A novel Leishmania infantum recombinant antigen which elicits interleukin 10 production by peripheral blood mononuclear cells of patients with visceral leishmaniasis

We report here the characterization of a novel Leishmania infantum protein termed papLe22 (22-kDa potentially aggravating protein of Leishmania). A positive clone from a cDNA library was identified by serum of a visceral leishmaniasis (VL) patient. Full-length cDNA obtained using rapid amplification of cDNA ends-PCR codes for a 22-kDa protein. In L. infantum promastigotes an endogenous nuclear protein of 14-kDa electrophoretic mobility was found by using an antiserum prepared against the fusion protein glutathione S-transferase-papLe22. Its expression was also shown in L. infantum amastigotes and in Leishmania major and Leishmania guyanensis promastigotes. VL patients' sera showed anti-papLe22 immunoglobulin M (IgM) and IgG reactivities, indicating that a primary response against the leishmanial protein papLe22 accompanied acute VL manifestations. Specific IgG levels were correlated with patients' clinical status. The presence of IgG1, IgG2, and IgG3 subclasses suggested a mixed Th1- and Th2-type response; there was no correlation between subclass reactivity and the disease course. The recombinant papLe22 specifically activated interleukin-10 production by VL patients' peripheral blood mononuclear cells collected at diagnosis and after treatment-induced cure, indicating its contribution to VL pathogenesis and concomitant immunosuppression and its potential role in the reactivation of latent parasites. As a dominant immunogen, papLe22 might be used as a vaccine component, provided that the vaccination protocol directs the response toward the Th1 pattern.     

Suicidal Ideation in Bipolar Disorder: The Relation with Clinical and Sociodemographic Variables

Psychiatric Quarterly - Bipolar disorder (BD) has the highest risk of suicide among all mental disorders. Thus, identifying factors related to suicidal ideation is essential for a better assessment...     

Impact of serum C-reactive protein measurements in the first 2 days on the 30-day mortality in hospitalized patients with severe community-acquired pneumonia: A cohort study

Introduction

The purpose of the study is to evaluate the impact of daily consecutive measurements of C-reactive protein (CRP) in the initial 2 days of hospitalization on the 30-day all-cause mortality in patients with severe community-acquired pneumonia (CAP).

Methods

We used 4 different thresholds of fractional decrease (FD) in CRP at the second day of admission (CRP2) of 25%, 30%, 40%, and 60%. In addition, we studied the association of each of these thresholds with the 30-day all-cause mortality.

Results

The mean age was 64 ± 20; males, 59%. The 30-day mortality rate was 18% (20/111). The mean serum CRP levels at the first day of all study group and CRP2 were 203 ± 98 vs 146 ± 92 mg/L, respectively, P = .05. The mean FD in CRP2 levels among the survivors was 33 %, whereas among the nonsurvivors, was 7%, P < .001. Multiple regression analysis revealed that FD less than 25% in CRP2 was associated with 30-day all-cause mortality, odds ratio of 3.07 (95% confidence interval, 2.84-5.03), P = .002, compared with those with FD more than 25% in CRP2.

Conclusions

Fractional decrease less than 25% in CRP levels at the second day was significantly associated with 30-day all-cause mortality in hospitalized patients with severe CAP.     

Performance of Bipolar Disorder Patients in Attention Testing: Comparison with Normal Controls and Among Manic,Depressive, and Euthymic Phases

Several studies on cognition in bipolar disorder (BD) have been developed on the last decade. Neuropsychological evaluation of attention in BD patients is fundamental since alterations in attention affect other cognitive functions. Evaluate if performance of BD patients in attention tests varies according to each phase of the disease and verify if there are differences in attention when comparing BD patients with normal controls. The study included 101 BD patients, with ages between 18 and 65 years, being 52 euthymic, 22 manic and 27 depressive, besides 30 normal controls. All subjects were evaluated though Hamilton Depression Scale, Young Mania Rating Scale and Global Assessment of Functioning, bipolar version (CGI-BP). Attention was evaluated through a neuropsychological battery. Normal controls had a better performance in selective attention tests than BD patients. No differences were found among manic, depressive and euthymic phases. Attention is markedly impaired in BD. Nevertheless, the results of this study do not imply that the severity of the attention deficit in BD patients varies according to decease phase.     

HAMLET (human α‐lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death

HAMLET, a complex of partially unfolded α‐lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double‐membrane‐enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3‐I) to granular (LC3‐II) staining in LC3‐GFP‐transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3‐methyladenine. HAMLET also caused accumulation of LC3‐II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin‐1 and Atg5. Suppression of Beclin‐1 and Atg5 improved the survival of HAMLET‐treated tumor cells and inhibited the increase in granular LC3‐GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET‐induced tumor cell death. © 2008 Wiley‐Liss, Inc.     

COVID-19 vaccination and cancer immunotherapy: should they stick together?

The combination of COVID-19 vaccination with immunotherapy by checkpoint inhibitors in cancer patients could intensify immunological stimulation with potential reciprocal benefits. Here, we examine more closely the possible adverse events that can arise in each treatment modality. Our conclusion is that caution should be exercised when combining both treatments.Subject terms: Cancer, Viral infection

The persisting spreading of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) has prompted the development of vaccine candidates at an accelerated rate with remarkable efficacy. To date, the most advanced vaccines are those that transfer nucleotide coding for the S protein as DNA (inactivated adenovirus-DNA delivered) such as the Astrazeneca vaccine or as lipid nanoparticle-encapsulated RNA forms such as those produced by Pfizer BioNTech and Moderna. The Johnson and Johnson (Janssen) and the Sputnik V vaccines as well as vaccines other than nucleic acid vectors are also joining the market in different regions. Given the disproportionate impact of COVID-19 in cancer patients, these vulnerable subjects should be included in the populations prioritised for early vaccination along with the transplanted patient, rheumatic disease patients and other immunosuppressed subjects [1].There is a scarcity of data on the consequences of COVID-19 vaccination in cancer patients under specific treatments, as recently stressed by Korompoki et al. [2], especially those in phase III vaccine trials [3]. One recent short article by Waissengrin et al. [4] reports on the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine administered in cancer patients under checkpoint inhibitors (CPIs). Based on a relatively limited number of cases, the authors note that when compared to matched controls, CPI therapy results in a constant and variable increase of all COVID-19 vaccination side effects, which is cause for alarm. The authors nevertheless consider their data as supporting the short-term safety of the mRNA COVID-19 vaccine in patients under CPIs. A larger set of patients would certainly be necessary to confirm their findings and deliver a clear message on this point. On the other hand, the report by Waissengrin et al. also mentions the apparent short-term absence of immunologically related adverse events (IRAEs) in a subgroup of 134 patients treated by CPIs who received the BNT162b2 mRNA COVID-19 vaccine [4]. However, the authors recognise the possibility that rare IRAEs [4] could be identified in larger cohorts of patients under COVID-19 vaccination.This possibility was clinically confirmed in the recent case report by Au et al. describing a close temporal association between BNT162b2 vaccination and the onset of a harmful cytokine release syndrome (CRS) in a patient with colorectal cancer on long-standing anti-programmed death-ligand 1 (PD-1) monotherapy [5]. The authors suggest that this CRS could be due to the vaccine and could occur on the background of immune activation secondary to the PD-1 blockade with an increase in T cell proliferation and effector function.The reports by Waissengrin et al. [4] and Au et al. [5] illustrate the view that interaction between immunotherapy and COVID-19 vaccination should be considered from both sides, i.e. how vaccination could influence immunotherapy and, conversely, how immunotherapy could impact COVID-19 vaccination (Fig. 1). Both treatments cause their own stimulation of the immunological system, and more particularly, at the T cell and dendritic cell levels, their coexistence could therefore lead to final effects that potentiate their respective activity. In this respect, it has recently been reported that influenza vaccination improves the survival of patients under CPIs without having any detrimental effects in terms of safety [6, 7]. But overall, COVID-19 vaccination generates more severe side effects than influenza vaccines; consequently, its impact on CPI-related side effects cannot be overlooked.Open in a separate windowFig. 1The reciprocal interaction between COVID-19 vaccination and cancer treatment by checkpoint inhibitors.ICI: Immune Checkpoint Inhibitors.CPIs induce IRAEs at a rate of 20–50% for any grade, and the risk for developing these toxicities is higher in elderly patients [8, 9]. Of note, one of these IRAEs is colitis, which can impact microbiota integrity with potential immune consequences. This could result from the complex interrelationship between the overall immune status and microbiota, which has been well elucidated [10]. Interestingly, the influence of microbiota on the immune response to vaccination has also been reported [11]. Therefore, more attention should be paid to a potential loss of COVID-19 vaccination efficacy in patients under CPI due to a possible occurrence of IRAEs and more particularly a case of colitis.In the context of rare unexpected findings under CPIs, one should consider in addition the rare but nevertheless concerning phenomenon of tumour hyper-progression (THP) [12]. This form of tumour flare, although infrequent, can cause a potentially fatal locoregional progression of the disease. The pathophysiology of THP is not clearly established but includes an expansion of activated T lymphocytes in the tumour itself and its microenvironment [13]. This excessive tumour infiltration by lymphocytes could be amplified by an increased bulk of activated lymphocytes resulting from the boosting effect of the vaccination itself (Fig. 1). We have recently shown that it may be possible to identify patients under CPIs at risk for this THP by discriminating germinal genetic profiles [14]. This could serve as a tool for screening CPI-treated patients scheduled to receive COVID-19 vaccination.The articles by Waissengrin et al. [4] and Au et al. [5] express more or less strong messages of caution and point to the need to gain a deeper knowledge of the reciprocal interaction between COVID-19 vaccination and CPI cancer treatment by investigating large cohorts of patients. To this end, along with the classical parameters of patient follow-up, more specific immunology-based investigations should be conducted to examine all the aspects of the long-term immune response. This is the main objective of the recently launched VOICE trial [15]. This prospective, multicentric trial aims to closely examine on a long-term basis whether immunotherapy and chemotherapy, alone or combined, influence COVID-19 vaccination in treated patients. Study parameters include the antibody response, the SARS-CoV-2-specific T cell response and the functional and phenotypical characterisation of the cellular immune response. This type of long-term follow-up is particularly necessary when considering current developments in CPI treatment and the increasing role played by their adjuvant setting. The immunotherapeutic management of malignant melanoma [16] and lung cancer [17] are clear illustrations of these current developments in CPI treatment. The association of chemotherapy and targeted therapies with CPI treatment in most therapeutic situations also generates potential difficulties in data interpretation, further increasing the need for multi-cohort studies. The ESMO recently emphasised the importance of monitoring COVID-19 vaccine effects in cancer patients through specific studies and registries [18]. In France, the ANRS S0001S COV-POPART cohort study was recently launched ({"type":"clinical-trial","attrs":{"text":"NCT04824651","term_id":"NCT04824651"}}NCT04824651). It monitors 8650 vaccinated subjects with various pathologies including cancer to evaluate their relative capacity to produce antibodies against SARS-CoV- 2 (the study includes a control group of 1850 subjects without the targeted pathologies). Concerning cancer treatment and more particularly early clinical trials, an international group of experts recently recommended that trials on anti-cancer drugs with unknown safety profiles should be avoided until 2 to 4 weeks after the second dose of the COVID-19 vaccine [19]. More generally, the reciprocal interaction between COVID-19 vaccination and cancer treatments should be examined in greater depth.In spite of a complex and still evolving SARS-COV2, COVID-19 vaccination is increasingly combined with CPI treatments in cancer patients and is likely to impact every treatment. At first sight, this combination should boost the immunological stimulation with potential reciprocal benefits. However, the clinical picture described in this article tempers this judgement. Its aim is to deliver a message of caution and raise the awareness of caregivers and prescribers to the particular attention that should be paid to patients at risk.