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Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGcHD rate after Haplo/PTCY was also lower (hazard ratio [HR] = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) within, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

Flooding in many areas is becoming more prevalent due to factors such as urbanization and climate change, requiring modernization of stormwater infrastructure. Retrofitting standard passive systems with controllable valves/pumps is promising, but requires real-time control (RTC). One method of automating RTC is reinforcement learning (RL), a general technique for sequential optimization and control in uncertain environments. The notion is that an RL algorithm can use inputs of real-time flood data and rainfall forecasts to learn a policy for controlling the stormwater infrastructure to minimize measures of flooding. In real-world conditions, rainfall forecasts and other state information are subject to noise and uncertainty. To account for these characteristics of the problem data, we implemented Deep Deterministic Policy Gradient (DDPG), an RL algorithm that is distinguished by its capability to handle noise in the input data. DDPG implementations were trained and tested against a passive flood control policy. Three primary cases were studied: (i) perfect data, (ii) imperfect rainfall forecasts, and (iii) imperfect water level and forecast data. Rainfall episodes (100) that caused flooding in the passive system were selected from 10 years of observations in Norfolk, Virginia, USA, 85 randomly selected episodes were used for training and the remaining 15 unseen episodes served as test cases. Compared to the passive system, all RL implementations reduced flooding volume by 70.5% on average, and performed within a range of 5%. This suggests that DDPG is robust to noisy input data, which is essential knowledge to advance the real-world applicability of RL for stormwater RTC.

Co-contraction of agonist-antagonist muscles is commonly observed when performing difficult motor tasks. The benefit of co-contraction is thought to be zero-delay corrections to unexpected disturbances from increased intrinsic muscle impedance. We used upper-limb postural and tracking tasks to characterize the effects of co-contraction on motor corrections to loads applied to the limb. We systematically controlled pre-perturbation muscle activity and showed that co-contraction improves subsequent corrective responses in both tasks. However, substantial improvements in the corrective response are only observed at the time when neural feedback pathways can also contribute. We demonstrate that muscle impedance appears to play a minor role in improving performance. Instead, co-contraction engages a dual agonist-antagonist control strategy to counter disturbances, that is distinct from the control strategy used when not co-contracting or selectively pre-activating a single muscle group. Critically, we showed that this dual agonist-antagonist control strategy improved performance even at low levels of co-contraction.

Increasing evidence suggests that oxidative stress plays a major role in the pathogenesis of sperm DNA damage. Oxidative stress was also recently found to modulate the epigenetic make up of sperm. Along these lines, a growing body of evidence in both experimental and clinical studies has implicated several regimens of antioxidants, by oral administration or in vitro supplementation to sperm-preparation media, in improving various sperm parameters namely DNA damage. While these studies exhibited heterogeneity in treatment regimens, and variability in methodology, there remains a lack of quality evidence on the association between micronutrients and sperm DNA integrity. Another ancillary effect of antioxidants administration on sperm is the shaping of the epigenome. It is beginning to surface that micronutrients function as potent modulators of the sperm epigenome-regulated gene expression through regulation of mainly DNA methylation in humans and experimental models. However, the few promising experimental studies on mice supported the notion that epigenetic marks in spermatogenesis are dynamic and can be modulated by nutritional exposure. More so, the sperm epigenome was proposed to transfer a so-called epigenomic map to the offspring which can influence their development. Here, we review and summarize the current evidence in human and animal models research regarding the link between genome and epigenome × micronutrients environment interactions on the sperm nuclear damage. Unfortunately, our conclusion is not very conclusive, rather, it opens an avenue to investigate the fortifying effect of antioxidants on sperm cells. Hopefully, further genome and epigenome-wide studies focusing on the prenatal environment, will serve as a promising route for embodying the possibility of “normalization” and restoration of some offspring health cues. Keywords: Sperm, Antioxidants, Micronutrients, Reactive oxygen species, Genome, Epigenome

Two different pathways for the synthesis of annulated pyrido[3,4-b]indoles are reported using metal-catalyzed cyclotrimerization reactions. A stepwise process using Rh(I)-catalysis in the final step of the synthesis and a multicomponent, tandem catalytic approach using Pd(0)-catalysis both lead to complex nitrogen-containing heterocycles in good yields. Substituent effects are investigated for both pathways, demonstrating that the Pd(0)-catalyzed approach is more sensitive to electron-withdrawing groups.

