Molecular Tailoring Approach for the Direct Estimation of Individual Noncovalent Interaction Energies in Molecular Systems.

The noncovalent interactions (NCIs) are omnipresent in chemistry, physics, and biology. The study of such interactions offers insights into various physicochemical phenomena. Some indirect approaches proposed in the literature for exploring the NCIs are briefly reviewed in Section 1 of this Perspective. These include: (i) Shift in the stretching frequency of an X-Y bond involved in X-Y···Z interaction. (ii) Topological analysis of molecular electron density. (iii) Empirical equations derived employing experimental and theoretical quantities. However, a direct method for estimating individual intramolecular/intermolecular interaction energies has been conspicuous by its absence from the literature. We have developed a molecular tailoring approach (MTA)-based method enabling a direct and reliable estimation of the energy of intra- as well as intermolecular interactions. This method offers a direct and reliable estimation of these interactions, in particular of the hydrogen bonds (HB) in molecules/weakly bound clusters along with the respective cooperativity contribution. In Section 2, the basis of our method is discussed, along with some illustrative examples. The application of this method to a variety of molecules and clusters, with a special emphasis on estimating the HB energy along with the energy of other NCIs is presented in Section 3. Section 4 discusses some computational strategies for applying our method to large molecular clusters. The last Section provides a summary and a discussion on future developments.

First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors.

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy. RESULTS: Forty-eight patients were enrolled (dose escalation, n = 40; dose expansion, n = 8). MTD was not reached; DRDE was 12 mg daily. DLTs were palmar-plantar erythrodysesthesia syndrome (8 mg, n = 1) and hypertension (15 mg, n = 2). The most common treatment-related adverse event was hypertension (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; n = 7) or stable disease (SD) ≥ 24 weeks (n = 6), including 4/11 (36.4%) with FGFR2 mutations/fusions and cholangiocarcinoma (PR n = 3; SD ≥ 24 weeks n = 1), 3/3 (100.0%) with hormone receptor (HR)-positive/HER2-negative breast cancer (PR n = 2; SD ≥ 24 weeks n = 1), 2/5 (40.0%) with triple-negative breast cancer (TNBC; PR n = 1; SD ≥ 24 weeks n = 1), and 1/1 (100.0%) with castrate-resistant prostate cancer (CRPC; PR). Four of 12 patients (33.3%; HR-positive/HER2-negative breast cancer, TNBC, prostate cancer, and cholangiocarcinoma) treated at DRDE had PRs. Tinengotinib's half-life was 28-34 hours. CONCLUSIONS: Tinengotinib was well tolerated with favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit in FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative breast cancer (including TNBC), and CRPC. Continued evaluation of tinengotinib is warranted in phase II trials.

Hydrogen bond energy estimation (H-BEE) in large molecular clusters: A Python program for quantum chemical investigations.

A procedure, derived from the fragmentation-based molecular tailoring approach (MTA), has been proposed and extensively applied by Deshmukh and Gadre for directly estimating the individual hydrogen bond (HB) energies and cooperativity contributions in molecular clusters. However, the manual fragmentation and high computational cost of correlated quantum chemical methods make the application of this method to large molecular clusters quite formidable. In this article, we report an in-house developed software for automated hydrogen bond energy estimation (H-BEE) in large molecular clusters. This user-friendly software is essentially written in Python and executed on a Linux platform with the Gaussian package at the backend. Two approximations to the MTA-based procedure, viz. the first spherical shell (SS1) and the Fragments-in-Fragments (Frags-in-Frags), enabling cost-effective, automated evaluation of HB energies and cooperativity contributions, are also implemented in this software. The software has been extensively tested on a variety of molecular clusters and is expected to be of immense use, especially in conjunction with correlated methods such as MP2, CCSD(T), and so forth.

Green Synthesis of Electrophilic Alkenes Using a Magnesium Catalyst under Aqueous Conditions and Mechanistic Insights by Density Functional Theory.

A green approach for the synthesis of electrophilic alkenes has been developed via Knoevenagel condensation between active methylene compounds and carbonyl compounds using Mg powder under aqueous conditions. In this strategy, Mg(OH)2 acts as a catalyst, which was generated in situ by the reaction between metallic Mg (20 mol %) and water. Mg was found to be an efficient, nontoxic, and inexpensive metal catalyst system for producing a range of electrophilic alkenes in excellent yields (≤98%). A gram-scale synthesis of electrophilic alkenes has been developed, and Mg metal was recovered and recycled up to three times without an appreciable loss of catalytic activity. A catalytic cycle was proposed, and the reaction mechanism was investigated using density functional theory. The key steps are enolization of ethyl cyanoacetate, C-C bond formation, and then regeneration of the catalyst via metathesis with H2O. The overall reaction occurs easily with a maximum ΔG°â§§ value of 7.9 kcal/mol for the rate-determining C-C bond formation step. Our protocol has several advantages and can be further extended to one-pot sequential Knoevenagel condensation and Michael addition, and one-pot sequential Knoevenagel condensation and chemoselective reduction can be used for the synthesis of valuable precursors of pharmaceutical products under green and aqueous conditions.

