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ABSTRACT Background Intensified systemic chemotherapy following minimally invasive surgery for patients with unresectable metastatic colorectal cancer is performed to achieve curative resection and improve quality of life. We report a case of initially unresectable rectal cancer with metastases treated with laparoscopic and thoracoscopic staged resections after triplet chemotherapy plus bevacizumab. Case A 71‐year‐old man was referred to our hospital to examine the cause of constipation. A circumferential adenocarcinoma with extramural invasion and lateral lymphadenopathy was identified in the lower rectum with simultaneous metastatic liver and lung tumors. Intensified triplet chemotherapy plus bevacizumab was conducted to treat oncologically unresectable rectal cancer to avoid positive radial margins during surgical resection. Eleven cycles of chemotherapy resulted in regression of the tumors with metastases. Laparoscopic low anterior resection with lateral lymph node dissection was performed. Three months later, laparoscopic liver resection of the posterosuperior segment was performed without complications. Finally, the patient underwent thoracoscopic‐assisted pulmonary segmentectomy of the right basal lobe. All resected tumors had negative surgical margins, and the patient has been surviving without adjuvant chemotherapy. Conclusion Minimally invasive staged resection and intensified chemotherapy for the treatment of initially unresectable metastatic colorectal cancer should be performed by a skilled surgical team in coordination with a multidisciplinary team.

Actinomycetes are well-known as the main producers of bioactive compounds such as antibiotics, anticancers, and immunosuppressants. Screening of natural products from actinomycetes has been an essential part of several drug discovery programs. Finding such novel biologically active metabolites is immensely important because of their beneficial health effects. Recently, the discovery of new compounds has diverted attention to rare actinomycetes, since they are rich sources of natural products. In this study, a collection of rare actinomycetes at Kitasato University has been screened for potential novel compound producers. Among the rare actinomycetes, Saccharopolyspora sp. KR21-0001 isolated from soil on Ōha Island, Okinawa, Japan was selected as a potential producer. The strain was cultured in 20 L of production medium in a jar fermenter and the culture broth was extracted. Further purification revealed the presence of a new compound designated KR21-0001A (1). The structure was elucidated by NMR, and the absolute stereochemistry was determined by advanced Marfey’s method. The results indicated that 1 is a new analog of dihydroxybenzoic acid. 1 has no antimicrobial activity against bacteria and fungi but showed potent antioxidant activity.

Effective antivirals are critical for combatting SARS-CoV-2 infections. Here, the authors develop two orally available small molecules, which specifically inhibit the activity of the SARS-CoV-2 main protease and potently block the infectivity and replication of various SARS-CoV-2 strains in cells and mice.

Abstract One new furanocembranoid diterpene, 11-hydroxy-Δ12(13)-pukalide (1), along with six known secondary metabolites, 11-acetoxy-Δ12(13)-pukalide (2), 13α-acetoxypukalide (3), pukalide (4), 3α-methoxyfuranocembranoid (5), Δ9(15)-africanene (6), and methyl (5′E)-5-(2′,6′-dimethylocta-5′,7′-dienyl)furan-3-carboxylate (7) were isolated from the Okinawan soft coral Sinularia sp. Their chemical structures were elucidated based on spectroscopic analysis (FTIR, NMR, and HRESIMS), and the relative stereochemistry of 1 was determined by NOESY experiments and acetylation, which yielded derivative 2. In addition, compounds 1 and 7 exhibited toxicity in the brine shrimp lethality test. Graphical Abstract

Abstract Subcutaneous insulin resistance syndrome is a rare condition that causes difficulty in glycemic control due to severe resistance to subcutaneous insulin injections. We herein present a case of a 40‐year‐old woman with type 2 diabetes mellitus who had been diagnosed with subcutaneous insulin resistance syndrome since the age of 29 years, and had been persistently treated with continuous subcutaneous insulin infusion using a mixture of insulin lispro and heparin. The patient was switched from insulin lispro plus heparin to ultra‐rapid insulin lispro; given that it contains treprostinil and citrate, it is expected to have similar effects as heparin, and shows similar glucose‐lowering effects and insulin absorption. Our results suggest that treatment with ultra‐rapid insulin lispro is effective for subcutaneous insulin resistance syndrome.

Abstract We examined the chemical constitution of the red alga Laurencia saitoi Perestenko, collected from Katsuura, Boso Peninsula, Chiba Prefecture, Japan. This specimen produced a new polyhalogenated acetogenin, named katsuurallene (1), which structure was determined by the spectral methods, along with known diterpene, deoxyparguerol (2) and triterpene, thyrsiferol (3). In this paper we describe the structural elucidation of katsuurallene together with some biological activities.

Abstract This paper presents a case with type 2 diabetes mellitus on a very‐low‐carbohydrate diet who developed euglycemic diabetic ketoacidosis (EDKA) 3 days after starting sodium‐glucose cotransporter 2 inhibitors (SGLT2i). When initiating SGLT2i, healthcare providers should confirm the implementation of a low‐carbohydrate diet and provide intensive guidance to prevent EDKA.

