Multi-omic approach to decipher the impact of skincare products with pre/postbiotics on skin microbiome and metabolome.

Introduction: Although pre/pro/postbiotics have become more prevalent in dermatologic and cosmetic fields, the mode of action when topically applied is largely unknown. A multi-omic approach was applied to decipher the impact of the skincare products with pre/postbiotics on skin microbiome and metabolome. Methods: Subjects with dry skin applied a body wash and body lotion with or without pre/postbiotics for 6 weeks. Skin hydration was measured at baseline, 3 and 6 weeks. Skin swabs were collected for 16S rRNA gene sequencing, metagenomics and metabolomics analysis. Results: Skin hydration significantly increased in both groups. The prebiotic group significantly reduced opportunistic pathogens, e.g., Pseudomonas stutzeri and Sphingomonas anadarae, and increased the commensals, e.g., Staphylococcus equorum, Streptococcus mitis, Halomonas desiderata. Bacterial sugar degradation pathways were enriched in the prebiotic group, while fatty acid biosynthesis pathways were reduced in control. The changes on skin metabolome profiles by the products were more prominent. The prebiotic group performed greater modulation on many clinically-relevant metabolites compared to control. Correlation analysis showed H. desiderata and S. mitis positively correlated with skin hydration, P. stutzeri and S. anadarae negatively correlated with the metabolites that are positively associated with skin hydration improvement. Conclusion: This holistic study supported a hypothesis that the pre/postbiotics increased skin hydration through the modulation of skin microbiome, metabolic pathways and metabolome.

Demystifying the mechanism of action of professional facial peeling: In-vivo visualization and quantification of changes in inflammation, melanin and collagen using Vivascope® and ConfoScan®.

Professional peeling using chemicals (chemical peeling) is a popular non-surgical procedure commonly used for the treatment for photoaging, pigmentary disorders, scarring, fine lines, and wrinkles. The objective of our case study was to elucidate the mechanism of action of professional peels/peeling. For proof-of-concept, we used a commercial blended peel containing trichloroacetic acid and lactic acid. The facial peeling was performed by a physician on four subjects. These subjects were followed over time in the clinic to take clinical pictures and monitor surface and anatomical changes in inflammation, melanin, and collagen at regular intervals post-peel (5 min, 48 h, and day 9). Dermoscope and Vivascope® were used to image surface and subsurface anatomical changes, respectively, and ConfoScan® was used to quantify aforementioned anatomical changes. Based on Vivascope and ConfoScan analysis, we could see clear visual clinical evidence of controlled injury-healing mechanism of peel's action: immediate but transient onset of inflammation within 5 min (indicate injury response by skin), followed by melanin redistribution evident at 48 h (indicate activation of skin's defense system), and remodeled fibrous collagen network without any inflammatory cells on day 9 (healing response). To our knowledge, this is the first ever clinical study to deconvolute the mysterious mechanism of action of peels, in-vivo.

Dissolved rubidium to strontium ratio as a conservative tracer for wastewater effluent-sourced contaminant inputs near a major urban wastewater treatment plant.

Municipal wastewater (MWW) effluent discharges can introduce contaminants to receiving waters which may have adverse impacts on local ecosystems and human health. Conservative chemical constituents specific to the MWW effluent stream can be used to quantify and trace wastewater effluent-sourced contaminant inputs. Gadolinium (Gd), a rare earth element used as a contrasting agent in medical magnetic resonance imaging, can be found in urban MWW streams. Dissolved anthropogenic Gd has been shown to be an indicator and potential conservative tracer for MWW effluent in receiving waters. Like other known MWW tracers, it can be difficult and expensive to measure. Dissolved rubidium (Rb) to strontium (Sr) ratio enrichment in biological materials such as blood and urine can lead to enriched Rb/Sr values in MWW effluent relative to natural waters. This ratio is relatively easy and inexpensive to measure and represents a promising additional indicator for MWW effluent in receiving waters in urbanized freshwater systems. In July 2015 and 2016 surface water samples were collected from sites in the tidal-fresh Potomac River in the vicinity of the Blue Plains Advanced Wastewater Treatment Plant (BPAWWTP) outfall near Washington, DC USA along with treated MWW effluent samples from the BPAWWTP. Dissolved Rb/Sr ratios were measured in these waters and compared to dissolved Gd concentrations in order to demonstrate the potential of the dissolved Rb/Sr ratio as a conservative indicator for MWW effluent. Results suggest the dissolved Rb/Sr ratio represents a simple and cost-effective indicator and conservative tracer for MWW effluent. It can be used with, or in place of, other proven tracers to investigate wastewater impacts in highly-urbanized, anthropogenically-impacted freshwater systems like the tidal fresh Potomac River and perhaps in a wider range of geologic settings than previously thought. A case study is presented as an example to demonstrate the potential of using dissolved Rb/Sr ratios to trace MWW-sourced nutrient inputs from a major WWTP like BPAWWTP to the receiving waters of tidal-fresh Potomac River.