Interplay of Hydrogen, Pnicogen, and Chalcogen Bonding in X(H2O)n=1-5 (X = NO, NO+, and NO-) Complexes: Energetics Insights via a Molecular Tailoring Approach.

Nitric oxide (NO) and its redox congeners (NO+ and NO-), designated as X, play vital roles in various atmospheric and biological events. Understanding the interaction between X and water is inevitable to explain the different reactions that occur during these events. The present study is a unified attempt to explore the noncovalent interactions in microhydrated networks of X using the MP2/aug-cc-pVTZ//MP2/6-311++G(d,p) level of theory. The interactions between X and water have been probed by the molecular electrostatic potential (MESP) by exploiting the features of the most positive (Vmax) and most negative potential (Vmin) sites. The individual energy and cooperativity contributions of various types of noncovalent interactions present in X(H2O)n=1-5 complexes are estimated with the help of a molecular tailoring-based approach (MTA-based). The MTA-based analysis reveals that among various possible interactions in NO(H2O)n complexes, the water···water hydrogen bonds (HBs) are the strongest. Neutral NO can form hydrogen and pnicogen bonds (PBs) with water depending on the orientation; however, such HBs and PBs are the weakest. On the other hand, in the NO+(H2O)n complexes, the NO+···water interactions that occur through PBs are the strongest; the next one is the chalcogen bonding (CB), and the water···water HBs are the weakest. In the case of the NO-(H2O)n complexes, the HB interactions via both N and O atoms of NO- and water molecules are the strongest ones. The strength of water···water HB interactions is also seen to increase with the increase in the number of water molecules in NO-(H2O)n. The present study exemplifies the applicability of MTA-based calculations for quantifying various types of individual noncovalent interactions and their interplay in microhydrated networks of NO and its related ions.

De novo design of anti-variant COVID-19 vaccine.

Recent studies highlight the effectiveness of hybrid Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) vaccines combining wild-type nucleocapsid and Spike proteins. We have further enhanced this strategy by incorporating delta and omicron variants' spike protein mutations. Both delta and omicron mark the shifts in viral transmissibility and severity in unvaccinated and vaccinated patients. So their mutations are highly crucial for future viral variants also. Omicron is particularly adept at immune evasion by mutating spike epitopes. The rapid adaptations of Omicron and sub-variants to spike-based vaccines and simultaneous transmissibility underline the urgency for new vaccines in the continuous battle against SARS-CoV-2. Therefore, we have added three persistent T-cell-stimulating nucleocapsid peptides similar to homologous sequences from seasonal Human Coronaviruses (HuCoV) and an envelope peptide that elicits a strong T-cell immune response. These peptides are clustered in the hybrid spike's cytoplasmic region with non-immunogenic linkers, enabling systematic arrangement. AlphaFold (Artificial intelligence-based model building) analysis suggests omitting the transmembrane domain enhances these cytoplasmic epitopes' folding efficiency which can ensure persistent immunity for CD4+ structural epitopes. Further molecular dynamics simulations validate the compact conformation of the modeled structures and a flexible C-terminus region. Overall, the structures show stability and less conformational fluctuation throughout the simulation. Also, the AlphaFold predicted structural epitopes maintained their folds during simulation to ensure the specificity of CD4+ T-cell response after vaccination. Our proposed approach may provide options for incorporating diverse anti-viral T-cell peptides, similar to HuCoV, into linker regions. This versatility can be promising to address outbreaks and challenges posed by various viruses for effective management in this era of innovative vaccines.

Palladium(II)-Catalyzed Decarboxylative Difunctionalization of Alkynoic Acids To Access (E)-ß-Sulfonylacrylamides and DFT Study.

A palladium(II)-catalyzed regio- and stereoselective difunctionalization of alkynoic acids has been achieved using sodium sulfinates and isocyanides to synthesize (E)-ß-sulfonylacrylamides. The reaction proceeds via decarboxylative isocyanide addition, followed by sulfonylation. This three-component process works well with aromatic, heteroaromatic, and aliphatic alkynoic acids with good functional group tolerance and excellent regio- and stereoselectivity. DFT calculations were carried out to explain the reaction mechanism and the stereoselective formation of (E)-ß-sulfonylacrylamides.

