Retrospective Outcomes of a New Acupuncture Service at a Comprehensive Cancer Center.

Introduction: Among cancer centers, patients' interest in acupuncture is growing, in addition to clinical research in the intervention. Their National Cancer Institute-designated comprehensive cancer center piloted an acupuncture service. Their aim was to assess whether acupuncture impacted patient self-reported symptoms as delivered clinically and discuss their implementation strategy. Methods: Patients undergoing acupuncture at a comprehensive cancer center from June 2019 to March 2020 were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS) before and after each session. The authors evaluated symptom changes after acupuncture in both outpatient and inpatient settings. A change of ≥1 U, on the 0-10 scale, was considered clinically significant. Results: Three hundred and nine outpatient and 394 inpatient acupuncture sessions were provided to patients at the comprehensive cancer center during this period, of which surveys from 186 outpatient (34 patients) and 124 inpatient (57 patients) sessions were available for analysis. The highest pretreatment symptoms reported by outpatients were neuropathy (5.78), pain (5.58), and tiredness (5.59). Outpatients receiving acupuncture reported clinically significant improvements in pain (ESAS score change of -2.97), neuropathy (-2.68), decreased lack of well-being (-2.60), tiredness (-1.85), nausea (-1.83), anxiety (-1.56), activities of daily living issues (-1.32), depression (-1.23), anorexia (-1.19), insomnia (-1.14), and shortness of breath (-1.14). The most severe pretreatment symptoms reported by inpatients were pain (6.90), insomnia (6.16), and constipation (5.44). Inpatients receiving acupuncture reported clinically significant improvements in anxiety (-3.69), nausea (-3.61), insomnia (-3.26), depression (-2.98), pain (-2.77), neuropathy (-2.68), anorexia (-2.20), constipation (-1.95), and diarrhea (-1.26). Conclusion: Both outpatient and inpatient participants in this pilot acupuncture program reported clinically significant improvements in symptoms after a single acupuncture treatment. Some differences between the outpatient and inpatient settings warrant further investigation.

Acupuncture in Multidisciplinary Treatment for Post-COVID-19 Syndrome.

Background: Post-COVID syndrome (PCS) is a complex, multisystem illness that may follow SARS-CoV-2/COVID-19 infection. As there is limited evidence for individual therapies and no singular treatment for PCS, guidelines endorse a multidisciplinary approach. This is a case report of a patient with PCS benefiting from a comprehensive approach including acupuncture with symptom-titrated physical activity (STPA). Case: A 50-year-old woman presented from a Long-COVID Clinic referral to an outpatient hospital-affiliated acupuncturist. She had 8 months of fatigue, anosmia, chest pressure, palpitations, and other symptoms following mild assay-confirmed COVID-19. Prior/concurrent medical testing revealed multisystem-inflammatory involvement (pericardial effusion, thyroid dysfunction, and elevated d-dimers). Cardiology/pulmonology cleared the patient for exercise to tolerance considering that serious pathology was absent. The acupuncturist's Traditional Chinese Medicine impression was of Qi Deficiency of the Heart, Lung, Spleen, and Kidney. This patient received 7 sessions of scalp, auricular, and body acupuncture. Physical-therapist (PT)-led STPA began 1-week post-acupuncture, involving 6 30-minute exercise sessions while monitoring her heart rate, with as-needed rest. Results: The patient's chest pressure and palpitations resolved after 1 acupuncture treatment. With 6 additional treatments, spanning 9 weeks, overlapping with PT-led SPTA, she recovered completely and resumed her normal exercise. Conclusions: Acupuncture appeared to facilitate PCS recovery. However, the independent effects of acupuncture are less clear, given the concurrent STPA/exercise therapy, and should be explored using large study designs. Acupuncture is an attractive potential PCS therapy, considering its holistic approach and that it may be added to a multidisciplinary, guideline-concordant regimen.

