Combining Desferriferrioxamine B and 1-Hydroxy-2-Piperidone ((PIPO)H) to Chelate Zirconium. Solution Structure of a Model Complex of the [89Zr]Zr-DFOcyclo*-mAb Radioimmunoconjugate.

89Zr-immunoPET is a hot topic as 89Zr cumulates the advantages of 64Cu and 124I without their drawbacks. We report the synthesis of a model ligand of a chiral bioconjugable tetrahydroxamic chelator combining the desferriferrioxamine B siderophore and 1-hydroxy-2-piperidone ((PIPO)H), a chiral cyclic hydroxamic acid derivative, and the study by NMR spectroscopy of its zirconium complex. Nuclear Overhauser effect measurements (ROESY) indicated that the complex exists in the form of two diastereomers, in 77 : 23 ratio, resulting from the combination of the central chiralities at the 3-C of the (PIPO)H component and at the Zr4+ cation. The 44 lowest energy structures out of more than 1000 configurations/conformations returned by calculations based on density functional theory were examined. Comparison of the ROESY data and the calculated interatomic H⋅⋅⋅H distances allowed us to select the most probable configuration and conformations of the major complex.

The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Cyclotribenzylene alkynylgold(I) phosphine complexes: synthesis, chirality, and exchange of phosphine.

Two different alkynyl-substituted C3-symmetric cyclotribenzylenes (CTB) were synthesized in racemic and enantiomerically pure forms, and six gold(I) phosphine complexes differing by the nature of the CTB and the phosphine were prepared and characterized, in particular by NMR spectroscopy, DOSY, electronic circular dichroism (ECD), and electrospray ionization mass spectrometry (ESI-MS). Their ECD patterns depended on the substitution of the starting CTBs and were shifted bathochromically by comparison with the latter. ESI-MS in the presence of HCO2H allowed us to detect the complexes as proton adducts. The intensities of the signals were stronger when the phosphine was more electron-rich. This technique was also used to investigate the exchange of phosphine betweeen pairs of CTB complexes. The scrambling reaction was demonstrated by the higher intensity of the signals of the complexes subjected to the exchange of a single phosphine ligand by comparison with the intensity of the signals of the starting complexes.

Different outcomes among patients with intermediate-risk metastastic renal cell carcinoma treated with first-line tyrosine-kinase inhibitors

Introduction Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. Material and methods All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. Results A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. Conclusion In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria(AU)

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

Different outcomes among patients with intermediate-risk metastastic renal cell carcinoma treated with first-line tyrosine-kinase inhibitors.

INTRODUCTION: Systemic therapy of patients with metastatic renal cell carcinoma (mRCC) has improved in the past years, with the advent of new immunotherapy-based combinations as a standard treatment option for first-line therapy. Nevertheless, particularly in good-risk patients by IMDC criteria, tyrosine-kinase inhibitors (TKI) may remain as an option for some patients. We reviewed our experience with TKI as first-line therapy for mRCC patients, trying to identify subgroups of patients that may still benefit from this strategy. MATERIAL AND METHODS: All patients with mRCC treated with first-line TKI, and adequate follow-up, in University Hospital La Paz (Madrid, Spain) between 2007 and 2020 were analyzed. Patients treated inside a clinical trial were excluded from this analysis. RESULTS: A total of 90 patients treated with first-line TKI were included. Regarding IMDC criteria, 33 patients (36.7%) were good-risk, 41 patients (45.5%) intermediate-risk, and 16 patients (17.8%) poor-risk. With a median follow-up of 49 months, the median overall survival (OS) for good, intermediate, and poor-risk patients was 54, 24, and 16 months (p = 0.004). When intermediate-risk was divided into patients with 1 or 2 risk factors, differences in OS were also statistically significant: patients with 1 risk factor had a median OS of 33 months, while patients with 2 risk factors had a median OS of 16 months, the same as poor-risk patients (p = 0.003). In the multivariate analysis, trying to find out which of the IMDC factors had a more remarkable weight in the prognosis of the patients, both ECOG and hemoglobin levels by themselves were significantly associated with OS. CONCLUSION: In our group of patients, survival outcomes were different among patients with intermediate-risk with 1 or 2 risk factors by IMDC criteria. These could help select patients that may benefit from first-line treatment with a TKI, particularly in settings with difficult access to novel therapies, such as immunotherapy-based combinations.

Carborane-based heteromolecular extended networks driven by directional C-Te⋯N chalcogen bonding interactions.

We demonstrate that o-closo-(TeMe)2carborane directs, in the presence of linear ditopic neutral Lewis bases, the formation of co-crystals with 1D extended supramolecular networks. Specifically, the network formation is systematically stabilized by short and quasi-linear C-Te⋯N chalcogen-bonding (ChB) interactions. In sum, we report efficient carborane-based tectons to rationally design high-dimensional neutral heteromolecular networks.

Multi-omics Characterization of Response to PD-1 Inhibitors in Advanced Melanoma.

Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.

Predicting Risk of Severe Toxicity and Early Death in Older Adult Patients Treated with Chemotherapy.

