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Inaccessibility to eye-care services may have a negative impact on the quality of life. Financial constraints and a shortage of professional eye care practitioners are among the main hindrances to implementing comprehensive eye care in most countries. Vision screening is commonly used to identify those who may have undetected vision problems. However, the existing instrument-based vision screening is also less than ideal. Online Eye Screening: Questionnaire and Vision Tests (OES:QVT) is developed as a new alternative vision screening when existing vision screening is impractical due to the time-cost-labour practicality challenge of equipment-based vision screening. There were three phases of the OES:QVT innovation process: (1) idea generation to enhance eye care accessibility for underprivileged communities; (2) problem-solving tactic to remove the dependency on instruments in existing vision screening style; (3) implementation – by substituting inconvenient instrument-based vision screening with a hybrid of the questionnaire and online vision tests. OES:QVT harnesses both benefits of questionnaires and simple vision tests to cover major vision problems for wide-ranging age groups. OES: QVT consists of three versions – adult version, paediatric version and people with intellectual disabilities version. OES:QVT displays good consistency and accuracy of vision screening via solid content and criteria validation. OES:QVT lessens the burden of expensive equipment-based vision screening by forming a hybrid between questionnaires and online vision tests. OES:QVT offers an alternative option when an ideal sophisticated vision screening program and full eye examination are not feasible.

Adoptive cellular therapies are making major strides in the treatment of cancer, both for hematologic and solid tumors. These cellular products include chimeric antigen receptor T cells and T-cell receptor-modified T cells, tumor-infiltrating lymphocytes, marrow-infiltrating T cells, natural killer cells as well as macrophage-based therapeutics. Advancement in genomics, computational biology, immunology, and cell therapy manufacturing has facilitated advancement of adoptive T cell therapies into the clinic, whereas clinical efficacy has driven Food and Drug Administration approvals. The growth of adoptive cellular therapy has, in turn, led to innovation in the preclinical models available, from ex vivo cell-based models to in vivo xenograft models of treatment. This review focuses on the development and application of in vitro models and in vivo models (cell line xenograft, humanized mice, and patient-derived xenograft models) that directly evaluate these human cellular products.

Lyonia doyonensis is a deciduous shrub native to high-altitude regions of Asia. So far, there is no report on any chemical and biological properties of L. doyonensis. An EtOH extract of L. doyonensis twigs and leaves showed inhibitory activities on PTP1B and lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells. Phytochemical investigation of this extract led to the isolation of a, so far only ambiguously described, 24-norursane-type triterpenoid, now named lyonensinol A (1), along with its two new derivatives, lyonensinols B and C (2 and 3), and six known triterpenoids (4–9). Their structures were elucidated by detailed analysis of spectroscopic data. A combination of chemical conversions, ECD, and Mo2(OAc)4-induced ECD was used to confirm their absolute configurations. Lyonensinols B (2) and C (3) represent the first examples of norursane-type triterpenoids acylated with a p-coumaroyl moiety. The potential anti-inflammatory and PTP1B inhibitory activities of all the isolates were evaluated. Compounds 3, 7, and 8 at 10 μM showed potent inhibitory activities on LPS-induced NO production in BV-2 microglial cells with NO levels decreased to 31.5%, 41.9%, and 27.1%, respectively, while compounds 3, 4, 7, and 8 exhibited notable inhibitory activities against PTP1B with IC50 values ranging from 1.7 to 18.2 μM. Interestingly, compounds 3 and 8 bearing a C-3 trans-p-coumaroyl group showed not only more potent anti-inflammatory effects, but also exhibited stronger PTP1B inhibition, than their respective stereoisomers (2 and 7) with a cis-p-coumaroyl group.

Lucanus jiaozishanus Qi, He, Su & Song, new species (Chinese common name: MŦƜẄƜṈƤ) Figs. 1A–B; 2A–F; 3A–D; 4A, E–H; 5A–B; 6A–F; 7A–E; 8A–D; 9A–X; 10A–X; 11B Type locality. China, Yunnan Province, Kunming City, Jiaozishan National Nature Reserve. Type material. Holotype: ♁ (FAF), CHINA, Yunnan Province, Kunming City, Dongchuan District, Hongtudi Town [IJ±ṂDz], Jiaozishan National Nature Reserve [MŦƜ国ẎṁbẍOiḞffl], 26°2'34.8''N, 102°55'47.9''E, alt. 2800–3000 m, 19.V.2022, Hao He leg. Paratypes: 2♁♁ (1♁ CZHQ, 1♁ CHH), same data as holotype; 5♁♁ (2♁♁ JNNR, 1♁ CZHQ, 1♁ CRXS, 1♁ CHH), 1♀ (FAF), same data but 9.VI.2022. Description of the holotype. ♁ (Fig. 1A–B), body length 33.3 mm. Length of particular body parts: head (4.7 mm), mandible (7.4 mm), pronotum (5.7 mm), elytra (16.5 mm); width: head (8.4 mm), pronotum (9.4 mm), elytra (11.8 mm). Habitus (Fig. 1A–B). Color mostly blackish, including mandibles, head, pronotum, scutellum, legs and ventral side; elytra dark brown. Whole body with a certain luster, densely tiny punctuated; dorsal surface of the body nearly smooth, without visible pubescence; ventral surface of thorax with yellow pubescence, pubescence on metasternum markedly longer than on other areas. Head (Fig. 2A) transverse. Anterior ridge obsolete at lateral sides and not markedly raised at middle. