Characteristics and management of Susac syndrome in an emergent country: a multi-center case series from Brazil.

BACKGROUND: Susac syndrome (SS) is a rare endotheliopathy with an estimated prevalence of 0.14-0.024 per 100,000. It is an important differential diagnosis in demyelinating disorders. There are few case series and no large randomized controlled trials, and most reports come from developed countries. We report six cases of SS in three centers in Brazil and discuss management challenges in emergent countries. METHODS: This is a retrospective case series of patients diagnosed with SS in three medical centers in Brazil between April 2018 and July 2021. The European Susac consortium (EuSaC) criteria were used for diagnosis of SS. Demographic data and clinical interventions were described and outcomes were assessed subjectively and by applying the modified Rankin Scale (mRS) on last follow-up. RESULTS: Six patients were diagnosed with SS (3 males, 3 females). Mean age at presentation was 36 years (range 17 to 54). The most common initial symptom was confusion, followed by visual impairment and hearing loss. Characteristic snowball lesions on magnetic resonance imaging (MRI) were present in four patients (66%). Retinal artery abnormalities were present in half (3/6) of patients, and sensorineural hearing loss was present in four patients (66%). Outcome was favorable (mRS ≤ 2) in five patients (86%). Patients treated early had a more favorable outcome. CONCLUSION: Emergent countries face challenges in the diagnosis and management of patients with SS, such as access to advanced tests (fluorescein angiography, serial MRI) and treatment drugs (rituximab, mycophenolate). Further research should consider particularities of patients with SS in emergent countries.

Asparagopsis Genus: What We Really Know About Its Biological Activities and Chemical Composition.

Although the genus Asparagopsis includes only two taxonomically accepted species, the published literature is unanimous about the invasive nature of this genus in different regions of the globe, and about the availability of large amounts of biomass for which it is important to find a commercial application. This review shows that extracts from Asparagospsis species have already been evaluated for antioxidant, antibacterial, antifungal, antiviral, antifouling, cytotoxic, antimethanogenic and enzyme-inhibitory activity. However, the tables presented herein show, with few exceptions, that the activity level displayed is generally low when compared with positive controls. Studies involving pure compounds being identified in Asparagopsis species are rare. The chemical compositions of most of the evaluated extracts are unknown. At best, the families of the compounds present are suggested. This review also shows that the volatile halogenated compounds, fatty acids and sterols that are biosynthesized by the Asparagopsis species are relatively well known. Many other non-volatile metabolites (halogen compounds, flavonoids, other phenolic compounds) seem to be produced by these species, but their chemical structures and properties haven'been investigated. This shows how much remains to be investigated regarding the secondary-metabolite composition of these species, suggesting further studies following more targeted methodologies.

Apathy and agitation in institutionalized older adults: an empirically derived classification.

BACKGROUND: Apathy and agitation are often recognized as the most problematic behavioural and psychological symptoms in care settings. In this study, we analyze the relationship between apathy and agitation symptoms other and their relationship with demographic, cognitive, and neuropsychiatric variables and psychotropic medication use. METHODS: A retrospective study was conducted at a gerontological care centre in Láncara, Spain. Participants were 196 residents of the gerontological care centre, including 143 with a diagnosis of dementia. Apathy and agitation were assessed with the Apathy Scale for Institutionalized Patients with Dementia, Nursing Home version, and the Spanish version of the Cohen-Mansfield Agitation Inventory, respectively. Two-stage hierarchical cluster analysis (hierarchical cluster analysis in a first exploratory stage and K-means clustering to obtain the final solution in the second stage) was conducted to assign residents to different groups based on apathy and agitation scores. RESULTS: In cluster 1, a certain level of apathy, the highest levels of agitation, and the most frequent intake of atypical antipsychotics and clomethiazole were observed. The highest levels of apathy and the most frequent intake of memantine were seen in cluster 2. The lowest levels of agitation and apathy and the highest levels of cognitive performance were found in cluster 3. CONCLUSIONS: In this study, subjects with dementia were in a state of high agitation and eventual apathy, had low cognitive status, and were very old. Patients with this profile require well-designed non-pharmacological interventions.

Design, synthesis and evaluation of novel, potent DNA alkylating agents and their antibody-drug conjugates (ADCs).

Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo.

Second brazilian consensus on the treatment of advanced prostate cancer - a SBOC-SBU-SBRT panel review.

Prostate cancer is the second most common cancer and the fi fth leading cause of cancer deaths. In Brazil, it is likewise the second most common cancer among men, second only to non-melanoma skin cancers. The aim of this consensus is to align different opinions and interpretations of the medical literature in a practical and patient-oriented approach. The fi rst Brazilian Consensus on the Treatment of Advanced Prostate Cancer was published in 2017, with the goal of reducing the heterogeneity of therapeutic conduct in Brazilian patients with metastatic prostate cancer. We acknowledge that in Brazil the incorporation of different technologies is a big challenge, especially in the Sistema Único de Saúde (SUS), which allows for the disparity in the options available to patients treated in different institutions. In order to update the recommendations and to make them objective and easily accessible, once more a panel of specialists was formed in order to discuss and elaborate a new Brazilian Consensus on Advanced Prostate Cancer. This Consensus was written through a joint initiative of the Brazilian Society of Clinical Oncology (SBOC) and the Brazilian Society of Urology (SBU) to support the clinical decisions of physicians and other health professionals involved in the care of patients with prostate cancer.

A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer.

Resistance to platinum-based therapy poses a significant clinical challenge for the management of advanced ovarian cancer, a leading cause of cancer mortality among women. Mirvetuximab soravtansine is a novel antibody-drug conjugate that targets folate receptor-α, a validated molecular target for therapeutic intervention in this disease. Here, we examine mirvetuximab soravtansine's mechanism of action and pharmacology, and review its clinical evaluation in ovarian cancer to date. We focus on the favorable tolerability and encouraging signals of efficacy that have emerged, most notably in patients with platinum-resistant disease. Ongoing Phase III monotherapy and Phase Ib/II combination trials evaluating its activity in the setting of platinum resistance are emphasized, which will help define its role in the evolving landscape of ovarian cancer therapy.

Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors.

BACKGROUND: Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. METHODS: Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. RESULTS: In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response. CONCLUSIONS: IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society.

Effects of Drug-Antibody Ratio on Pharmacokinetics, Biodistribution, Efficacy, and Tolerability of Antibody-Maytansinoid Conjugates.

Antibody-drug conjugates (ADCs) are being actively pursued as a treatment option for cancer following the regulatory approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla). ADCs consist of a cytotoxic agent conjugated to a targeting antibody through a linker. The two approved ADCs (and most ADCs now in the clinic that use a microtubule disrupting agent as the payload) are heterogeneous conjugates with an average drug-to-antibody ratio (DAR) of 3-4 (potentially ranging from 0 to 8 for individual species). Ado-trastuzumab emtansine employs DM1, a semisynthetic cytotoxic payload of the maytansinoid class, which is conjugated via lysine residues of the antibody to an average DAR of 3.5. To understand the effect of DAR on the preclinical properties of ADCs using maytansinoid cytotoxic agents, we prepared a series of conjugates with a cleavable linker (M9346A-sulfo-SPDB-DM4 targeting folate receptor α (FRα)) or an uncleavable linker (J2898A-SMCC-DM1 targeting the epidermal growth factor receptor (EGFR)) with varying DAR and evaluated their biochemical characteristics, in vivo stability, efficacy, and tolerability. For both formats, a series of ADCs with DARs ranging from low (average of ∼2 and range of 0-4) to very high (average of 10 and range of 7-14) were prepared in good yield with high monomer content and low levels of free cytotoxic agent. The in vitro potency consistently increased with increasing DAR at a constant antibody concentration. We then characterized the in vivo disposition of these ADCs. Pharmacokinetic analysis showed that conjugates with an average DAR below ∼6 had comparable clearance rates, but for those with an average DAR of ∼9-10, rapid clearance was observed. Biodistribution studies in mice showed that these 9-10 DAR ADCs rapidly accumulate in the liver, with maximum localization for this organ at 24-28% percentage injected dose per gram (%ID/g) compared with 7-10% for lower-DAR conjugates (all at 2-6 h post-injection). Our preclinical findings on tolerability and efficacy suggest that maytansinoid conjugates with DAR ranging from 2 to 6 have a better therapeutic index than conjugates with very high DAR (∼9-10). These very high DAR ADCs suffer from decreased efficacy, likely due to faster clearance. These results support the use of DAR 3-4 for maytansinoid ADCs but suggest that the exploration of lower or higher DAR may be warranted depending on the biology of the target antigen.

