How does plastic compare with alternative materials in the packaging sector? A systematic review of LCA studies.

In the recent years, packaging made of conventional plastics has been increasingly replaced by materials believed to be more sustainable. However, perceived sustainability must align with scientific assessments, such as life cycle assessments (LCAs). This review analysed 53 peer-reviewed studies published in the time range 2019-2023, aiming at understanding the state of the art in LCA about the environmental impacts of packaging by focusing on the comparison between plastics and alternative materials. The literature showed that consumer perceptions often differ from LCA findings and revealed that, frequently, conventional plastics are not the least environmentally friendly choice. Bioplastics typically show benefits only in the climate change and the fossil resource depletion impact categories. The heavy weight of glass turns out to affect its environmental performances with respect to the light plastics, with reuse being an essential strategy to lower the burdens. The comparison between plastics and metals is more balanced, leaning more towards plastics for food packaging. Similarly, paper resulted often preferable than plastics. Finally, for the other materials (i.e. wood and textiles), the picture is variable. To be competitive with plastics, the alternative materials require improvements like the optimisation of their production processes, their reuse and enhanced end-of-life options. At the same time, recycled polymers could boost the eco-performance of virgin plastics.

The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors.

α5 subunit-containing γ-aminobutyric acid type A (GABAA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the ß-carboline, methyl 6,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.

Infections and Colon Surgery: Preliminary Results from a Surveillance Program in an Italian Hospital.

Surgical site infections (SSIs) represent a valid indicator of the healthcare quality. This study described the preliminary results of one-year active surveillance program on colon surgeries in a hospital in Molise region, central Italy. Patients who had undergone colon surgery according to National Healthcare Safety Network were included. Data on intervention, perioperative antibiotic prophylaxis, and SSIs occurrence were collected. Chi-square and Fisher's Exact test were used to evaluate any association between risk factors and SSIs. Sixty-eight patients (mean age 70.6 years) were included, and 44 (64.7%) were males. The most frequent interventions were right (n = 17, 25.0%) and left (n = 15, 22.0%) hemicolectomy. Surgical interventions were largely elective (n = 43, 63.2%) and with laparotomy (n = 56, 82.4%). During hospital stay, 10 (14.7%) SSIs were detected, including five superficial, three deep and two organ/space infections. Three (4.4%) additional SSIs were detected at post-discharge follow-up, for 13 (19.1%; CI95%: 9.7%-28.5%) total cases detected. Metronidazole plus Ceftriaxone (third generation cephalosporin) was the antibiotics combination mostly used (n = 36, 52.9%) for the perioperative antibiotic prophylaxis within 60 minutes of incision. The study underlines the need of improvements of the practices currently adopted, since SSIs could be significantly reduced through a multimodal strategy generating bundles. As third generation cephalosporins may facilitate resistant strains emergence, for perioperative prophylaxis in clean-contaminated interventions with entry into gastrointestinal tract, Cefazolin plus Metronidazole or only second generation cephalosporin are recommended. Due to the large variability of post-intervention antibiotic therapy, antimicrobial stewardship approach is strictly necessary.

LipMetE (Lipophilic Metabolism Efficiency) as a Simple Guide for Half-Life and Dosing Regimen Prediction of Oral Drugs.

The in vivo half-life is a key property of every drug molecule, as it determines dosing regimens, peak-to-trough ratios and often dose. However, half-life optimization can be challenging due to its multifactorial nature, with in vitro metabolic turnover, plasma protein binding and volume of distribution all impacting half-life. We here propose that the medicinal chemistry design parameter Lipophilic Metabolism Efficiency (LipMetE) can greatly simplify half-life optimization of neutral and basic compounds. Using mathematical transformations, examples from preclinical GABAA projects and clinical compounds with human pharmacokinetic data, we show that LipMetE is directly proportional to the logarithm of half-life. As the design parameter LipMetE can be swiftly calculated using the readily available parameters LogD, intrinsic clearance and fraction unbound in human liver microsomes or hepatocytes, this approach enables rational half-life optimization from the early stages of drug discovery projects.