The potential prebiotic effect of 2-Butyloctanol on the human axillary microbiome.

OBJECTIVE: The human axilla is colonized by a wide array of microorganisms that contribute to the generation of body odour. Traditional antiperspirant/deodorant products are used to reduce perspiration in the axillary region and to treat or prevent the growth of bacteria in this region, thereby reducing or eliminating body odour. However, they may also compromise the axillary microbiome balance. The personal care industry has been seeking new ingredients, such as prebiotics or probiotics, to maintain a healthy balance of the skin microbiome by inhibiting odour-causing bacteria, whilst maintaining and promoting the growth of good bacteria. The aim of this study was to investigate the prebiotic effect of a skin-care ingredient, 2-butyloctanol, on the human axillary microbiome. METHODS: An in vitro growth inhibition/promotion assay was performed to test whether 2-butyloctanol inhibited or promoted skin bacterial growth. The impact of 2-butyloctanol on the axillary microbiome was also investigated in a human clinical study using 16S rRNA gene sequencing. RESULTS: In-vitro testing showed that 2-butyloctanol significantly inhibited the growth of corynebacteria at concentrations of 0.64%, 2.56% and 5.12%, whilst the growth of Staphylococcus epidermidis was maintained at the same concentrations. The impact of 2-butyloctanol on the axillary microbiome was also validated in a human clinical study. A deodorant roll-on product containing 3% of 2-butyloctanol significantly reduced the relative abundance of corynebacteria, whilst increasing the relative abundance of Staphylococcus and the ratio of Staphylococcus to corynebacteria after four weeks of application, whilst the placebo showed no significant change. CONCLUSION: For the first time, it was demonstrated that 2-butyloctanol had a potential prebiotic effect on the human underarm microbiome in inhibiting odour-causing Corynebacterium, whilst maintaining and promoting skin-friendly Staphylococcus in both in-vitro and in-vivo studies. Therefore, 2-butyloctanol could be used as a potential prebiotic ingredient in personal care products for underarm microbiome protection.

OBJECTIF: les aisselles humaines sont colonisées par un large éventail de micro-organismes qui contribuent à la génération de l'odeur corporelle. Les produits antitranspirants/déodorants traditionnels sont utilisés pour réduire la transpiration et traiter ou prévenir la croissance des bactéries dans la région axillaire, réduisant ou éliminant ainsi l'odeur corporelle. Cependant, ils peuvent également compromettre l'équilibre du microbiome axillaire. Le secteur des soins personnels recherche de nouveaux composants, tels que des prébiotiques ou des probiotiques, afin de maintenir un équilibre sain du microbiome cutané, en inhibant les bactéries responsables des odeurs tout en maintenant et en favorisant la croissance des bonnes bactéries. L'objectif de cette étude était d'étudier l'effet prébiotique sur le microbiome axillaire humain du 2-butyloctanol, un composant indiqué dans les soins cutanés. MÉTHODES: un test in vitro d'inhibition/de promotion de la croissance a été mené afin de déterminer si le 2-butyloctanol inhibait ou favorisait la croissance bactérienne cutanée. Les effets du 2-butyloctanol sur le microbiome axillaire a également fait l'objet d'une étude clinique chez l'homme qui reposait sur le séquençage du gène ARNr 16S. RÉSULTATS: les tests in vitro ont montré que le 2-butyloctanol inhibait significativement la croissance des corynébactéries à des concentrations de 0,64 %, de 2,56 % et de 5,12 %, tandis que la croissance de Staphylococcus epidermidis se maintenait aux mêmes concentrations. Une étude clinique chez l'homme a également permis de confirmer les effets du 2-butyloctanol sur le microbiome axillaire. Un produit déodorant à bille contenant 3 % de 2-butyloctanol a réduit significativement l'abondance relative des corynébactéries, tout en augmentant l'abondance relative de Staphylococcus et le rapport entre Staphylococcus et les corynébactéries après quatre semaines d'application, tandis que le placebo n'a montré aucun changement significatif. CONCLUSION: pour la première fois, des études in vitro et in vivo ont démontré que le 2-butyloctanol avait un possible effet prébiotique sur le microbiome axillaire humain, en inhibant Corynebacterium, la bactérie responsable des odeurs, tout en maintenant et en favorisant la croissance de Staphylococcus, une bactérie respectueuse de la peau. Par conséquent, le 2-butyloctanol pourrait servir de possible composant prébiotique dans les produits de soins personnels pour la protection du microbiome axillaire.