Understanding How the Stability of the Thiol-Maleimide Linkage Impacts the Pharmacokinetics of Lysine-Linked Antibody-Maytansinoid Conjugates.

Antibody-drug conjugates (ADCs) have become a widely investigated modality for cancer therapy, in part due to the clinical findings with ado-trastuzumab emtansine (Kadcyla). Ado-trastuzumab emtansine utilizes the Ab-SMCC-DM1 format, in which the thiol-functionalized maytansinoid cytotoxic agent, DM1, is linked to the antibody (Ab) via the maleimide moiety of the heterobifunctional SMCC linker. The pharmacokinetic (PK) data for ado-trastuzumab emtansine point to a faster clearance for the ADC than for total antibody. Cytotoxic agent release in plasma has been reported with nonmaytansinoid, cysteine-linked ADCs via thiol-maleimide exchange, for example, brentuximab vedotin. For Ab-SMCC-DM1 ADCs, however, the main catabolite reported is lysine-SMCC-DM1, the expected product of intracellular antibody proteolysis. To understand these observations better, we conducted a series of studies to examine the stability of the thiol-maleimide linkage, utilizing the EGFR-targeting conjugate, J2898A-SMCC-DM1, and comparing it with a control ADC made with a noncleavable linker that lacked a thiol-maleimide adduct (J2898A-(CH2)3-DM). We employed radiolabeled ADCs to directly measure both the antibody and the ADC components in plasma. The PK properties of the conjugated antibody moiety of the two conjugates, J2898A-SMCC-DM1 and J2898A-(CH2)3-DM (each with an average of 3.0 to 3.4 maytansinoid molecules per antibody), appear to be similar to that of the unconjugated antibody. Clearance values of the intact conjugates were slightly faster than those of the Ab components. Furthermore, J2898A-SMCC-DM1 clears slightly faster than J2898A-(CH2)3-DM, suggesting that there is a fraction of maytansinoid loss from the SMCC-DM1 ADC, possibly through a thiol-maleimide dependent mechanism. Experiments on ex vivo stability confirm that some loss of maytansinoid from Ab-SMCC-DM1 conjugates can occur via thiol elimination, but at a slower rate than the corresponding rate of loss reported for thiol-maleimide links formed at thiols derived by reduction of endogenous cysteine residues in antibodies, consistent with expected differences in thiol-maleimide stability related to thiol pKa. These findings inform the design strategy for future ADCs.

Global sharing, local innovation: Four schools, four countries, one curriculum.

BACKGROUND: Many internal and external obstacles, must be overcome when establishing a new medical school, or when radically revising an existing medical curriculum. AIMS: Twenty-five years after the Flinders University curriculum was introduced as the first graduate-entry medical programme (GEMP) in Australia, we aim at describing how it has been adopted and adapted by several other schools, in Australia and in Europe (UK, Ireland, and Portugal). METHOD/RESULTS: This paper reports on the experience of four schools establishing a new medical school or new curriculum at different times and in different settings. CONCLUSIONS: We believe that these experiences might be of interest to others contemplating a similar development.

Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing.

Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each of the AaMCs, except the AaMC bearing a d-Ala-d-Ala peptide linker, displayed more bystander killing in vitro than maytansinoid ADCs that utilize disulfide linkers. In mouse models, the anti-CanAg AaMC bearing a d-Ala-l-Ala dipeptide in the linker was shown to be more efficacious against heterogeneous HT-29 xenografts than maytansinoid ADCs that utilize disulfide linkers, while both types of the conjugates displayed similar tolerabilities.

"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

Neuropsychiatric Symptoms after Liver Transplantation in a 65-Year-Old Male Patient.

The development of immunosuppressants has been key for the advancement of solid organ transplant surgery. Specifically, cyclosporine, tacrolimus, or everolimus have significantly increased the survival rate of patients by reducing the risk of a rejection of the transplanted organ and limiting graft-versus-host disease. We report the case of a 65-year-old man who, after undergoing a liver transplantation and receiving an immunosuppressive treatment with cyclosporine and everolimus, presented severe obsessive, psychotic, and behavioral symptoms over the past three years, and describe the pharmacological and non-pharmacological interventions implemented against these symptoms. In this case, the immunosuppressants used have been cyclosporine and, preferably, everolimus. On the other hand, potential adverse reactions to the treatment have been observed, including neuropsychiatric symptoms such as tremor, anxiety, dysthymia, psychosis, and behavioral disorders, which make it necessary to use corrective psychoactive drugs such as benzodiazepines, antidepressants, and antipsychotics, combined with non-pharmacological interventions. A transversal approach, from the medical and psychosocial disciplines, facilitates success in managing neuropsychiatric symptoms after soft organ transplants.

Histomorphometric evaluation of human extraction sockets treated with autologous fibrin, sticky bone or biphasic calcium phosphate.

It is essential to maintain the alveolar bone ridge to ensure the success of implant therapy. Platelet-rich fibrin (PRF) may benefit bone repair, but its quantitative microscopic results are still inconclusive. The aim of this study was to histomorphometrically analyze human dental alveoli after extraction treated with autologous fibrin, biphasic calcium phosphate or sticky bone. The sample consisted of healthy adult volunteer patients, with clinical and tomographic indication for single post-extraction graft of upper premolars for maintenance of the alveolar ridge and subsequent implantation. The 10 remaining patients in the study were divided into three groups according to the type of filling used in the dental socket: autologous PRF plug covered by a PRF membrane (G1), PRF associated with an alloplastic graft based on hydroxyapatite with beta tricalcium phosphate covered by a collagen membrane (G2) or alloplastic graft based on beta tricalcium phosphate covered by collagen membrane (control). After 8 months, bone biopsies were performed at the grafted sites and the patients underwent implant-prosthetic rehabilitation. Paraffin-embedded tissue blocks were routinely processed and sectionsfrom different depths were mounted in 3 slides and stained with HE. The histomorphometric evaluation analyzed 30 photomicrographs per block, quantifying the percentage presence of newly formed bone, connective tissue and remaining biomaterial using the ImageJ software. Parametric data enabled intergroup comparisons using ANOVA and Tukey's post-hoc test for multiple comparison with statistical significance of 5% (p<0.05), with normality of the 3 groups by the Jarque-Bera test (p>0.05). There was a higher mean of newly formed bone in G1 (68.83%) compared to G2 (35.69%) and control (16.28%). There was greater presence of connective tissue in the control (61.56%). Remaining biomaterial was higher in G2 (15.75%), but did not differ statistically from the control. Bone regeneration obtained with PRF alone or sticky bone suggests the efficacy of these therapies, encouraging the clinical use of this blood concentrate in dental procedures.