The Cholangiocarcinoma in the Young (CITY) Study: Tumor Biology, Treatment Patterns, and Survival Outcomes in Adolescent Young Adults With Cholangiocarcinoma.

PURPOSE: Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS: A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS: Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation (P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION: Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Clinical Profiles of Children With Sickle Cell Anaemia Presenting With Acute Clinical Events: A Single-Center Study.

BACKGROUND: Sickle cell disease is a common genetic disorder characterised by chronic haemolytic anaemia and vaso-occlusive crisis. Sickle cell anaemia (SCA) has both short-term effects in the form of acute clinical events and long-term repercussions seen with chronic multiorgan involvement. It is associated with significant morbidity and mortality. In India, the disease is largely undocumented. Thus, there is an urgent need to highlight the features of the disease so that locally appropriate models of care may be implemented. OBJECTIVE: This study aims to evaluate acute clinical events in SCA and to provide data that may help to reduce the rate of morbidity and mortality associated with this disease by early interventions. MATERIALS AND METHODS: A cross-sectional observational study was conducted between November 2020 and May 2022 at Indira Gandhi Government Medical College and Hospital, Nagpur, Central India. The inclusion criteria included previously diagnosed patients of SCA (homozygous sickle cell disease) on high-performance liquid chromatography (HPLC) between the age groups of six months and 12 years, presenting with acute clinical events. The exclusion criteria included patients younger than six months and older than 12 years of age, and all patients with other haemoglobinopathies and sickle cell trait. The study was approved by the Institutional Ethical Committee. All the data was entered into a well-designed Microsoft Office Excel spreadsheet (v 2019, Microsoft, Washington, USA). All the clinical, biochemical, and haematological data were tabulated and analysed. RESULTS: A total of 100 children with sickle cell disease diagnosed by HPLC were enrolled during the study period. About 215 acute clinical events among the 100 cases were recorded, for which they were admitted to the paediatric ward or PICU. The majority (35%, n=35) were seen in the age group of six to nine years (school-going age). About 52% were male and 48% were female (male-to-female ratio= 1.08:1). Pain was the most common symptom. The highest incidence of 36.75% (n=79) was seen with acute painful crises and was the most common indication of hospitalisation, followed by acute febrile illness (AFI) (34.42%, n=74), aplastic crisis (10.23%, n=22), splenic sequestration crisis (9.77%, n=21), hepatobiliary involvement (3.72%, n=8), acute chest syndrome and haemolytic crisis (each 1.86%, n=4), and stroke (1.40%, n=3). In cases of having foetal haemoglobin (HbF) ≥20%, the incidence of acute painful crisis (p=0.0001), hand-foot syndrome (p=0.047), aplastic crisis (p=0.033), splenic sequestration crisis (p=0.039), and AFI (p=0.035) was low as compared to cases having HbF ≤20% which was statistically significant. The incidence of acute painful crisis, hand-foot syndrome, and an aplastic crisis was significantly low in patients receiving hydroxyurea therapy as compared to patients who were not on hydroxyurea. Out of 100 cases, four died during the study period, three died because of splenic sequestration crisis with septic shock, and one died due to hepatic encephalopathy due to haemolytic crisis with septic shock. CONCLUSION: Acute clinical events in sickle cell disease can have significant morbidity and mortality in the paediatric age group. The nutritional status of sickle cell disease children must be given due importance. Early initiation of hydroxyurea must be encouraged to maintain higher HbF levels, which plays a significant role in reducing morbidity.

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain.

BACKGROUND AND PURPOSE: Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. EXPERIMENTAL APPROACH: To identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species, and imputed commonalities, as well as differences in cellular pathways and gene regulation. KEY RESULTS: We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signalling nodes. We investigated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor spleen associated tyrosine kinase (Syk), which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406 and another Syk inhibitor P505-15, significantly reversed pain hypersensitivity in both sexes. CONCLUSIONS AND IMPLICATIONS: Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.

NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma (IHCC) develop recurrence after resection. Adjuvant capecitabine remains the standard of care for resected IHCC. A combination of gemcitabine, cisplatin, and nab-paclitaxel (GAP) was associated with a 45% response rate and 20% conversion rate among patients with unresectable biliary tract cancers. The aim of this study was to evaluate the feasibility of delivering GAP in the neoadjuvant setting for resectable, high-risk IHCC. METHODS: A multi-institutional, single-arm, phase II trial was conducted for patients with resectable, high-risk IHCC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Patients received preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) for a total of 4 cycles prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of both preoperative chemotherapy and surgical resection. Secondary endpoints were adverse events, radiologic response, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection. CONCLUSION: Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Comparison of Baska Mask Versus Proseal Laryngeal Mask Airway in Elective Surgeries Under General Anaesthesia: A Randomized Clinical Trial.