Severe hypotension with loss of motor evoked potentials during cervical surgery prompting immediate cardiovascular resuscitation.

BACKGROUND: Intraoperative neuromonitoring (IONM) is a well-established adjunct to spinal surgery to ensure safety of the neural elements.IONM has extremely high sensitivity and specificity for impending neurologic damage. In very rare instances, hypoperfusion of the cord may lead to a loss of IONM modalities that may be reversed if blood pressure issues responsible for the drop out of potentials are immediately addressed. CASE DESCRIPTION: The authors describe a case in which IONM documented hypoperfusion of the cord intraoperatively due to hypotension. Recognition of this problem and reversal of the hypotension resulted in normalization of postoperative function. CONCLUSION: The use of IONM allowed for quick recognition of an impending neurological insult during spinal deformity surgery. Prompt response to signaling changes allowed for the correction of hypotension and favorable neurologic outcome.

Efficacy Evaluation of a Topical Hyaluronic Acid Serum in Facial Photoaging.

INTRODUCTION: Hyaluronic acid (HA) acts as a biologic humectant, thus retaining water in the skin, making HA useful as a topical moisturizing ingredient. The goal of the research was to evaluate the ability of a HA facial serum to deliver skin benefits. METHODS: Forty females 30-65 years of age with Fitzpatrick skin types I-VI who exhibited photoaging used the HA facial serum twice daily with sunscreen. The dermatologist investigator evaluated smoothness, plumping, hydration, fine lines/wrinkles, and global appearance issues on a 5-point ordinal scale. The subjects assessed product tolerability in terms of stinging, itching, and burning. Corneometry was undertaken, with assessments performed at baseline, immediately after application, and at weeks 2, 4, and 6. Facial swabbing and photography were performed at the same intervals on a subset of 15 subjects. RESULTS: The HA serum demonstrated excellent tolerability and produced an increase in skin hydration (as measured by corneometry) immediately after application of 134% (p < 0.001), with a sustained increase of 55% (p < 0.001) at week 6. At week 6, there was also improvement (p ≤ 0.001) in all evaluated attributes: smoothness (64%), plumping (60%), hydration (63%), fine lines (31%), wrinkles (14%), and overall global assessment (43%). Facial swabbing confirmed an increase in topical HA at week 6 (p = 0.04), accounting for the enhanced skin appearance, but there was no statistically significant increase in IL-1a, indicating no product irritation. CONCLUSION: Topical HA in a serum formulation provides excellent skin hydration, as demonstrated through clinical, photographic, chemical, and instrumental assessments.

Efficacy and safety of ofatumumab and bendamustine followed by ofatumumab maintenance in patients with relapsed indolent non-Hodgkin lymphoma after prior rituximab.