BACKGROUND: Determining the risk of grade 3-5 toxicity and early death (ED) is important to plan chemotherapy in older adult patients with cancer. Our objective was to identify factors predicting these complications at the time of treatment initiation. METHODS: 234 patients aged ≥70 were subjected to a geriatric assessment and variables related to the tumor and the treatment were also collected. Logistic regression multivariable analysis was used to relate these factors with the appearance of grade 3-5 toxicity and ED. Predictive scores for both toxicity and ED were then developed. RESULTS: Factors related to grade 3-5 toxicity were hemoglobin, MAX2 index, ADL, and the CONUT score. Factors related to ED were tumor stage and the GNRI score. Two predictive scores were developed using these variables. ROC curves for the prediction of toxicity and ED were 0.71 (95% CI: 0.64-0.78) and 0.73 (95% CI: 0.68-0.79), respectively. CONCLUSIONS: Two simple and reliable scores were developed to predict grade 3-5 toxicity and ED in older adult patients with cancer. This may be helpful in treatment planning.

Efficacy of second and third lines of treatment in advanced soft tissue sarcomas: a real-world study.

BACKGROUND: Soft tissue sarcomas (STSs) are an uncommon and heterogeneous group of tumours. Several drugs and combinations have been used in clinical practice as second-line (2L) and third-line (3L) treatment. The growth modulation index (GMI) has previously been used as an exploratory efficacy endpoint of drug activity and represents an intra-patient comparison. METHODS: We performed a real-world retrospective study including all patients with advanced STS who had received at least 2 different lines of treatment for advanced disease between 2010 and 2020 at a single institution. The objective was to study the efficacy of both 2L and 3L treatments, analysing the time to progression (TTP) and the GMI (defined as the ratio of TTP between 2 consecutive lines of therapy). RESULTS: Eighty-one patients were included. The median TTP after 2L and 3L treatment was 3.16 and 3.06 months, and the median GMI was 0.81 and 0.74, respectively. The regimens most frequently used in both treatments were trabectedin, gemcitabine-dacarbazine, gemcitabine-docetaxel, pazopanib and ifosfamide. The median TTP by each of these regimens was 2.80, 2.23, 2.83, 4.10, and 5.00 months, and the median GMI was 0.78, 0.73, 0.67, 1.08, and 0.94, respectively. In terms of histotype, we highlight the activity (GMI > 1.33) of gemcitabine-dacarbazine in undifferentiated pleomorphic sarcoma (UPS) and in leiomyosarcoma, pazopanib in UPS, and ifosfamide in synovial sarcoma. CONCLUSIONS: In our cohort, regimens commonly used after first-line STS treatment showed only slight differences in efficacy, although we found significant activity of specific regimens by histotype.

Metabolomics unravels subtype-specific characteristics related to neoadjuvant therapy response in breast cancer patients.

INTRODUCTION: Breast cancer is the most diagnosed tumor and the leading cause of cancer death in women worldwide. Metabolomics allows the quantification of the entire set of metabolites in blood samples, making it possible to study differential metabolomics patterns related to neoadjuvant treatment in the breast cancer neoadjuvant setting. OBJECTIVES: Characterizing metabolic differences in breast cancer blood samples according to their response to neoadjuvant treatment. METHODS: One hundred and three plasma samples of breast cancer patients, before receiving neoadjuvant treatment, were analyzed through UPLC-MS/MS metabolomics. Then, metabolomics data were analyzed using probabilistic graphical models and biostatistics methods. RESULTS: Metabolomics data allowed the identification of differences between groups according to response to neoadjuvant treatment. These differences were specific to each breast cancer subtype. Patients with HER2+ tumors showed differences in metabolites related to amino acids and carbohydrates pathways between the two pathological response groups. However, patients with triple-negative tumors showed differences in metabolites related to the long-chain fatty acids pathway. Patients with Luminal B tumors showed differences in metabolites related to acylcarnitine pathways. CONCLUSIONS: It is possible to identify differential metabolomics patterns between complete and partial responses to neoadjuvant therapy, being this metabolomic profile specific for each breast cancer subtype.

Impacts of plasma microbial lipopolysaccharide translocation on B cell perturbations and anti-CD4 autoantibody production in people with HIV on suppressive antiretroviral therapy.

BACKGROUND: . Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear. METHODS: . Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG-producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro. RESULTS: . Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro. CONCLUSION: . Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

Adjuvant dabrafenib and trametinib for patients with resected BRAF -mutated melanoma: DESCRIBE-AD real-world retrospective observational study.

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.

Sorting Transcriptomics Immune Information from Tumor Molecular Features Allows Prediction of Response to Anti-PD1 Therapy in Patients with Advanced Melanoma.

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy.

Proteomics Characterization of Clear Cell Renal Cell Carcinoma.