Background Baska Mask (BM) is a third-generation supraglottic airway device with a self-inflating cuff. This study aimed to evaluate the efficacy of the BM compared to ProSeal laryngeal mask airway (PLMA) regarding insertion time, ease of insertion, and oropharyngeal seal pressure in patients undergoing elective surgeries under general anesthesia for less than two hours. Methods This prospective, randomized, double-blind comparative study was done on 64 patients randomly divided into two groups, with 32 patients in the PLMA group (Group A) and 32 in the BM group (Group B). Individuals with a body mass index (BMI) of more than 30, a history of nausea/vomiting, or pharyngeal pathology were excluded from the trial. After induction with propofol 3-4 mg/kg, fentanyl 1-2 mcg/kg, and the neuromuscular blockade was achieved with atracurium 0.5 mg/kg, patients were inserted with either BM (n= 32) or PLMA (n= 32). The primary outcome measure was the time taken for insertion and ease of insertion. Secondary outcome measures included the number of attempts, oropharyngeal seal pressure (OSP), and laryngopharyngeal morbidity (trauma to lips, blood staining, and sore throat) immediately and 24 hours postoperatively. Results Demographic data were comparable and statistically insignificant. Regarding time and ease of insertion, the BM could be inserted in a lesser time of 24±1.136 seconds compared to PLMA which took 28.59±1.682 seconds, with a high success rate in the first attempt which was statistically significant. The BM provided a higher OSP (31.34 +1.638 cmH2O) when compared to PLMA (24.81±1.469 cmH2O) and was statistically significant. Complications associated with insertion trauma to the lip, blood staining, and sore throat were more in PLMA (15.6%, 15.6 %, 9.4%, respectively) compared to the BM (6.3%, 3.1%, 3.1%, respectively), and statistically insignificant. Conclusion  BM had higher first-attempt successful insertion with better OSP compared to PLMA in patients under controlled ventilation.

On the Short-Range Nature of Cooperativity in Hydrogen-Bonded Large Molecular Clusters.

The variation in the hydrogen bond (HB) strength has considerable consequences on the physicochemical properties of molecular clusters. Such a variation mainly arises due to the cooperative/anti-cooperative networking effect of neighboring molecules connected by HBs. In the present work, we systematically study the effect of neighboring molecules on the strength of an individual HB and the respective cooperativity contribution toward each of them in a variety of molecular clusters. For this purpose, we propose a use of a small model of a large molecular cluster called the spherical shell-1 (SS1) model. This SS1 model is constructed by placingg the spheres of an appropriate radius centered on X and Y atoms of the X-H···Y HB under consideration. The molecules falling within these spheres constitute the SS1 model. Utilizing this SS1 model, the individual HB energies are calculated within the molecular tailoring approach-based framework and the results are compared with their actual counterparts. It is found that the SS1 is a reasonably good model of large molecular clusters, providing 81-99% of the total HB energy estimated using the actual molecular clusters. This in turn suggests that the maximum cooperativity contribution toward a particular HB is due to the fewer number of molecules (in the SS1 model) directly interacting with two molecules involved in its formation. We further demonstrate that the remaining part of the energy or cooperativity (∼1 to 19%) is captured by the molecules falling in the second spherical shell (SS2) centered on the hetero-atom of the molecules in the SS1 model. The effect of increasing size of a cluster on the strength of a particular HB, calculated by the SS1 model, is also investigated. The calculated value of the HB energy remains unchanged with the increase in the size of a cluster, emphasizing the short-ranged nature of the HB cooperativity in neutral molecular clusters.

Fragments-in-fragments method for efficient and reliable estimates of individual hydrogen bond energies in large molecular clusters.

The knowledge of individual hydrogen bond (HB) strength in molecular clusters is indispensable to get insights into the bulk properties of condensed systems. Recently, we have developed the molecular tailoring approach based (MTA-based) method for the estimation of individual HB energy in molecular clusters. However, the direct use of this MTA-based method to large molecular clusters becomes progressively difficult with the increase in the size of a cluster. To overcome this caveat, herein, we propose the use of linear scaling method (such as the original MTA method) for the estimation of single-point (SP) energies of large-sized parent molecular cluster and their respective fragments. Because the fragments of the MTA-based method, for the estimation of HB energy, are further fragmented, this proposed strategy is called as Fragments-in-Fragments (Frags-in-Frags) method. The SP energies of fragments and parent cluster calculated by the Frags-in-Frags approach were utilized to estimate the individual HB energy. The estimated individual HB energies, in various molecular clusters, by Frags-in-Frags method are found to be in excellent linear agreement with their MTA-based counterparts (R2 = 0.9975 of 348 data points). The difference being less than 0.5 kcal/mol in most of the cases. Furthermore, RMSD is 0.43 kcal/mol, MAE is 0.33 kcal/mol, and the standard deviation is 0.44 kcal/mol. Importantly, the Frags-in-Frags method not only enables the reliable estimation of HB energy in large molecular clusters but also requires less computational time and can be possible even with off-the-shelf hardware.