In indolent non-Hodgkin's lymphoma (iNHL), patients treated with rituximab, alone or in combination with various chemotherapeutic agents eventually relapse. This study evaluated the combination of ofatumumab and bendamustine, followed by maintenance ofatumumab in patients with relapsed iNHL with prior sensitivity to rituximab. Among the 49 patients enrolled, 24.5% achieved a complete response (CR) and 42.9% achieved a partial response (PR), with an overall response rate of 67.3% at the end of the induction therapy. Additionally, six patients with PR during induction phase achieved CR during the maintenance phase. Treatment-related adverse event was observed in 95.9% patients. The most common hematologic and biochemical abnormalities were decrease in lymphocytes (85.7%) and increase in glucose (91.8%), respectively. Overall, 42.9% progressed and 14.3% died during the study. Thus, ofatumumab in combination with bendamustine, followed by ofatumumab maintenance, was effective in the treatment of patients with iNHL with a manageable safety profile (NCT01294579).

A Phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma.

PURPOSE: Polyamines are absolutely essential for maintaining tumor cell proliferation. PG-11047, a polyamine analogue, is a nonfunctional competitor of the natural polyamine spermine that has demonstrated anticancer activity in cells and animal models of multiple cancer types. Preclinical investigations into the effects of common chemotherapeutic agents have revealed overlap with components of the polyamine metabolic pathway also affected by PG-11047. This report describes a Phase Ib clinical trial investigating PG-11047 in combination with cytotoxic and anti-angiogenic chemotherapeutic agents in patients with advanced refractory metastatic solid tumors or lymphoma. METHODS: A total of 172 patients were assigned to treatment arms based on cancer type to receive the appropriate standard-of-care therapy (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil (5-FU), or sunitinib as directed) along with once weekly intravenous infusions of PG-11047. PG-11047 dose escalation ranged from 50 to 590 mg. RESULTS: The maximum tolerated dose (MTD) of PG-11047 in combination with bevacizumab, erlotinib, cisplatin, and 5-FU was 590 mg. Dose-limiting toxicities (DLTs) in these groups were rare (5 of 148 patients). Overall partial responses (PR) were observed in 12% of patients treated with PG-11047 and bevacizumab, with stable disease documented in an additional 40%. Stable disease occurred in 71.4% of patients in the 5-FU arm, 54.1% in the cisplatin arm, and 33.3% in the erlotinib arm. Four of the patients receiving cisplatin + PG-11047 (20%) had unconfirmed PRs. MTDs for gemcitabine, docetaxel, and sunitinib could not be determined due to DLTs at low doses of PG-11047 and small sample size. CONCLUSIONS: Results of this Phase Ib trial indicate that PG-11047 can be safely administered to patients in combination with bevacizumab, erlotinib, cisplatin, and 5-FU on the once weekly dosing schedule described and may provide therapeutic benefit. The manageable toxicity profile and high MTD determination provide a safety profile for further clinical studies.

A novel skin brightening topical technology.

BACKGROUND: Effective skin lightening remains an unmet need in over-the-counter formulations. AIMS: This research examined a topical facial formulation containing hexylresorcinol, silymarin, 20% vitamin C, and 5% vitamin E in a proprietary anhydrous vehicle in skin explants for UVB photoprotective effects and clinical benefits. PATIENTS/METHOD: In vitro investigation examined 12 skin explants to assess the test product and vehicle. Six skin explants received 10 µL of the study product, and six skin explants received the 10 µL of the vehicle. After 96 hours, half the skin samples were exposed to 250 mJ/cm2 of UVB radiation while the other half unexposed. Clinically, 42 female subjects with normal or dry skin 35-55 years with skin types I-VI were enrolled possessing discoloration, uneven skin tone, and fine lines. The dermatologist investigator evaluated brightening, evenness, fine lines, wrinkles, and global appearance. RESULTS: Explants treated with the study product experienced no significant change in gene marker expression of pro-collagen and pro-inflammatory gene markers upon UVB exposure. In contrast, skin explants treated with the vehicle experienced significant decreases in pro-collagen expression and significant increases in pro-inflammatory gene marker expression. Clinically, the greatest improvement as compared to baseline was seen at week 12 (P < .001) with 45% improvement in brightening, 27% improvement in evenness, 25% improvement in lines, and 25% improvement in global facial appearance. CONCLUSION: Hexylresorcinol, silymarin, 20% vitamin C, and 5% vitamin E in a proprietary anhydrous vehicle are effective in decreasing UVB-induced photodamage in skin explants while clinically producing skin brightness improvement.