A manutenção do rebordo ósseo alveolar é prerrogativa para o sucesso da terapia com implantes. A fibrina rica em plaquetas (PRF) poderia beneficiar o reparo ósseo, mas seus resultados microscópicos quantitativos são ainda inconclusivos. O objetivo deste trabalho foi analisar histomorfometricamente alvéolos dentários humanos pós-extração tratados com fibrina autóloga, fosfato de cálcio bifásico ou sua associação. A amostra consistiu de pacientes adultos voluntários saudáveis, com indicação clínica e tomográfica de enxerto unitário pós-exodontia de pré-molares superiores para manutenção de rebordo alveolar e posterior implante. Os 10 pacientes remanescentes no estudo foram divididos em 3 grupos de acordo com o tipo de preenchimento usado no alvéolo dentário: plug de PRF autóloga recoberto por membrana de PRF (G1), PRF associada a enxerto aloplástico de hidroxiapatita com beta fosfato tricálcio recoberto por membrana de colágeno (G2) ou enxerto aloplástico de beta fosfato tricálcio recoberto por membrana de colágeno (controle). Após 8 meses, foram realizadas biópsias ósseas nos locais enxertados e os pacientes seguiram a reabilitação implanto-protético. Blocos histológicos incluídos em parafina foram microtomizados para gerar 3 lâminas de secções em diferentes profundidades, que foram coradas em HE. A avaliação histomorfométrica analisou 30 fotomicrografias por bloco, quantificando a presença percentual de osso neoformado, tecido conjuntivo e biomaterial remanescente pelo programa ImageJ. Os dados paramétricos permitiram comparações intergrupos usando ANOVA e pós-teste de comparações múltiplas de Tukey com significância estatística de 5% (p<0,05), havendo normalidade dos 3 grupos pelo teste Jarque-Bera (p>0,05). Houve maior média de osso neoformado em G1 (68,83%) em comparação a G2 (35,69%) e controle (16,28%). Houve maior presença de tecido conjuntivo no controle (61,56 %). Biomaterial remanescente foi maior em G2 (15,75%), mas não diferiu estatisticamente para o controle. A regeneração óssea obtida com PRF isolada ou em associação sugere a eficácia destas terapias, encorajando o uso clínico deste concentrado sanguíneo em procedimentos odontológicos.

Factors Related to Greater Functional Recovery after Suffering a Stroke.

BACKGROUND: In a stroke, the importance of initial functional status is fundamental for prognosis. The aim of the current study was to investigate functional status, assessed by the Functional Independence Measure (FIM) scale, and possible predictors of functional outcome at discharge from inpatient rehabilitation. METHODS: This is a retrospective study that was carried out at the Physical Medicine and Rehabilitation Service in A Coruña (Spain). A total of 365 consecutive patients with primary diagnosis of stroke were enrolled. The functional assessments of all patients were performed through the FIM. A descriptive and a bivariate analysis of the variables included in the study was made and a succession of linear regression models was used to determine which variables were associated with the total FIM at discharge. RESULTS: Prior to having the stroke, 76.7% were totally independent in activities of daily living. The FIM scale score was 52.5 ± 25.5 points at admission and 83.4 ± 26.3 at hospital discharge. The multivariate analysis showed that FIM scores on admission were the most important predictors of FIM outcomes. CONCLUSIONS: Our study indicates that the degree of independence prior to admission after suffering a stroke is the factor that will determine the functionality of patients at hospital discharge.

Antibody Co-Administration Can Improve Systemic and Local Distribution of Antibody-Drug Conjugates to Increase In Vivo Efficacy.

