p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients.

Preoperative chemotherapy administered to breast cancer (BC) patients is a model for studying in vivo the interaction between cytotoxic treatment and clinical and biological parameters. Apoptosis induced by anticancer agents is a mechanism of treatment activity; therefore, overexpression of genes inhibiting the apoptotic pathway could produce drug resistant tumors. In the present study, the two most studied inhibitors of apoptosis, the bcl-2 gene and the mutant p53, have been evaluated to assess whether they may play a role in modulating response of BC to primary chemotherapy. From August 1990 to January 1997, 143 patients bearing T(2-4)N(0-1)M0 primary BC were submitted to two different chemotherapeutic regimens before surgery. The first 64 received the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen (on days 1 and 8 and every 28 days thereafter) associated with tamoxifen (30 mg daily) in case of estrogen receptor (ER)-positive BC, and the remaining 79 were submitted to single agent epirubicin (120 mg/m2 every 21 days). The expression of p53, bcl-2, Ki67, ER, progesterone receptor, c-erbB2, and the multidrug resistance P-glycoprotein (gp-170) was evaluated in BC specimens obtained at diagnosis by incision biopsy and at postchemotherapy surgery. At the end of chemotherapy administration (median, 3 cycles; range, 2-6), the clinical complete response (cCR) rate was superimposable in the patient subgroups with bcl-2-positive or -negative primary tumors; conversely, p53 expression, at a cutoff of 10% positive cells, was significantly associated with a lower cCR rate (9.4 versus 27.0%; P < 0.04). p53 was a significant predictor for poor cCR in the subset submitted to epirubicin (3.6 versus 25.5%; P < 0.02; in patients with p53+ and p53- BC, respectively); by contrast, only a trend toward lower cCR has been observed in patients with p53+ tumors receiving CMF +/- tamoxifen with respect to p53- ones. The distribution of cCR according to the gp-170-positive or -negative tumors was 8 versus 22% in patients submitted to epirubicin and 29 versus 30% in those receiving CMF +/- tamoxifen, respectively. In a multivariate regression analysis, after adjusting for treatment administered (epirubicin versus CMF +/- tamoxifen), menopausal status, tumor and node status, histology grade, ER, progesterone receptor, c-erbB2, Ki67, bcl-2, and gp-170 expression, the p53 status maintained an independent predictive role for cCR. Most of the tumors undergoing change in percentage of p53 expression after both treatments originally harbored mutant protein, and only four BC specimens that were p53 negative before chemotherapy became positive afterward. These data confirm in vivo the concept that the responsiveness of tumors to chemotherapy in part derives from the capability of BC cells to undergo apoptosis. The role of mutated p53 in preventing response is more evident in patients submitted to epirubicin, and this may be caused by the up-regulation of multidrug resistance gene expression by p53 inactivation. p53 is a stable phenotype and is not inducible by at least three or four chemotherapy cycles.     

Taste sensitivity,nutritional status and metabolic syndrome: Implication in weight loss dietary interventions

AIM: We investigated the relationship between taste sensitivity, nutritional status and metabolic syndrome and possible implications on weight loss dietary program. METHODS: Sensitivity for bitter, sweet, salty and sour tastes was assessed by the three-Alternative-Forced-Choice method in 41 overweight(OW), 52 obese(OB) patients and 56 normal-weight matched controls. OW and OB were assessed also for body composition(by impedence), resting energy expenditure(by indirect calorimetry) and presence of metabolic syndrome(MetS) and were prescribed a weight loss diet. Compliance to the weight loss dietary program was defined as adherence to control visits and weight loss ≥ 5% in 3 mo. RESULTS: Sex and age-adjusted multiple regression models revealed a significant association between body mass index(BMI) and both sour taste(P 0.05) and global taste acuity score(GTAS)(P 0.05), with lower sensitivity with increasing BMI. This trend in sensitivity for sour taste was also confirmed by the model refitted on the OW/OB group while the association with GTAS was marginally significant(P = 0.06). MetS+ subjects presented higher thresholds for salty taste when compared to MetS- patients while no significant difference was detected for the other tastes and GTAS. As assessed by multiple regression model, the association between salty taste and MetS appeared to be independent of sex, age and BMI. Patients continuing the program(n = 37) did not show any difference in baseline taste sensitivity when compared to drop-outs(n = 29). Similarly, no significant difference was detected between patients reporting and not reporting a weight loss ≥ 5% of the initial body weight. No significant dif-ference in taste sensitivity was detected even after dividing patients on the basis of nutritional(OW and OB) or metabolic status(MetS+ and MetS-). CONCLUSION: There is no cause-effect relationship between overweight and metabolic derangements. Taste thresholds assessment is not useful in predicting the outcome of a diet-induced weight loss program.     