Structural and biochemical studies of actin in complex with synthetic macrolide tail analogues.

The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. Structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.

Enantioselective direct α-amination of aldehydes via a photoredox mechanism: a strategy for asymmetric amine fragment coupling.

The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated N-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require postreaction manipulation.

Concomitant boost radiotherapy and multidrug chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer: results of a phase II study.

BACKGROUND: An intensified multidrug chemotherapy regimen (raltitrexed plus oxaliplatin, Tom-Ox) plus concomitant boost radiotherapy, in the neoadjuvant treatment of locally advanced rectal cancer patients, was shown feasible in our previous study. The aim of this study was to evaluate the efficacy in terms of pathologic complete response to pre-operative therapy. MATERIAL AND METHODS: A Phase II study was designed and clinical stage T3-T4 and/ or N ≥ 1 patients were treated with concomitant boost radiotherapy (55 Gy/5 weeks) plus concurrent chemotherapy (Tom-Ox). The primary endpoint was the assessment of efficacy in terms of clinical and pathologic response to pre-operative therapy. According to the Gehan's design study, 25 patients were enrolled. Toxicity was assessed according to the RTOG-EORTC and CTCAE v.3.0 criteria. RESULTS: Twenty-five consecutive patients were treated. Twenty-two of the 25 (88%) patients had a partial clinical response at the time of pre-operative magnetic resonance imaging (MRI). Only one patient showed progressive systemic disease at pre-surgical revaluation and was subjected only to biopsy to evaluate pathological response. Twenty-four patients (96%) underwent surgery. Overall, pathologic complete response was observed in eight patients (32%; CI 0.95:12-55%) and only microscopic tumor foci (pTmic) in two patients (pT0-mic: 40%; CI 0.95:18-63%). Nineteen patients (76%) showed tumor down-staging. Proctitis and/or diarrhea were the most frequent acute side effects experienced. Eighteen patients had grade 1-2 toxicity (77%); whereas two patients experienced grade 3 toxicity (8%). Two-year Local control and actuarial Disease Free Survival were 100% and 91%, respectively. CONCLUSION. An intensified regimen of concomitant boost radiotherapy plus concurrent raltitrexed and oxaliplatin, can be safely administered in patients with locally advanced rectal cancer. This regimen produces high rates of pathological complete response. Based on available data, this type of treatment could be offered to patients with more advanced tumors (T4 or local recurrence).

Synthetic mimetics of actin-binding macrolides: rational design of actin-targeted drugs.

Actin polymerization and dynamics are involved in a wide range of cellular processes such as cell division and migration of tumor cells. At sites of cell lysis, such as those occurring during a stroke or inflammatory lung diseases, actin is released into the serum where it polymerizes, leading to problems with clot dissolution and sputum viscosity. Therefore, drugs that target these actin-mediated processes may provide one mechanism to treat these conditions. Marine-organism-derived macrolides, such as reidispongiolide A, can bind to, sever, and inhibit polymerization of actin. Our studies show that the function of these complex macrolides resides in their tail region, whereas the head group stabilizes the actin-drug complex. Synthetic compounds derived from this tail region could therefore be used as a mimetic of the natural product, providing a range of designer compounds to treat actin-associated diseases or as probes to study actin polymerization.

Total synthesis of (-)-reidispongiolide A, an actin-targeting macrolide isolated from the marine sponge Reidispongia coerulea.

A stereocontrolled total synthesis of the microfilament-destabilizing cytotoxic macrolide (-)-reidispongiolide A, isolated from the New Caledonian marine sponge Reidispongia coerulea, is described. This synthesis utilizes a convergent aldol-based strategy to construct the 26-membered macrolactone, followed by the late-stage coupling of a derived aldehyde with an N-vinylformamide-containing ketone subunit to install the full side chain. Two alternative routes were examined for the introduction of the 2E,4E-dienoate region, and a complex Mukaiyama aldol coupling was used to connect the northern and southern hemispheres to install the C13 stereocenter. This constitutes the first chemical synthesis of any member of the reidispongiolide/sphinxolide family of marine macrolides and unequivocally establishes the relative and absolute configuration.