Abstract Cathode materials are essential for enhancing electrocatalytic activity in energy-conversion devices. Carbon is one of the most suitable cathodic materials for Li–O2 batteries owing to its chemical and thermal stability. Carbon materials synthesized from tributyl borate (TBB) using a nonthermal solution plasma method were characterized using x‐ray diffraction, Raman, field emission scanning electron microscopy (FE-SEM), transmission electron microscopy, and x-ray photoelectron spectroscopy and were evaluated as additive materials for cathodes in a Li–O2 battery. Two separate carbon materials were formed at the same time, a carbon dispersed in solution and a carbon precipitate at the bottom of the reactor, which had amorphous and graphite-like structures, respectively. The amorphous carbon contained boron and tungsten carbide, and the graphite-like carbon had more defects and electronic conductivity. The crystallinity and density of defects in the graphite-like carbon could be tuned by changing the SP operating frequency. The Li–O2 battery with the amorphous carbon containing boron and tungsten carbide was found to have a high capacity, while the one with the graphite-like carbon showed an affinity for the formation of Li2O2, which is the desired discharge product, and exhibited high cycling performance.

Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent in vitro and in vivo studies have raised serious concerns regarding the efficacy and safety of the “shock and kill” strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency in vitro when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity in vitro and in vivo. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.

In order to realize a high speed and high space use efficiency transportation system in a vertical plane, authors conceived a concept to compose the system by multiple vertical rails and multiple self-propelled loading platforms so that such platforms can independently move along each rail and transfer between them. This paper focuses on the design of drive mechanism for such a self-propelled loading platform utilizing the friction force between the rail and the driving wheels. In order to enable to generate a large grip force enough to support and move the platform with payload without using additional actuators while flat rails with small unevenness and gaps are used, the following three principles of operation are applied: the friction drive wheels with less vibration and noise, grip force generation using self-servo effect, and wheel load equalizing based on the rocker-bogie. Through the kineto-static analysis of the proposed mechanism, the relationship between the design parameters such as the angle of the self-servo link and the dimensions of the wheel load equalizer link, operating conditions such as the loading weight, the eccentricity of the center of gravity, and the inclination of the body, and the grip force and the wheel load is studied, and the design parameters and their tendency which enable to run vertically have been clarified. Furthermore, based on the knowledge obtained through the analysis, a prototype was designed, and the stable and high-speed vertical running and running over unevenness and gap has been successfully achieved. From the above, it was shown that the design of drive mechanism based on the principle proposed in this paper was effective as the mechanism that can run on flat vertical rail.

Background: The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial. Methods: This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS). Results: A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 versus 2.0 months) and OS (median 12.9 versus 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 versus 1.8 months) and a trend of longer OS (median 3.9 versus 6.1 months) in patients with ⩾2 of these factors. Conclusions: Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.

Several bacterial strains, including probiotic strains, have undergone evaluations for their safety and potential beneficial health effects. Some of these strains have been introduced into various markets, including that for infant products. However, certain probiotic strains have been linked to serious infections in infants, such as septicemia and meningitis. Given this, it is crucial to assess the safety of each probiotic strain, including those of Bifidobacterium, which is a common genus of probiotics. One such strain, Bifidobacterium bifidum OLB6378 (NITE BP-31), referred to as OLB6378 hereafter, has been selected for use in infants. To determine its genotoxicity and general toxicity potential, a heat-treated OLB6378 concentrate was subjected to various tests, including the bacterial reverse mutation test, in vitro chromosome aberration test, in vivo micronucleus test, and single- and 90-day oral gavage toxicity studies in rats. No significant differences were observed compared with negative controls in any of genotoxicity tests. The single-dose toxicity study employed dose levels of 560, 1,693, and 5,092 mg/kg, representing the total solid contents of culture concentrates containing OLB6378 (equivalent to 8.1 × 1011, 2.4 × 1012, and 7.4 × 1012 cells/kg of Bifidobacterium, respectively). In the 90-day toxicity study, dose levels of 280, 853, and 2,546 mg/kg/day were used (equivalent to 4.0 × 1011, 1.2 × 1012, and 3.7 × 1012 cells/kg/day, respectively). Importantly, the heat-treated OLB6378 concentrate did not induce any signs of toxicity in any of the conducted toxicity studies. In conclusion, the heat-treated OLB6378 concentrate exhibited no genotoxicity potential, and the no-observed-adverse-effect level in the 90-day toxicity study was determined to be 2,546 mg/kg/day (equivalent to 3.7 × 1012 cells/kg/day). This suggests that heat-treated OLB6378 can be safely utilized as a food source. [ABSTRACT FROM AUTHOR]

Members of the marine soft coral genus Xenia are rich in a diversity of diterpenes. A total of 199 terpenes consisting of 14 sesquiterpenes, 180 diterpenes, and 5 steroids have been reported to date. Xenicane diterpenes were reported to be the most common chemical skeleton biosynthesized by members of this genus. Most of the literature reported the chemical diversity of Xenia collected from the coral reefs in the South China Sea and the coastal waters of Taiwan. Although there was a brief review on the terpenoids of Xenia in 2015, the present review is a comprehensive overview of the structural diversity of secondary metabolites isolated from soft coral genus Xenia and their potent biological activity as reported between 1977 to 2019.