Molecular profiling and treatment pattern differences between intrahepatic and extrahepatic cholangiocarcinoma.

BACKGROUND: Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. METHODS: This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. RESULTS: Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P < .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P < .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P < .001). CONCLUSIONS: Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

Effects of a Pragmatic Home-based Exercise Program Concurrent With Neoadjuvant Therapy on Physical Function of Patients With Pancreatic Cancer: The PancFit Randomized Clinical Trial.

OBJECTIVE: To determine the effects of a preoperative, home-based exercise program on fitness and physical function in patients with pancreatic cancer. BACKGROUND: We previously established a well-tolerated preoperative exercise program after finding a high frequency of sarcopenia and frailty in patients with pancreatic cancer. METHODS: In this randomized, controlled trial (NCT03187951), patients with pancreatic cancer were randomized to Arm A: enhanced usual care or Arm B: prescribed aerobic and resistance exercise during neoadjuvant therapy. Patients received nutrition counseling and activity trackers. The primary endpoint was a 6-minute walk distance (6MWD; ≥14 meters improvement was clinically meaningful). Secondary endpoints included additional physical function tests, health-related quality of life, and clinical outcomes. RESULTS: One hundred fifty-one patients were randomized. Objectively measured weekly activity (153.2±135.6 and 159.8±122.8 min in Arm A and B, respectively, P =0.62) and self-reported weekly moderate-to-strenuous physical activity (107.4±160.4 and 129.6±161.6 min in Arm A and Arm B, respectively, P =0.49) were similar, but weekly strength training sessions increased more in Arm B (by 1.8±1.8 vs 0.1±2.4 sessions, P <0.001). 6MWD improved in both Arm A (mean change 18.6±56.8 m, P =0.01) and Arm B (27.3±68.1 m, P =0.002). Quality of life and clinical outcomes did not significantly differ between arms. Pooling patients in both study groups, exercise, and physical activity was favorably associated with physical performance and clinical outcomes. CONCLUSIONS: In this randomized trial of prescribed exercise versus enhanced usual care during neoadjuvant therapy for pancreatic cancer, a high volume of physical activity and increased exercise capacity were observed in both arms, highlighting the importance of activity among patients preparing for surgery.

A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors.

BACKGROUND: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. METHODS: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m2 ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. RESULTS: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. CONCLUSION: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.

Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers. APPROACH AND RESULTS: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%). CONCLUSIONS: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.

Characterization of non-covalent contacts in mono- and di-halo substituted acetaldehydes: probing the substitution effects of electron donating and withdrawing groups.

In the current work, a systematic evaluation of the different types of non-covalent interactions (NCIs) in acetaldehyde dimers, including dimers of mono-halo (XCH2CHO)2, di-halo (X2CHCHO)2 and tri-halo substituted (X3CCHO)2 acetaldehydes via the associated stabilization energy of these dimers has been performed. Furthermore, a topological analysis of the electron density based on the quantum theory of atoms in molecules (QTAIM) and non-covalent interaction reduced density gradient (NCI-RDG) isosurfaces has also been performed to evaluate the nature of these NCIs. The geometrical and electronic characteristics have been evaluated via the presence of different electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) or substituents in dimers of these molecules, namely, XCH(Y)CHO and X2C(Y)CHO (wherein X = -F, -Cl, and -Br and Y = -SO3H, -CN, -NO2, -NH2, -CH3, -OCH3, and -SMe3). The C-H⋯O, C-H⋯X, X⋯X, X⋯O and C⋯O tetrel bonded contacts have been recognized to play an important role in the stabilization of the formed dimers. This study also establishes the fact that the overall stability of the dimeric assemblies is governed by the contributions from the mutual and complex interplay of a variety of interactions in the investigated dimers. Hence considerations based on strong H-bond donor-acceptor characteristics hold relevance for simple systems only, but slight alteration in the electronic environment can affect the overall stabilization energies of the system being investigated and the nature of the interactions that contribute towards the same.