Perovskite solar cells (PSCs) have now achieved efficiencies in excess of 22%, but very little is known about their long-term stability under thermal stress. So far, stability reports have hinted at the importance of substituting the organic components, but little attention has been given to the metal contact. We investigated the stability of state-of-the-art PSCs with efficiencies exceeding 20%. Remarkably, we found that exposing PSCs to a temperature of 70 degrees C is enough to induce gold migration through the hole-transporting layer (HTL), Spiro-MeOTAD, and into the perovskite material, which in turn severely affects the device performance metrics under working conditions. Importantly, we found that the main cause of irreversible degradation is not due to decomposition of the organic and hybrid perovskite layers. By introducing a Cr metal interlayer between the HTL and gold electrode, high-temperature-induced irreversible long-term losses are avoided. This key finding is essential in the quest for achieving high efficiency, long-term stable PSCs which, in order to be commercially viable, need to withstand hard thermal stress tests.

Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic stem cell transplantation. We hypothesized that FO is associated with transplantation outcomes and evaluated this complication in 2 cohorts of patients. FO was graded based on post-transplantation weight gain, symptoms, and need for treatment, scored in real time by an independent team. The first cohort (study cohort; n = 145) underwent haploidentical transplantation for hematologic malignancies following a melphalan-based conditioning regimen. In univariate analysis, factors associated with day +100 nonrelapse mortality (NRM) were FO grade ≥2 (hazard ratio [HR], 15; 95% confidence interval [CI], 4.2 to 55; P .001), creatinine1 mg/dL (HR, 4.7; 95% CI, 1.6 to 14; P = .005), and age55 years (HR, 4.5; 95% CI, 1.5 to 13; P = .008). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 13.1; 95% CI, 3.4 to 50; P .001) and serum creatinine level1 mg/dL at transplantation admission (HR, 3.5; 95% CI, 1.1 to 11; P = .03). These findings were verified in a separate cohort (validation cohort) of patients with acute myelogenous leukemia/myelodysplastic syndrome who underwent HLA-matched transplantation with busulfan-based conditioning (n = 449). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 34; 95% CI, 7.2 to 158; P .001) and, in patients with FO grade2, advanced disease status (HR, 5; 95% CI, 1.1 to 22; P = .03). A higher NRM translated to significantly poorer 1-year overall survival rates for patients with FO ≥2 than for patients without FO (70% versus 42%, P .001 in the study cohort and 64% versus 38%, P .001 in the validation cohort). In conclusion, FO grade ≥2 is strongly associated with higher NRM and shorter survival and should be considered an important prognostic factor in transplantation.

To the editor: Allogeneic hematopoietic stem cell transplantation (ASCT) is an effective consolidative strategy to decrease relapse for patients with acute myeloid leukemia (AML) and can cure ∼30% to 50% of patients with AML.[1][1],[2][2] It has been recognized that survival can vary widely after

Hematopoietic stem cell transplantation (HSCT) is the cornerstone therapy for many hematological disorders. Advances in HSCT with better supportive care and earlier referral for HSCT have led to an increase in the number of patients undergoing HSCT. However, the post-HSCT period is often accompanied by infections and complications involving the liver, the lungs and the hematopoietic system.

Autologous hematopoietic stem cell transplantation in light chain amyloidosis (AL) with renal involvement

There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.

Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin–containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT.

We analysed 21 years of surface O3 data at the Mt. Cimone station (2165 m, Italy). High O3 values were observed during summer in the Mediterranean region. O3 increased over 1991-2011, no trends were detected for the 1996-2011. Negative trend (-0.13 nmol/mol/year) for the period 1996 - 2013. Summer O3 growth-rates showed a slowing-down in recent years. A few reliable long-term O3 time series in the Mediterranean basin