Psychological Aspects of Treatment with Intragastric Balloon for Management of Obesity: A Systematic Review of the Literature

IntroductionOptimizing maintenance of weight loss for people with obesity following intragastric balloon (IGB) therapy hinges on the degree to which health care providers can recognize both the impact of emotional problems and mood difficulties on their capacity to self-manage, and requirements for additional support. However, there is limited research on the psychological correlates of IGB therapy. This systematic review, for the first time, attempts to identify and synthesize the empirical evidence for the reciprocal influence between psychological variables and IGB outcomes.MethodsA literature search was performed in the PubMed, SCOPUS, MEDLINE, and Google Scholar databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed using rigorous inclusion criteria and screening by at least 2 reviewers. The selected articles were assessed for quality using the Strengthening the Reporting of Observational Studies Epidemiology (STROBE) checklist. Data were extracted to address the review aims and presented as a narrative synthesis. The review protocol was preregistered (Prospero CRD42019121291).ResultsA total of 16,179 titles, 14,369 abstracts, and 51 full-text articles were screened, of which 16 studies were included. Findings suggest that female gender, older age, basic educational level, and single/divorced civil status, together with lower levels of depression, binge eating, higher perceived quality of life, and motivation to change were predictors of enhanced IGB treatment outcomes. Dissatisfaction with treatment was higher in those with impaired obesity-related social-life difficulties. The IGB treatment was effective in reducing weight and improving depression, anxiety, eating disorder symptoms, and the overall life quality of patients with obesity − mainly within 6 months from the device positioning and in conjunction with conventional therapies.Discussion/ConclusionIn line with the available literature on obesity and bariatric surgery interventions, poor mental health appears to be an important barrier for successful weight loss among patients with obesity undergoing IGB treatment. In order to improve the efficacy and effectiveness of the IGB therapy, more comprehensive and standardized studies are needed to provide insight into the psychological mechanisms maintaining weight management issues.     

Intra-rater reliability of an experienced physiotherapist in locating myofascial trigger points in upper trapezius muscle

Objectives:

Myofascial trigger points (MTrPs) are considered the principal clinical feature of myofascial pain syndrome (MPS). An MTrP consists of spot tenderness within a taut band of muscle fibers and its stimulation can produce both local and referred pain. The clinical diagnosis of MPS depends on correct history taking and a physical examination aimed at identifying the presence of MTrP. The purpose of this study was to investigate the intra-rater reliability of a palpation protocol used for locating an MTrP in the upper trapezius muscle.

Methods:

Twenty-four subjects with MTrP in the upper trapezius muscle were examined by an experienced physiotherapist. During each of eight experimental sessions, subjects were examined twice in randomized order using a palpation protocol. An anatomical landmark system was defined and the MTrP location established using X and Y values.

Results:

The intraclass correlation coefficient ICC_(1,1) values were 0.62 (95% CI: 0.30–0.81) for X and 0.81 (95% CI: 0.61–0.91) for Y. The Bland–Altman plots for X and Y showed a mean of difference of 0.04 and −0.2 mm, respectively. Limits of agreement for X ranged from −26.3 to 26.2 mm and for Y from −27 to 26.4 mm.

Discussion:

The ICC_(1,1) for the observed values revealed a moderate to high correlation and the Bland–Altman analysis showed means of difference very close to zero with narrow limits of agreement. An experienced physiotherapist can reliably identify MTrP locations in upper trapezius muscle using a palpation protocol.     

Weight Loss Management and Lifestyle Changes during COVID-19 Lockdown: A Matched Italian Cohort Study

During the COVID-19 lockdown, lifestyle deterioration had a negative impact on weight, and yet no study has focused on patients already undergoing dietary therapy. We performed a cohort study among adults to evaluate the effect of lockdown on weight loss programs, and we investigated changes in eating habits and chronotype. We matched confined cases with non-confined cases among individuals who followed the same diet in 2017–2019. At baseline, all patients underwent a clinical examination and completed questionnaires on lifestyle. At follow-up, patients of the confined group were interviewed by a web call, and questionnaires were re-evaluated. We recruited 61 patients. The confined sample was mainly composed of middle-aged (52 (43,58) years) females (46 (75%)) with overweight (27 (44%)) or obesity (24 (39%)) and a moderate physical activity level (48 (81%)). Body weight at follow-up was significantly higher (1.1 (95% CI: 0.14, 2.1) kg) in the confined group adjusting for all matching variables. Adherence to the Mediterranean diet and eating behavior generally improved. Concerning chronotype, patients differentiated from Neither-types to Evening- and Morning-types. A well-monitored dietary therapy maintains weight loss during lockdown. Improvement in eating habits was observed; however, a shift of the circadian typology occurred.     