Threes Company: discovery of a third syntype of Stegonotus lividus, a species of colubrid snake from Pulau Semau, Lesser Sunda Islands, Indonesia, with comments on an unpublished 19th Century manuscript by the naturalist Salomon Mller.

We report on the discovery of a third, male specimen of Stegonotus lividus in the collection of the Musum National dHistoire Naturelle in Paris, France, and demonstrate that it is not only a member of the original type series but the only one of the three syntypes, whose morphology was detailed in the original description. We herein identify it as a paralectotype. In their description of S. lividus, Dumril et al. (1854) attributed authorship of the name to the German zoologist Salomon Mller, whose work was never published. By the rules of zoological nomenclature, author attribution solely via an unpublished manuscript is inadmissible, and the species is therefore properly listed as Stegonotus lividus (Dumril et al., 1854). The recent discovery of Mllers handwritten manuscript, along with an unpublished drawing of one of these snakes by the Dutch artist Pieter van Oort, allows a better assessment of color and pattern for a species that remains known from only three preserved vouchers, as well as improved differentiation from other taxa occurring in the Lesser Sundas and Moluccas.

A new species of Stegonotus (Serpentes: Colubridae) from the remnant coastal forests of southern Timor-Leste.

During the first amphibian and reptile survey of Timor-Leste, we discovered a population of groundsnakes, genus Stegonotus, in the last remnant of lowland coastal forest along the countrys southern coast, which represents a new species. This sexually dimorphic species can be differentiated from all other Wallacean Stegonotus by a combination of 17-17-15 dorsals, ventrals (female 206; males 197207), paired subcaudals (female 61; males 7175), the gull wing + condition of the rostral, large squared prefrontals that each are 2.5 times the area of the internasals and two-thirds the size of the frontal, a snout-scale ratio of near 0.4 and a frontal-parietal suture ratio of ≤ 1.0, a labial scale formula of 73+4 | 94, five gulars separating the posterior genial and the anteriormost ventral, and an overall brown body coloration that lightens progressively from the vertebral scale row in a dorsallateral direction and features color gradients of dark brown posterior edges to lighter brown anterior edges on individual scales. The species is most similar in overall morphology to S. modestus from the central Moluccas and to S. lividus, a species known only from tiny Semau Island that lies off the western end of Timor Island, in close proximity to Kupang, the capital of the Indonesian province of East Nusa Tenggara.

Carefully examining Bornean Stegonotus (Serpentes, Colubridae): the montane groundsnake population in Sabah is a new and distinct species.

During a taxonomic revision of species in the genus Stegonotus Duméril et al., 1854, we re-examined over 90% of all known museum specimens from this taxon. Of the five specimens available to us from the island of Borneo, three are clearly distinct from the other two. The latter are from the lowland rainforest in Sarawak, Malaysia, which includes the type locality of S. borneensis, and therefore these specimens retain that name. We here describe the other three, which include the paratype of S. borneensis, as a new species from Sabah, Malaysia. The new species can be differentiated from S. borneensis and all other species of Stegonotus by the combination of a high number of ventrals ( 210) combined with a low number of subcaudals ( 70), a short tail (indicated by a low subcaudal ratio of 0.25), 17-17-15 dorsal scale rows, a snout-scale ratio of 1/4-1/3, the "gull wing +" condition of the rostral, the number of supralabials touching the eye, and a dorsal color pattern featuring a dark gray-brown head offset from a lighter-brown rest of the body. The number of subcaudals in the holotype of the new species is only 21% of the number of ventrals, the lowest proportion in the genus. The new species is found at elevations above 1000 m in the cool, montane habitats of the Crocker Range and around the foot of Mt. Kinabalu, Southeast Asia's tallest mountain, from where it has been known but taxonomically unrecognized since at least the 1880s.

