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The purpose of this systematic review was to evaluate the impact of saturated fatty acid chain lengths on the development of cardiovascular disease (CVD). The importance of replacement macronutrients is also discussed. PubMed, CINAHL, and Cochrane library were searched for relevant prospective cohort studies that measured SFA chain length via diet analysis through October of 2020. A second updated PubMed search was conducted from October 2020 to 7 August 2022. Five prospective cohort studies were added. All studies used food frequency questionnaires to assess dietary intake. For all five added studies, the main sources of saturated fat were palmitic and steric acid from meat and cheese. Most studies discovered an association with increased risk of CVD and long-chain saturated fatty acid intake, as well as a neutral (potentially beneficial) association with short- and medium-chain saturated fatty acids. Isocaloric substitutions were associated with a higher risk for CVD when saturated fats were replaced with refined carbohydrates and protein from meat, but a reduced or neutral impact when relaced with plant-based protein, unsaturated fat, or complex carbohydrates. When examining the impact of diet on CVD risk, it is critical to consider the macronutrient replacing saturated fat as well as the saturated fat chain length, whole foods, and diet patterns on CVD risk. The studies included in this review suggest that LCSFA (C12–18) may increase the risk for CVD development, while SCFA and MCFA (C4–-C10) may be more beneficial or neutral.

Five patients with acute myelogenous leukemia received hematopoietic stem-cell transplants from a haploidentical donor. They also received T cells from the donor. All five patients had a relapse, and at the time of relapse, genomic HLA typing of leukemic blasts could not detect the recipient's HLA haplotype that differed from the donor's. The loss of the haplotype was due to uniparental disomy. In vitro, the donor's T cells reacted against leukemic blasts obtained at the time of diagnosis, not against blasts obtained at relapse. The results indicate the presence of a mutation that allowed the leukemic cells to escape the immunosurveillance of the donor's T cells. Five patients with acute myelogenous leukemia received hematopoietic stem-cell transplants from a haploidentical donor. They also received T cells from the donor. All five patients had a relapse, and at the time of relapse, genomic HLA typing of leukemic blasts could not detect the recipient's HLA haplotype that differed from the donor's. Transplantation of hematopoietic stem cells from a haploidentical family donor who shares only one HLA haplotype with the recipient is a potentially curative option for patients with high-risk hematologic cancers who lack an HLA-matched donor. 1 – 3 The major limitation of this strategy is the risk of severe graft-versus-host disease (GVHD), which can result from alloreactions mediated by donor T cells against the recipient's unshared HLA haplotype. Since the publication of studies on extensively T-cell–depleted grafts, 1 , 2 a variety of strategies have been developed to prevent or control GVHD after transfer of haploidentical T cells. 4 , 5 The feasibility and efficacy of . . .

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetically determined renal disease. In affected patients, renal function may progressively decline up to end-stage renal disease (ESRD), and approximately 10% of those with ESRD are affected by ADPKD. The somatostatin analog octreotide long-acting release (octreotide-LAR) slows renal function deterioration in patients in early stages of the disease. We evaluated the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD. We did an internally funded, parallel-group, double-blind, placebo-controlled phase III trial to assess octreotide-LAR in adults with ADPKD with glomerular filtration rate (GFR) 15-40 ml/min/1.73 m2. Participants were randomized to receive 2 intramuscular injections of 20 mg octreotide-LAR (n = 51) or 0.9% sodium chloride solution (placebo; n = 49) every 28 days for 3 years. Central randomization was 1:1 using a computerized list stratified by center and presence or absence of diabetes or proteinuria. Co-primary short- and long-term outcomes were 1-year total kidney volume (TKV) (computed tomography scan) growth and 3-year GFR (iohexol plasma clearance) decline. Analyses were by modified intention-to-treat. Patients were recruited from 4 Italian nephrology units between October 11, 2011, and March 20, 2014, and followed up to April 14, 2017. Baseline characteristics were similar between groups. Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Reduction in the median (95% CI) rate of GFR decline (0.56 [-0.63 to 1.75] ml/min/1.73 m2 per year) was not significant (p = 0.295). TKV analyses were adjusted for age, sex, and baseline TKV. Over a median (IQR) 36 (24 to 37) months of follow-up, 9 patients on octreotide-LAR and 21 patients on placebo progressed to a doubling of serum creatinine or ESRD (composite endpoint) (hazard ratio [HR] [95% CI] adjusted for age, sex, baseline serum creatinine, and baseline TKV: 0.307 [0.127 to 0.742], p = 0.009). One composite endpoint was prevented for every 4 treated patients. Among 63 patients with chronic kidney disease (CKD) stage 4, 3 on octreotide-LAR and 8 on placebo progressed to ESRD (adjusted HR [95% CI]: 0.121 [0.017 to 0.866], p = 0.036). Three patients on placebo had a serious renal cyst rupture/infection and 1 patient had a serious urinary tract infection/obstruction, versus 1 patient on octreotide-LAR with a serious renal cyst infection. The main study limitation was the small sample size. In this study we observed that in later-stage ADPKD, octreotide-LAR slowed kidney growth and delayed progression to ESRD, in particular in CKD stage 4. ClinicalTrials.gov NCT01377246; EudraCT: 2011-000138-12.

Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

Pleural malignant mesothelioma (MPM) is a detrimental neoplasm affecting pleural sheets and determining a high rate of mortality. In this study, we have enrolled 14 consecutive patients (13 males and 1 female) with MPM (mean age: 70.3 ± 4.6 years). We have collected serum for the determination of a miRNA profiling using a low-density microarray real time PCR system in the serum of patients and comparing it with that one of 10 control counterparts affected by not-cancer-related pleural effusions. In the patients 5 miRNAs were up-regulated (miR101, miR25, miR26b, miR335 and miR433), 2 miRNA were downregulated (miR191, miR223) and two miRNAs were expressed exclusively in patients (miR29a and miR516). Based upon the changes in the expression of the above mentioned miRNAs we detected two distinctive miRNA signatures predicting histotype and survival in these patients: I) patients with more than 3/9 upregulated miRNAs or 3/9 upregulated miRNAs and miR516 not recordable or unchanged (signature A); II) patients with at least 3/9 downregulated or unchanged miRNAs and/or miR29a downregulated (signature B). Based upon these criteria, 5 patients were stratified in signature A and the remaining 9 in signature B. Patients with signature A had a significant shorter median survival than those with signature B (7 months vs. 17 months, 95% CI: 0.098-1.72, p = 0.0021), had a sarcomatoid or mixed histological MPM subtype and were diagnosed in stage II (3/5) and stage III (2/5). In conclusion, we suggest that miRNA signature A is predictive of sarcomatoid histotype and of worse prognosis in MPM.

Procedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality. In a phase I–II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per μL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00423124. From Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17–66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34–127) from transplantation and 23 days (13–42) from infusion. Ten patients developed acute GVHD (grade I–IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25–73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure. Infusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation. MolMed SpA, Italian Association for Cancer Research.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133 hi /ER lo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133 hi /ER lo /IL6 hi cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133 hi /ER lo /OXPHOS lo . These cells exit metabolic dormancy via an IL6-driven feed-forward ER lo -IL6 hi -Notch hi loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133 hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133 hi /ER lo cells mediating metastatic progression, which is sensitive to dual targeted therapy. ER + breast cancer patients treated with endocrine therapies often acquire resistance and develop metastasis. In this study, the authors demonstrate that endocrine therapies can promote the self-renewal of CD133 hi /ER lo drug resistant cells with metastatic potential driven through the IL6-Notch3 axis activation.

The protein kinase p38α plays a key role in cell homeostasis, and p38α signaling in intestinal epithelial cells protects against colitis‐induced tumorigenesis. However, little is known on the contribution of p38α signaling in intestinal stromal cells. Here, we show that myeloid cell‐specific downregulation of p38α protects mice against inflammation‐associated colon tumorigenesis. The reduced tumorigenesis correlates with impaired detection in the colon of crucial chemokines for immune cell recruitment. We identify insulin‐like growth factor‐1 (IGF‐1) as a novel mediator of the p38α pathway in macrophages. Moreover, using genetic and pharmacological approaches, we confirm the implication of IGF‐1 produced by myeloid cells in colon inflammation and tumorigenesis. We also show a correlation between IGF‐1 pathway activation and the infiltration of myeloid cells with active p38α in colon samples from patients with ulcerative colitis or colon cancer. Altogether, our results uncover an important role for myeloid IGF‐1 downstream of p38α in colitis‐associated tumorigenesis and suggest the interest in evaluating IGF‐1 therapies for inflammation‐associated intestinal diseases, taking into consideration IGF‐1 signaling and immune cell infiltration in patient biopsies. Synopsis The molecular & cellular events involved in the pathogenesis of colitis‐associated tumorigenesis are not fully understood. Targeted inhibition of the p38α pathway in myeloid cells could be therapeutically useful in colon diseases associated with inflammatory cell infiltration. Myeloid cells rely on p38α to promote intestinal inflammation and inflammation‐ associated colon tumorigenesis. IGF‐1 functions as an effector of p38α in myeloid cells, which are an important source of IGF‐1 in the colon. Genetic or pharmacological inhibition of IGF‐1 suppresses inflammatory cell recruitment and reduces colitis‐associated colon tumor burden. Samples from ulcerative colitis and colon cancer patients showed a positive correlation between recruitment of myeloid cells with active p38α and activation of the IGF‐1 pathway. Graphical Abstract The molecular & cellular events involved in the pathogenesis of colitis‐associated tumorigenesis are not fully understood. Targeted inhibition of the p38α pathway in myeloid cells could be therapeutically useful in colon diseases associated with inflammatory cell infiltration.

Obesity is associated with multiple comorbidities that contribute to increased mortality among affected individuals. There are multiple treatments for this condition, including nutritional interventions, pharmacological therapies, and surgical procedures. Within these, bariatric surgery is an effective treatment option that requires a multidisciplinary approach, both before and after surgery. Nutritional management prior to surgery aims to achieve metabolic control and reduce comorbidities associated with the procedure. Postoperative nutritional management focuses on preventing complications, ensuring adequate nourishment, and providing necessary supplementation for optimal recovery and long-term success. This narrative review examines all these critical aspects of nutritional management in bariatric surgery, including preoperative nutrition, postoperative nutrition and physical activity recommendation, different nutritional aspects according to the type of bariatric surgery, and future directions for investigation.

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy. VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion. Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.