A total of 36 consecutive patients with AML in CR underwent reduced-intensity allogeneic hematopoietic SCT (RISCT) with fludarabine and melphalan conditioning. All patients were ineligible for myeloablative transplantation because of age or comorbidity. In total, 30 patients were in first CR and six patients were in second CR. Donors were siblings in 21 (58%) patients and were unrelated in 15 (42%) patients. Hematopoietic cell transplant specific comorbidity scores ⩾3 were present in 26 (72%) patients. With a median follow-up of 52 months (range, 34–103 months), OS and PFS rates at 4 years were 71% (s.e., 8%) and 68% (s.e., 8%), respectively. At 4 years, the cumulative incidence of non-relapse mortality was 20% (s.e., 7%) and of relapse mortality was 8% (s.e., 5%). Neither OS nor PFS was affected by older age (>60 years), unrelated donor, melphalan dose, or comorbidity score. At last follow up, of the 24 surviving patients, 21 (88%) had performance status (ECOG) of 0 without any active chronic GVHD requiring steroids. Hence, RISCT with fludarabine and melphalan conditioning produces durable long-term remission in older patients with AML.

Patients with steroid-resistant acute graft versus host disease (aGVHD) have a dismal prognosis, with mortality rates in excess of 90%. We sought to identify a subgroup of patients less likely to benefit from initial therapy with corticosteroids as well as the impact of response on day 14 on outcome. Retrospective evaluation was performed of patients with biopsy-proven aGVHD treated with corticosteroids after allogeneic HSCT at M.D. Anderson Cancer Center from 1998 through 2002 (). Overall response to first-line therapy on day 14 was 56%. Grade III-IV aGVHD and hyperacute GVHD were the most significant factors predicting failure. Patients who fail to respond to steroids by day 14 should be considered for clinical trials. Severity of aGVHD, hyperacute GVHD, and sex mismatch could be integrated into prognostic scoring systems which may allow for pretreatment identification of patients unlikely to benefit from standard therapy with corticosteroids.

The long-term outcome of graft failure after allogeneic stem cell transplantation (SCT) has not been well described. To fill this knowledge gap we performed a retrospective analysis of patients with graft failure over a 10-year time period in a single institution. Cases were included for analysis if they had failed to achieve an absolute neutrophil count (ANC) of 500/μL or more by 28 days post-SCT or 42 days after cord blood transplantation (primary graft failure); had a decrease in their ANC to

Nonmyeloablative stem cell transplantation in patients with follicular lymphoma has been designed to exploit the graft-versus-lymphoma immunity. The long-term effectiveness and toxicity of this strategy, however, is unknown. In this prospective study, we analyzed our 8-year experience. Patients received a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and rituximab (375 mg/m2 for 1 day plus 1000 mg/m2 for 3 days). They were then given an infusion of human leukocyte antigen-matched hematopoietic cells from related (n = 45) or unrelated donors (n = 2). Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively. All 18 patients who were tested and had evidence of JH/bcl-2 fusion transcripts in the bone marrow at study entry experienced continuous molecular remission. The incidence of grade 2-IV acute GVHD was 11%. Only 5 patients were still undergoing immunosuppressive therapy at the time of last follow-up. We believe that the described results are a step forward toward developing a curative strategy for recurrent follicular lymphoma.

For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (

Most candidates for hematopoietic stem cell transplantation (HSCT) lack a human leukocyte antigen (HLA)-identical sibling donor. Some patients may have a related donor with whom they are mismatched at 1 antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We evaluated the outcomes (survival, relapse, nonrelapse mortality [NRM]) of all 28 patients with a single HLA antigen/allele mismatch identified through high-resolution HLA typing at HLA-A, -B, -C, -DRB1, and -DQB1, and all 318 patients with myeloid malignancies who received transplants from a 10/10 MUD treated during the same period of time at a single institution. Overall, outcomes for patients treated from a 1-antigen/allele mismatch related donor were significantly worse than from a MUD, primarily because of increased NRM. Overall survival (OS) rates at 3 years for 1-antigen/allele mismatched related donor and MUD transplant recipients were 19% and 45% (P = .007), and NRM rates were 40% and 26% (P = .05), respectively. Patients with class I mismatches appeared to have poorer OS than did patients with class II mismatches. A higher incidence of graft rejection was identified in the mismatched related donor group (P = .02). These results indicate that transplant outcomes are better with a MUD than with a 1 antigen/allele-mismatched related donor.