A new species of Indo-Papuan groundsnake, genus Stegonotus Duméril et al., 1854 (Serpentes, Colubridae), from the Bird's Head Peninsula of West Papua, Indonesia, with comments on differentiating morphological characters.

We describe a new species of Indo-Papuan groundsnake (Stegonotus) from a single adult male specimen collected in 1953 near Kamro, a village in Maybrat Regency, West Papua, Indonesia. The specimen had been considered a member of S. batjanensis, a well-defined species from the northern Maluku Islands over 500 km to the northwest with which it shares the key characteristic of having the 3rd, 4th, and 5th supralabial scales touching the eyes. The new species can be differentiated from S. batjanensis as well as all other species of Stegonotus by having its 5th supralabial scale projecting forward from behind the eye to form a narrow contact zone with the eye. In addition, it is differentiated by the combination of the following characteristics: seven supralabials, the 3rd-5th touching the eye; eight infralabials, the 1st-4th touching the anterior genial; four scales separating the posterior genial and the first gastrostege; dorsal scales in 17 rows, diminishing to 15 posteriorly; a low number of ventrals (181 in the holotype) combined with a high number of subcaudals (105 in the holotype), the latter comprising 37% of the scales on the ventral surface, the highest proportion in the genus. The description of this species is of interest beyond adding to the species diversity of Stegonotus: it allowed us to explore additional characteristics to resolve taxonomic questions in a morphologically conservative genus, it illustrates the need for additional herpetological survey work on the Bird's Head Peninsula, and its initial misidentification serves as a reminder of the continued relevance and importance of natural history collections as repositories for specimens and data that influence our knowledge today by reaching out from the past.

Corrigenda and Addenda to the Article "The taxonomic history of Indo-Papuan groundsnakes, genus Stegonotus Duméril et al., 1854 (Colubridae), with some taxonomic revisions and the designation of a neotype for S. parvus (Meyer, 1874)" by Kaiser et al. (2018).

Kaiser et al. (2018) recently presented a comprehensive history of snakes in the genus Stegonotus Duméril et al., 1854 that included substantial taxonomic revisions. Given the scope and production of this work a few issues remained uncorrected during several proof stages, which we correct herein. Furthermore, after the paper was published some relevant information emerged that we do not want to leave unexposed, and which we hereby add to our discussion.

The taxonomic history of Indo-Papuan groundsnakes, genus Stegonotus Duméril et al., 1854 (Colubridae), with some taxonomic revisions and the designation of a neotype for S. parvus (Meyer, 1874).

Since its conceptualization in 1854, 29 species of the colubrid genus Stegonotus have been recognized or described, of which 15 (admiraltiensis, batjanensis, borneensis, cucullatus, derooijae, diehli, florensis, guentheri, iridis, heterurus, melanolabiatus, modestus, muelleri, parvus, poechi) are still considered valid today. Original species descriptions for the members of this genus were published in Dutch, English, French, German, and Italian and, perhaps as a consequence of these polyglot origins, there has been a considerable amount of confusion over which species names should be applied to which populations of Stegonotus throughout its range across Borneo, the Philippines, Wallacea, New Guinea, Australia, and associated archipelagos. In addition, the terminology used to notate characteristics in the descriptions of these forms was not uniform and may have added to the taxonomic confusion. In this paper, we trace in detail the history of the type specimens, the species, and the synonyms currently associated with the genus Stegonotus and provide a basic, species-specific listing of their characteristics, derived from our examination of over 1500 museum specimens. Based on our data, we are able to limit the distribution of S. modestus to the islands of Ambon, Buru, and Seram in the central Moluccas of Indonesian Wallacea. We correct the type locality of S. cucullatus to the Manokwari area on the Bird's Head Peninsula of West Papua, Indonesian New Guinea and designate a neotype for S. parvus, a species likely to be a regional endemic in the Schouten Archipelago of Cenderawasih Bay (formerly Geelvink Bay), Indonesian New Guinea. We unequivocally identify and explain the problematic localities of the type specimens of S. muelleri and Lycodon muelleri, which currently reside in the same specimen jar. We remove L. aruensis and L. lividum from the synonymy of S. modestus and recognize them as S. aruensis n. comb. and S. lividus n. comb., respectively. We remove S. keyensis and Zamenophis australis from the synonymy of S. cucullatus and recognize them as S. keyensis n. comb. and S. australis n. comb., respectively. We further remove S. reticulatus from the synonymy of S. cucullatus, S. dorsalis from the synonymy of S. diehli, and S. sutteri from the synonymy of S. florensis. We designate lectotypes for S. guentheri, S. heterurus, S. lividus, and S. reticulatus. Lastly, we introduce S. poechi, a valid species not mentioned in the scientific literature since its description in 1924. This brings the diversity in the genus Stegonotus to 22 species. We also caution that in a complex group of organisms like Stegonotus any rush to taxonomic judgment on the basis of molecular and incomplete morphological data sets may perpetuate errors and introduce incongruities. Only through the careful work of connecting type material with museum specimens and molecular data can the taxonomy and nomenclature of complex taxa be stabilized.