PURPOSE: To explore the tumor proteome of patients diagnosed with localized clear cell renal cancer (ccRCC) and treated with surgery. MATERIAL AND METHODS: A total of 165 FFPE tumor samples from patients diagnosed with ccRCC were analyzed using DIA-proteomics. Proteomics ccRCC subtypes were defined using a consensus cluster algorithm (CCA) and characterized by a functional approach using probabilistic graphical models and survival analyses. RESULTS: We identified and quantified 3091 proteins, including 2026 high-confidence proteins. Two proteomics subtypes of ccRCC (CC1 and CC2) were identified by CC using the high-confidence proteins only. Characterization of molecular differences between CC1 and CC2 was performed in two steps. First, we defined 514 proteins showing differential expression between the two subtypes using a significance analysis of microarrays analysis. Proteins overexpressed in CC1 were mainly related to translation and ribosome, while proteins overexpressed in CC2 were mainly related to focal adhesion and membrane. Second, a functional analysis using probabilistic graphical models was performed. CC1 subtype is characterized by an increased expression of proteins related to glycolysis, mitochondria, translation, adhesion proteins related to cytoskeleton and actin, nucleosome, and spliceosome, while CC2 subtype showed higher expression of proteins involved in focal adhesion, extracellular matrix, and collagen organization. CONCLUSIONS: ccRCC tumors can be classified in two different proteomics subtypes. CC1 and CC2 present specific proteomics profiles, reflecting alterations of different molecular pathways in each subtype. The knowledge generated in this type of studies could help in the development of new drugs targeting subtype-specific deregulated pathways.

Palbociclib Rechallenge for Hormone Receptor-Positive/HER-Negative Advanced Breast Cancer: Findings from the Phase II BioPER Trial.

PURPOSE: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC). PATIENTS AND METHODS: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. RESULTS: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6-53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2-27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8-6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71-282.9; P = 0.018). CONCLUSIONS: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials.

Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial.

In patients with previously treated metastatic uveal melanoma, the historical 1 year overall survival rate is 37% with a median overall survival of 7.8 months. We conducted a multicenter, single-arm, open-label phase 2 study of tebentafusp, a soluble T cell receptor bispecific (gp100×CD3), in 127 patients with treatment-refractory metastatic uveal melanoma (NCT02570308). The primary endpoint was the estimation of objective response rate based on RECIST (Response Evaluation Criteria in Solid Tumours) v1.1. Secondary objectives included safety, overall survival, progression-free survival and disease control rate. All patients had at least one treatment-related adverse event, with rash (87%), pyrexia (80%) and pruritus (67%) being the most common. Toxicity was mostly mild to moderate in severity but was greatly reduced in incidence and intensity after the initial three doses. Despite a low overall response rate of 5% (95% CI: 2-10%), the 1 year overall survival rate was 62% (95% CI: 53-70%) with a median overall survival of 16.8 months (95% CI: 12.9-21.3), suggesting benefit beyond traditional radiographic-based response criteria. In an exploratory analysis, early on-treatment reduction in circulating tumour DNA was strongly associated with overall survival, even in patients with radiographic progression. Our findings indicate that tebentafusp has promising clinical activity with an acceptable safety profile in patients with previously treated metastatic uveal melanoma, and data suggesting ctDNA as an early indicator of clinical benefit from tebentafusp need confirmation in a randomized trial.

N-Chlorobenzimidazoles as efficient and structurally diverse amphoteric halogen bond donors in crystal engineering.

The ability of amphoteric N-chlorobenzimidazoles to self-associate into 1D chains through strong and linear N-Cl⋯N halogen bond interactions is demonstrated. The less polarisable Cl atom is strongly activated thanks to the intramolecular amphoteric character and the intermolecular cooperativity effect. The obtained family of compounds featuring different substitution patterns provides opportunities toward the elaboration of macroscopic polar structures.

N-Iodosaccharin-pyridine co-crystal system under pressure: experimental evidence of reversible twinning.

This work presents a single-crystal X-ray diffraction study of an organic co-crystal composed of N-iodosaccharin and pyridine (NISac·py) under hydrostatic pressure ranging from 0.00 (5) GPa to 4.5 (2) GPa. NISac·py crystallizes in the monoclinic system (space group B21/e). The unconventional setting of the space group is adopted (the conventional setting is P21/c, No. 14) to emphasise the strongly pseudo-orthorhombic symmetry of the lattice, with a ß angle very close to 90°. The crystal structure contains one molecule each of N-iodosaccharin (NISac) and pyridine (py) in the asymmetric unit (Z' = 1), linked via an Nsac...I...N'py halogen-bonding motif. A gradual modification of this motif is observed under pressure as a result of changes in the crystalline environment. Mechanical twinning is observed under compression and the sample splits into two domains, spanning an unequal volume that is mapped by a twofold rotation about the [100] direction of the B21/e unit cell. The twinning is particularly significant at high pressure, being reversible when the pressure is released. The structure of the twinned sample reveals the continuity of a substantial substructure across the composition plane. The presence of this common substructure in the two orientations of the twinned individuals can be interpreted as a structural reason for the formation of the twin and is the first observed example in a molecular crystal. These results indicate that the anisotropy of intermolecular interactions in the crystal structure results in an anisotropic strain generated upon the action of hydrostatic compression. Periodic density functional theory calculations were carried out by considering an isotropic external pressure, the results showing good agreement with the experimental findings. The bulk modulus of the crystal was obtained from the equations of state, being 7 (1) GPa for experimental data and 6.8 (5) GPa for theoretical data.