Okinawa propolis (OP) and its major ingredients were reported to have anti-cancer effects and lifespan-extending effects on Caenorhabditis elegans through inactivation of the oncogenic kinase, p21-activated kinase 1 (PAK1). Herein, five prenylated flavonoids from OP, nymphaeol-A (NA), nymphaeol-B (NB), nymphaeol-C (NC), isonymphaeol-B (INB), and 3′-geranyl-naringenin (GN), were evaluated for their anti-inflammatory, anti-diabetic, and anti-Alzheimer’s effects using in vitro techniques. They showed significant anti-inflammatory effects through inhibition of albumin denaturation (half maximal inhibitory concentration (IC50) values of 0.26–1.02 µM), nitrite accumulation (IC50 values of 2.4–7.0 µM), and cyclooxygenase-2 (COX-2) activity (IC50 values of 11.74–24.03 µM). They also strongly suppressed in vitro α-glucosidase enzyme activity with IC50 values of 3.77–5.66 µM. However, only INB and NA inhibited acetylcholinesterase significantly compared to the standard drug donepezil, with IC50 values of 7.23 and 7.77 µM, respectively. Molecular docking results indicated that OP compounds have good binding affinity to the α-glucosidase and acetylcholinesterase proteins, making non-bonded interactions with their active residues and surrounding allosteric residues. In addition, none of the compounds violated Lipinski’s rule of five and showed notable toxicity parameters. Density functional theory (DFT)-based global reactivity descriptors demonstrated their high reactive nature along with the kinetic stability. In conclusion, this combined study suggests that OP components might be beneficial in the treatment of inflammation, type 2 diabetes mellitus, and Alzheimer’s disease.

Sea cucumbers have long been utilized in foods and Asiatic folk medicines for their nutritive and health benefits. Herein, three sea cucumber species were investigated and Holothuria atra showed the highest cytotoxicity among these. Next, a desulfated saponin, desulfated echinoside B (DEB), was purified from H. atra through bioassay-guided fractionation. LC-ESI-MS (Liquid chromatography-electrospray ionization mass spectrometry) analysis also showed H. atra to be a rich source of saponins. DEB showed cytotoxicity on cancer cells with IC50 values of 0.5–2.5 µM, and on brine shrimps with an IC50 value of 9.2 µM. In molecular docking studies, DEB was found to bind strongly with the catalytic domain of PAK1 (p21-activated kinase 1) and it showed binding energy of −8.2 kcal/mol compared to binding energy of −7.7 kcal/mol for frondoside A (FRA). Both of them bind to the novel allosteric site close to the ATP-binding cleft. Molecular dynamics (MD) simulation demonstrated that DEB can form a more stable complex with PAK1, remaining inside the allosteric binding pocket and forming the maximum number of hydrogen bonds with the surrounding residues. Moreover, important ligand binding residues were found to be less fluctuating in the DEB-PAK1 complex than in the FRA-PAK1 complex throughout MD simulation. Our experimental and computational studies showed that both DEB and FRA can act as natural allosteric PAK1 inhibitors and DEB appeared to be more promising than FRA.

A new cembrane diterpene, 6-acetoxy-7,8-epoxynephthenol acetate (1) was isolated along with a known compound, epoxynephthenol acetate (2), from the organic extract of a Bornean soft coral Nephthea sp. Their structures were elucidated on the basis of spectroscopic analyses and comparison with those previous literature data.

In our continuous interest to study the diversity of halogenated metabolites of Malaysian species of the red algal genus Laurencia, we examined the chemical composition of five populations of unrecorded Laurencia sp. A new brominated diterpene, 10-acetoxyangasiol (1), and four other known metabolites, aplysidiol (2), cupalaurenol (3), 1-methyl-2,3,5-tribromoindole (4), and chamigrane epoxide (5), were isolated and identified. Isolated metabolites exhibited potent antibacterial activities against clinical bacteria, Staphylococcus aureus, Staphylococcus sp., Streptococcus pyogenes, Salmonella sp. and Vibrio cholerae.

A new germacrane-type norsesquiterpenoid, 1-acetoxy-germacra-5E,10(14)-diene-4-one (1), as well as three known compounds, were isolated from the organic extracts of a Bornean soft coral Nephthea sp. Their structures were elucidated on the basis of spectroscopic data analysis.

A new 4α-methyl sterol, 4α-methyl-ergosta-6,8(14),22E-triene-3β-ol (1), was isolated along with cholesterol from a Nephthea sp. Bornean soft coral The structure of compound 1 was elucidated on the basis of spectroscopic analysis and comparison of the data with those of the related compounds.

Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.