Ecosystem Capacity for Microbial Biodegradation of Munitions Compounds and Phenanthrene in Three Coastal Waterways in North Carolina, United States.

Munitions compounds (i.e., 2,4,6-trinitrotoluene (TNT), octahy-dro-1,3,5,7-tetranitro-1,3,5,7-tetrazocin (HMX), and hexadydro-1,3,5-trinitro-1,3,5-triazin (RDX), also called energetics) were originally believed to be recalcitrant to microbial biodegradation based on historical groundwater chemical attenuation data and laboratory culture work. More recently, it has been established that natural bacterial assemblages in coastal waters and sediment can rapidly metabolize these organic nitrogen sources and even incorporate their carbon and nitrogen into bacterial biomass. Here, we report on the capacity of natural microbial assemblages in three coastal North Carolina (United States) estuaries to metabolize energetics and phenanthrene (PHE), a proxy for terrestrial aromatic compounds. Microbial assemblages generally had the highest ecosystem capacity (mass of the compound mineralized per average estuarine residence time) for HMX (21-5463 kg) > RDX (1.4-5821 kg) ≫ PHE (0.29-660 kg) > TNT (0.25-451 kg). Increasing antecedent precipitation tended to decrease the ecosystem capacity to mineralize TNT in the Newport River Estuary, and PHE and TNT mineralization were often highest with increasing salinity. There was some evidence from the New River Estuary that increased N-demand (due to a phytoplankton bloom) is associated with increased energetic mineralization rates. Using this type of analysis to determine the ecosystem capacity to metabolize energetics can explain why these compounds are rarely detected in seawater and marine sediment, despite the known presence of unexploded ordnance or recent use in military training exercises. Overall, measuring the ecosystem capacity may help predict the effects of climate change (warming and altered precipitation patterns) and other perturbations on exotic compound fate and transport within ecosystems and provide critical information for managers and decision-makers to develop management strategies based on these changes.

A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma.

BACKGROUND: Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody-drug conjugate targeting CD70, SGN-CD70A, was developed to treat patients with CD70-positive RCC. METHODS: The objective of this phase 1, open-label, dose-escalation, multicenter study was to evaluate the safety and tolerability of SGN-CD70A and establish its maximum tolerated dose in patients with CD70-positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose-limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model-based, modified continual-reassessment method was used to estimate the probabilities of DLT and response. RESULTS: The maximum tolerated dose was determined to be 30 µg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1-8 prior lines of therapy), and diminishing response potential. CONCLUSIONS: The modest antitumor activity of SGN-CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.

A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma.

Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure.

CC-486 (oral azacitidine) in patients with myelodysplastic syndromes with pretreatment thrombocytopenia.

Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 109/L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 109/L and 198 × 109/L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 109/L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, then increased thereafter. Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia.

Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial.

BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. METHODS: This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelodysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0·1 or 0·3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0·5, 1·0, and 2·0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement-erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012-002601-22, and is ongoing. FINDINGS: Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0·1 mg/kg sotatercept, six to 0·3 mg/kg, 21 to 0·5 mg/kg, 35 to 1·0 mg/kg, and five to 2·0 mg/kg). 36 (49%; 95% CI 38-60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35-59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32-81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1·5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3-4 TEAEs that were considered to be treatment related. The most common grade 3-4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. INTERPRETATION: Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options. FUNDING: Celgene Corporation.

Idelalisib in Combination With Rituximab or Bendamustine or Both in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia.