Are People with Obesity Attracted to Multidisciplinary Telemedicine Approach for Weight Management?

The forced isolation due to the COVID-19 pandemic interrupted the lifestyle intervention programs for people with obesity. This study aimed to assess: (1) the behaviors of subjects with obesity towards medical care during the pandemic and (2) their interest in following a remotely delivered multidisciplinary program for weight loss. An online self-made survey addressed to subjects with obesity was linked to the official website of our institute. Four hundred and six subjects completed the questionnaire (90% females, 50.2 ± 11.6 years). Forty-six percent of the subjects cancelled any scheduled clinical assessments during the pandemic, 53% of whom had chronic disease. Half of the subjects were prone to following a remotely delivered lifestyle intervention, especially with a well-known health professional. About 45% of the respondents were favorable towards participating in remote psychological support and nutritional intervention, while 60% would practice physical activity with online tools. Male subjects and the elderly were more reluctant than those female and younger, especially for online psychological support. Our survey showed an interest on the part of the subjects with obesity to join a multidisciplinary weight loss intervention remotely delivered. Male subjects and the elderly seem less attracted to this intervention, and this result highlights that, even with telemedicine, the approach to weight management should be tailored.     

Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups,and outcome in acute myeloid leukemia

Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.Subject terms: Acute myeloid leukaemia, Myelopoiesis     

Early reduction of the splicing factor2/alternative splicing factor: a cellular inhibitor of the JC polyomavirus in natalizumab-treated MS patients long before developing progressive multifocal leukoencephalopathy

Natalizumab is effective against relapsing-remitting multiple sclerosis (MS) but increases the risk of progressive multifocal leukoencephalopathy (PML), which is caused by the activation of the JCV polyomavirus. SF2/ASF (splicing factor2/alternative splicing factor) is a potent cellular inhibitor of JCV replication and large T-antigen (T-Ag) expression. We reported that SF2/ASF levels in blood cells increase during the first year of natalizumab therapy and decrease thereafter, inversely related to T-Ag expression, and suggested a correlation with JCV reactivation. Here, we report SF2/ASF levels of longitudinal blood samples of two patients undergoing natalizumab therapy, who developed PML while monitored, in comparison to natalizumab-treated controls and to one-off PML samples. After 6 months of therapy, SF2/ASF levels of the two cases were reduced, instead of increased, and their overall SF2/ASF levels were lower than those from natalizumab controls. Since SF2/ASF inhibits JCV, its early reduction might have a role in subsequent PML. We are aware of the limitations of the study, but the uniqueness of serial blood samples collected before and after PML onset in natalizumab-treated patients must be stressed. If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18–24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy.     

Vaccinia Virus Arrests and Shifts the Cell Cycle

Modulation of the host cell cycle is a common strategy used by viruses to create a pro-replicative environment. To facilitate viral genome replication, vaccinia virus (VACV) has been reported to alter cell cycle regulation and trigger the host cell DNA damage response. However, the cellular factors and viral effectors that mediate these changes remain unknown. Here, we set out to investigate the effect of VACV infection on cell proliferation and host cell cycle progression. Using a subset of VACV mutants, we characterise the stage of infection required for inhibition of cell proliferation and define the viral effectors required to dysregulate the host cell cycle. Consistent with previous studies, we show that VACV inhibits and subsequently shifts the host cell cycle. We demonstrate that these two phenomena are independent of one another, with viral early genes being responsible for cell cycle inhibition, and post-replicative viral gene(s) responsible for the cell cycle shift. Extending previous findings, we show that the viral kinase F10 is required to activate the DNA damage checkpoint and that the viral B1 kinase and/or B12 pseudokinase mediate degradation of checkpoint effectors p53 and p21 during infection. We conclude that VACV modulates host cell proliferation and host cell cycle progression through temporal expression of multiple VACV effector proteins. (209/200.)