Several antibody-drug conjugates (ADC) showing strong clinical responses in solid tumors target high expression antigens (HER2, TROP2, Nectin-4, and folate receptor alpha/FRα). Highly expressed tumor antigens often have significant low-level expression in normal tissues, resulting in the potential for target-mediated drug disposition (TMDD) and increased clearance. However, ADCs often do not cross-react with normal tissue in animal models used to test efficacy (typically mice), and the impact of ADC binding to normal tissue antigens on tumor response remains unclear. An antibody that cross-reacts with human and murine FRα was generated and tested in an animal model where the antibody/ADC bind both human tumor FRα and mouse FRα in normal tissue. Previous work has demonstrated that a "carrier" dose of unconjugated antibody can improve the tumor penetration of ADCs with high expression target-antigens. A carrier dose was employed to study the impact on cross-reactive ADC clearance, distribution, and efficacy. Co-administration of unconjugated anti-FRα antibody with the ADC-improved efficacy, even in low expression models where co-administration normally lowers efficacy. By reducing target-antigen-mediated clearance in normal tissue, the co-administered antibody increased systemic exposure, improved tumor tissue penetration, reduced target-antigen-mediated uptake in normal tissue, and increased ADC efficacy. However, payload potency and tumor antigen saturation are also critical to efficacy, as shown with reduced efficacy using too high of a carrier dose. The judicious use of higher antibody doses, either through lower DAR or carrier doses, can improve the therapeutic window by increasing efficacy while lowering target-mediated toxicity in normal tissue.

A Case Study on Polypharmacy and Depression in a 75-Year-Old Woman with Visual Deficits and Charles Bonnet Syndrome.

Depression is one of the most prevalent pathologies in older adults. Its diagnosis and treatment are complex due to different factors that intervene in its development and progression, including intercurrent organic diseases, perceptual deficits, use of drugs, and psycho-social conditions associated with the aging process. We present the case of a 75-year-old woman (who lives in the community) with a diagnosis of major depression with more than 10 years of history, analyzing her evolution and therapeutic approach.

Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumour necrosis factor receptor monoclonal antibody.

Adjuvants, including antibodies to tumour necrosis factor receptor superfamily members, augment immune responses. One member of this family, glucocorticoid-induced tumour necrosis factor receptor (GITR), is expressed at low levels on naive/resting T cells, B cells and macrophages, but at higher levels on T regulatory cells. The aim of this study was to determine the ability of a rat anti-mouse GITR monoclonal antibody, 2F8, to stimulate murine humoral and cellular immunity in a prime boost model with particular attention to posology and antigen-specific effects. 2F8 enhanced the humoral immune response to ovalbumin and haemagglutinin (HA) compared with controls and this enhancement was equal to or greater than that obtained in mice dosed with standard adjuvants. 2F8 F(ab')(2) fragments were as effective as intact antibody in boosting humoral immunity, indicating that FcR-mediated cross-linking of 2F8 is not required for efficacy. Moreover, the enhanced response was durable and antigen specific. Administration of 2F8 shifted the immune response towards a T helper type 1 response with significant enhancement of immunoglobulin G2a- and G2b-specific anti-HA antibodies, as well as enhanced cellular immunity as measured by ELISPOT. 2F8-treated mice also generated significantly more neutralizing antibodies to HA than control mice. Our findings show that anti-GITR is a robust, versatile adjuvant that, unlike commonly used adjuvants that primarily enhance humoral immunity, enhances both humoral and cellular immunity. These results support the continued development of anti-GITR for such indications as haematological and solid tumours, chronic viral infections, and as a vaccine adjuvant.

Dementia and Challenging Behaviors in Gerontological Centers. A Case Report.

Among the main challenges in geriatric and gerontological centers, we consider, central, the individualized attention to those elderly persons with challenging behaviors, to the extent that it is possible to design preventive strategies that delay cognitive deterioration and minimize consequences of behavior disorders. The first step will be to develop the correct interpretation of symptoms and deficits as a guarantee of a correct diagnosis which, in addition to not always being easy, has to be adapted to the progression of the disease. We present the case of a 68-year-old institutionalized individual, with an initial diagnosis of diffuse Lewy bodies dementia, analyzing his cognitive and behavioral evolution, and the pharmacological and non-pharmacological approach to the case.

Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs).

Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody-drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). These ADCs possess linkers that have been incorporated into a central substituted phenyl spacer. Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs.