drug fasudil (1) and the IKK-ß inhibitor LASSBio-1524 (2). Among the synthesized compounds, the N-methylated derivative 11 (LASSBio-2065) showed the best inhibitory profile for both ROCK isoforms, with IC50 values of 3.1 and 3.8 µM for ROCK1 and ROCK2, respectively. Moreover, these compounds were also active in the scratch assay performed in human breast cancer MDA-MB 231 cells and did not display toxicity in MTT and LDH assays. Molecular modelling studies provided insights into the possible binding modes of these N-sulphonylhydrazones, which present a new molecular architecture capable of being optimized and developed as therapeutically useful ROCK inhibitors.

Unusual Intestinal Involvement by Paracoccidioidomycosis Diagnosed After Oral Manifestation.

Paracoccidioidomycosis is a common deep fungus infection in South America, particularly in Brazil. It is acquired through inhalation and primary involvement of lungs. Subsequently, dissemination may occur and oral mucosa is frequently affected and actually, in most of the cases the diagnosis is established because of the oral lesions. Thus, the role of the dentist is fundamental to correct diagnosis. However, the involvement of intestine is rarely reported. The current case describes a 36-year-old man who presented abdominal pain and intestinal constipation, being suspected and then confirmed as paracoccidioidomycosis after already be diagnosed with this disease by a dentist through oral manifestations.