Modulating Antibody Structure and Function through Directed Mutations and Chemical Rescue.

Monoclonal antibody therapeutics have revolutionized the treatment of diseases such as cancer and autoimmune disorders, and also serve as research reagents for diverse and unparalleled applications. To extend their utility in both contexts, we have begun development of tunable antibodies, whose activity can be controlled by addition of a small molecule. Conceptually, we envision that incorporating cavity-forming mutations into an antibody can disrupt its structure, thereby reducing its affinity for antigen; addition of a small molecule may then restore the active structure, and thus rescue antigen binding. As a first proof of concept toward implementing this strategy, we have incorporated individual tryptophan to glycine mutations into FITC-E2, an anti-fluorescein single-chain variable fragment (scFv). We find that these can disrupt the protein structure and diminish antigen binding, and further that both structure and function can be rescued by addition of indole to complement the deleted side chain. While the magnitude of the affinity difference triggered by indole is modest in this first model system, it nonetheless provides a framework for future mutation/ligand pairs that may induce more dramatic responses. Disrupting and subsequently rescuing antibody activity, as exemplified by this first example, may represent a new approach to "design in" fine-tuned control of antibody activity for a variety of future applications.

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression.

Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex-interactive compound presents a new mechanism to modulate gene expression.

Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators.

The RAS proteins play a role in cell differentiation, proliferation, and survival. Aberrant RAS signaling has been found to play a role in 30% of all cancers. KRAS, a key member of the RAS protein family, is an attractive cancer target, as frequent point mutations in the KRAS gene render the protein constitutively active. A number of attempts have been made to target aberrant KRAS signaling by identifying small molecule compounds that (1) are synthetic lethal to mutant KRAS, (2) block KRAS/GEF interactions, (3) inhibit downstream KRAS effectors, or (4) inhibit the post-translational processing of RAS proteins. In addition, inhibition of novel targets outside the main KRAS signaling pathway, specifically the cell cycle related kinase PLK1, has been shown have an effect in cells that harbor mutant KRAS. Herein we review the use of various high-throughput screening assays utilized to identify new small-molecule compounds capable of targeting mutant KRAS-driven cancers.

Gaining insights into the small molecule targeting of the G-quadruplex in the c-MYC promoter using NMR and an allele-specific transcriptional assay.

G-quadruplexes (four-stranded DNA secondary structures) are showing promise as new targets for anticancer therapies. Specifically, G-quadruplexes in the proximal promoter region of regulatory genes have the potential to act as silencer elements and thereby turn off transcription. Thus, compounds that are capable of binding to and stabilizing G-quadruplexes would be of great benefit. In this chapter we describe two recent studies from our labs. In the first case, we use NMR to elucidate the structure of a 2:1 complex between a small molecule and the G-quadruplex in the c-MYC promoter. In the second case, we use an allele-specific transcription assay to demonstrate that the effect of a G-quadruplex-interactive compound is mediated directly through the G-quadruplex. Finally, we use this information to propose models for the interaction of various small molecules with the c-MYC G-quadruplex.

Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation.

A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.

Softening the Rule of Five--where to draw the line?

In order to improve the discovery and development of new drugs, a broad effort is being made to assess the 'drug-like' properties of molecules in early stages of the discovery-research process. Although there are numerous approaches to this problem, perhaps the simplest and most widespread one is that developed by Chris Lipinski and his co-workers at Pfizer, which is generally referred either as the Lipinski Rules or the Rule of Five (ROF). The ROF is based on four properties of molecules, namely, molecular weight (MW), log P, number of hydrogen bond donors (HBD), and the number of hydrogen bond acceptors (HBA). A 'flag' is set if the value of a given property exceeds the chosen threshold value for that property-MW 500 Da, log P 5, the number of HBDs 5, and the number of HBAs 10. Each flag corresponds to an ROF violation. The total number of violations is the ROF-Score, which lies between '0' and '4'. Molecules with ROF-Scores greater than one are considered to be marginal for further development. The difficulty with this approach is that two molecules with nearly identical property values can, nonetheless, possess ROF-Scores that can differ by two or more. Thus, one molecule could be considered for further studies while the other, nearly identical molecule (in terms of its four ROF properties), would most likely not be. This problem arises because of the sharp thresholds imposed by the present formulation of the ROF, which is based upon classical sets. In the current work an alternative approach based on the use of utility functions, within the framework of the analytic hierarchy process (AHP), are employed to 'soften' the sharp boundaries inherent in classical sets. This provides a more realistic assessment of compounds in terms of their potential suitability in drug-discovery research programs.

Concise Two-Step Solution Phase Syntheses of four novel Dihydroquinazoline scaffolds.

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble desired diversity and acid treatment enables ring closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring forming transformation.

Chemogenomic analysis identifies Macbecin II as a compound specific for SMAD4-negative colon cancer cells.

The tumor suppressor gene, SMAD4, is mutated in approximately 30% of colon cancers. To identify compounds with enhanced potency on cells with a SMAD4-negative context, we combined genomic and cheminformatic analyses of publicly available data relating to the colon cancer cell lines within the NCI60 panel. Two groups of cell lines were identified with either wild-type or negative SMAD4 status. A cheminformatic analysis of the NCI60 screening data was carried out, which led to the identification of 14 compounds that preferentially inhibited cell growth of the SMAD4-negative cell lines. Using cell viability assays, the effect of these compounds was validated on four colon cancer cell lines: HCT-116 and HCT-15 (SMAD4-expressing), and HT-29 and COLO-205 (SMAD4-negative). Our data identified Macbecin II, a hydroquinone ansamycin antibiotic, as having increased potency in the SMAD4-negative cells compared to SMAD4 wild-type cells. In addition, we showed that silencing of SMAD4 using siRNA in HCT-116 enhanced Macbecin II potency. Our results demonstrate that Macbecin II is specifically active in colon cancer cells having a SMAD4-negative background and thus is a potential candidate for further investigation in a drug discovery perspective.

4-(Piperidin-1-yl)-4H-benzo[b]tetra-zolo[1,5-d][1,4]diazepin-5(6H)-one.

There are two crystallographically unique mol-ecules present in the asymmetric unit of the title compound, C(14)H(16)N(6)O; in both mol-ecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each mol-ecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between mol-ecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N-H⋯O inter-actions and the second formed by C-H⋯O and C-H⋯N inter-actions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between mol-ecule B and symmetry equivalents forms one ring motif by inversion-related N-H⋯O inter-actions and a second ring motif by C-H⋯O inter-actions, which propagate as a single tape parallel with the c axis.