Phosphatidylinositol 3-kinase-delta (PI3Kδ) signaling is critical for proliferation, survival, homing, and tissue retention of malignant B cells. Idelalisib, a selective oral inhibitor of PI3Kδ, has shown considerable single-agent activity in patients with heavily pretreated chronic lymphocytic leukemia (CLL). This study evaluated the safety and clinical activity of idelalisib in combination with bendamustine (IB) or rituximab (IR) or both (IBR) in patients with relapsed or refractory (R/R) CLL. Idelalisib was given continuously at 100 or 150 mg twice daily in combination with rituximab (375 mg/m2 weekly × 8 doses), bendamustine (70 or 90 mg/m2, days 1 and 2 every 4 weeks × 6 cycles) or BR (rituximab, 375 mg/m2 every 4 weeks and bendamustine, 70 mg/m2, days 1 and 2 every 4 weeks × 6 cycles). The primary endpoint was safety; secondary endpoints included overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Fifty-two patients (median age 64 years) with a median of 3 prior therapies were enrolled. ORR was 84.6% (89.5% IR group, 77.8% IB group, and 86.7% IBR group). The overall median PFS was 25.6 months, and median DOR was 26.6 months. The most common grade ≥3 adverse events (≥10% of patients) were pneumonia (19.2%), diarrhea (13.5%), and febrile neutropenia (17.3%). Idelalisib-based combination therapy with bendamustine and/or rituximab was highly active, resulting in durable tumor control in patients with heavily pretreated R/R CLL. However, its tolerability profile suggests that these regimens should be used cautiously in this patient population. ClinicalTrials.gov ID: NCT01088048.

Treatment of CD30-Expressing Germ Cell Tumors and Sex Cord Stromal Tumors with Brentuximab Vedotin: Identification and Report of Seven Cases.

BACKGROUND: Cytotoxic therapy for relapsed and refractory germ cell tumors or metastatic sex cord stromal tumors is rarely effective and is often accompanied by high adverse event rates. Expression of CD30 has been observed in testicular cancers, and patients with CD30-expressing embryonal carcinomas have worse progression-free survival and overall survival than those with CD30-negative tumors. The objective of this study (NCT01461538) was to characterize the antitumor activity of brentuximab vedotin in patients with CD30-expressing nonlymphomatous malignancies. Enrolled patients included seven patients with relapsed or refractory germ cell tumors or metastatic sex cord stromal tumors described in this case series. MATERIALS AND METHODS: Forty patients with relapsed or refractory germ cell tumors, metastatic sex cord stromal tumors, or testicular tumors were screened for CD30 expression; 14 patients had tumors that expressed CD30. Seven patients with CD30-expressing testicular cancer were enrolled in the treatment study: five patients with germ cell tumors, one patient with a Leydig cell tumor, and one patient with a Sertoli cell tumor. Patients were treated with brentuximab vedotin at initial doses of 1.8 or 2.4 mg/kg every 3 weeks. Response assessments were performed at cycles 2 and 4 and every 4 cycles thereafter while the patient was receiving treatment. RESULTS: Two of seven patients achieved an objective response, including one durable complete response and one partial response at a single time point. Both responding patients had germ cell tumors. Treatment with brentuximab vedotin was generally well tolerated. CONCLUSION: Treatment of relapsed or refractory germ cell tumors with brentuximab vedotin can induce durable responses with a manageable toxicity profile. IMPLICATIONS FOR PRACTICE: This case series of seven patients with relapsed or refractory CD30-expressing germ cell tumors (GCTs) or sex cord stromal tumors demonstrates that brentuximab vedotin has activity against GCTs and is well tolerated in heavily pretreated patients with these aggressive tumor types. One patient achieved a complete response that has been durable for almost 4 years since the discontinuation of treatment with brentuximab vedotin. Therefore, brentuximab vedotin may be a valuable option for physicians who care for this difficult-to-treat patient population.

POMzites: A Family of Zeolitic Polyoxometalate Frameworks from a Minimal Building Block Library.

We describe why the cyclic heteropolyanion [P8W48O184]40- (abbreviated as {P8W48}) is an ideal building block for the construction of intrinsically porous framework materials by classifying and analyzing >30 coordination polymers incorporating this polyoxometalate (POM) ligand. This analysis shows that the exocyclic coordination of first-row transition metals (TMs) to {P8W48} typically yields frameworks which extend through {W-O-TM-O-W} bridges in one, two, or three dimensions. However, despite the rich structural diversity of such compounds, the coordination of TMs to the {P8W48} ring is poorly understood, and therefore largely unpredictable, and had not until now been present with any structural classification that could allow rational design. Herein, not only do we present a new approach to understand and classify this new class of materials, we also present three {P8W48}-based frameworks which complement those frameworks which have previously been described. These new compounds help us postulate a new taxonomy of these materials. This is possible because the TM coordination sites of the {P8W48} ring are found, once fully mapped, to lead to well-defined classes of connectivity. Together, analysis provides insight into the nature of the building block connectivity within each framework, to facilitate comparisons between related structures, and to fundamentally unite this family of compounds. Hence we have tentatively named these compounds as "POMzites" to reflect the POM-based composition and zeolitic nature of each family member, although crucially, POMzites differ from zeolites in the modular manner of their preparation. As the synthesis of further POMzites is anticipated, the classification system and terminology introduced here will allow new compounds to be categorized and understood in the context of the established materials. A better understanding of TM coordination to the {P8W48} ring may allow the targeted synthesis of new frameworks rather than the reliance on serendipity apparent in current methods.

A metamorphic inorganic framework that can be switched between eight single-crystalline states.

The design of highly flexible framework materials requires organic linkers, whereas inorganic materials are more robust but inflexible. Here, by using linkable inorganic rings made up of tungsten oxide (P8W48O184) building blocks, we synthesized an inorganic single crystal material that can undergo at least eight different crystal-to-crystal transformations, with gigantic crystal volume contraction and expansion changes ranging from -2,170 to +1,720 Å3 with no reduction in crystallinity. Not only does this material undergo the largest single crystal-to-single crystal volume transformation thus far reported (to the best of our knowledge), the system also shows conformational flexibility while maintaining robustness over several cycles in the reversible uptake and release of guest molecules switching the crystal between different metamorphic states. This material combines the robustness of inorganic materials with the flexibility of organic frameworks, thereby challenging the notion that flexible materials with robustness are mutually exclusive.

Laboratory growth of denitrifying water column microbial consortia from deep-sea shipwrecks in the northern Gulf of Mexico.

Background: Shipwrecks serve as a rich source for novel microbial populations that have largely remained undiscovered. Low temperatures, lack of sunlight, and the availability of substrates derived from the shipwreck's hull and cargo may provide an environment in which microbes can develop unique metabolic adaptations.   Methods: To test our hypothesis that shipwrecks could influence the microbial population involved in denitrification when a consortium is grown in the laboratory, we collected samples proximate to two steel shipwrecks in the northern Gulf of Mexico. Then under laboratory conditions, we grew two independent denitrifying microbial consortia. Each consortium was grown by using the BART assay system and analyzed based on growth kinetics, ion chromatography and 16S amplicon sequencing. Results: Both denitrifying consortia were different from each other based on varied growth profiles, rates of nitrate utilization and 16S amplicon sequencing. Conclusions: Our observations conclude that the laboratory grown water column microbial consortia from deep-sea shipwrecks in the Gulf of Mexico are able to undergo aggressive denitrification.

Measuring Carbon-based Contaminant Mineralization Using Combined CO2 Flux and Radiocarbon Analyses.

A method is described which uses the absence of radiocarbon in industrial chemicals and fuels made from petroleum feedstocks which frequently contaminate the environment. This radiocarbon signal - or rather the absence of signal - is evenly distributed throughout a contaminant source pool (unlike an added tracer) and is not impacted by biological, chemical or physical processes (e.g., the 14C radioactive decay rate is immutable). If the fossil-derived contaminant is fully degraded to CO2, a harmless end-product, that CO2 will contain no radiocarbon. CO2 derived from natural organic matter (NOM) degradation will reflect the NOM radiocarbon content (usually <30,000 years old). Given a known radiocarbon content for NOM (a site background), a two end-member mixing model can be used to determine the CO2 derived from a fossil source in a given soil gas or groundwater sample. Coupling the percent CO2 derived from the contaminant with the CO2 respiration rate provides an estimate for the total amount of contaminant degraded per unit time. Finally, determining a zone of influence (ZOI) representing the volume from which site CO2 is collected allows determining the contaminant degradation per unit time and volume. Along with estimates for total contaminant mass, this can ultimately be used to calculate time-to-remediate or otherwise used by site managers for decision-making.