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (CY) after ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections when compared to historical prophylaxis with a calcineurin-inhibitor (CNI) and methotrexate (MTX). We conducted a phase II trial of post-transplantation CY (post-CY) after reduced-intensity conditioning (RIC) using intravenous busulfan (area under the curve of 4000 micromolar minute), fludarabine (40 mg/m2) for 4 days, and CY 50 mg/kg on days +3 and +4 after BM or peripheral blood (PB) transplantations from matched related (MRD) or unrelated donors (MUD). MUD recipients received antithymocyte globulin (ATG); however, a later amendment removed ATG. Forty-nine patients were treated (acute myeloid leukemia/myelodysplastic syndrome, 82%). Median age was 62 years (range, 39 to 72). Fifteen patients received an MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II to IV acute GVHD, III to IV acute GVHD, and chronic GVHD was 58%, 22%, and 18%, respectively. A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P = .02) and treatment-related mortality (HR, 3.3; P = .035) and worse overall survival (HR, 1.9; P = .04) with post-CY. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-CY should not be used as sole GVHD prophylaxis after a RIC transplantation from HLA-matched donors.

Leukemic transformation (LT) from myelofibrosis has a very poor prognosis with the current treatment strategies. We hypothesized that allogeneic stem cell transplantation (ASCT) can improve outcomes for patients with LT, and reviewed 55 consecutive patients that were treated for myelofibrosis with ASCT at our institution. Fourteen patients (25%) were identified to have LT. Thirteen of these patients received induction chemotherapy and 6 achieved remission at the time of transplant. Conditioning regimen was melphalan (Mel)-based in 9 patients. All patients engrafted and achieved remission after transplant, whereas 4 subsequently relapsed. After a median follow-up of 31 months, 6 patients (49%) survived long term. Although limited by a small number of patients, this study suggests that patients with myelofibrosis and LT may achieve long-term remission after induction chemotherapy and ASCT.

The optimal pretransplant regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients ≥ 55 years of age remains to be determined. The myeloablative reduced-toxicity 4-day regimen i.v. busulfan (Bu) (130 mg/m(2)) and i.v. fludarabine (Flu) (40 mg/m(2)) is associated with low morbidity and mortality. We analyzed 79 patients ≥ 55 years of age (median, 58 years) with AML (n = 63) or MDS (n = 16) treated with i.v. Bu-Flu conditioning regimens between 2001 and 2009 (median follow-up, 24 months). The patients who received this regimen had a good performance status. The 2-year overall survival (OS) rates for patients in first complete remission (CR1), second CR (CR2), or refractory disease and for all patients at time of transplantation were 71%, 44%, 32%, and 46%, respectively; 2-year event-free survival (EFS) rates for patients in CR1, CR2, or refractory disease at time of transplantation and for all patients were 68%, 42%, 30%, and 44%, respectively. One-year transplant-related mortality (TRM) rates for patients who were in CR or who had active disease at the time of transplantation were 19% and 20%, respectively. Grade II-IV acute graft-versus-host (aGVHD) disease was diagnosed in 40% of the patients. Our results suggest that age alone should not be the primary reason for exclusion from receiving myeloablative reduced-toxicity conditioning with i.v. Bu-Flu preceding transplantation in patients with AML/MDS.

Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation For Relapsed/Refractory Hodgkin Lymphoma In The Brentuximab Vedotin Era Paolo Anderlini , Rima Saliba , Celina Ledesma , Christina M. Chancoco , Tamera R. Alexander , Amin M. Alousi , Chitra Hosing , Issa F. Khouri , Yago Nieto , Uday R. Popat , Elizabeth J. Shpall , Michelle A. Fanale , Yasuhiro Oki , Jorge E. Romaguera , Sattva S. Neelapu , Anas Younes , Richard E. Champlin . Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Stem Cell Transplantation and Cellular Therapy, University of Texas, MD Anderson Cancer Center, Houston, TX; Department of Stem Cell Transplantation & Cellular Therapy, University of Texas, MD Anderson Cancer Center, Houston, TX; Stem Cell Transplantation & Cellular Therapy, UT M.D. Anderson Cancer Center, Houston, TX; Department of Lymphoma/Myeloma, University of Texas, MD Anderson Cancer Center, Houston, TX; Lymphoma, Memorial Sloan-Kettering Cancer Center, New York, NY; Stem Cell Transplantation & Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX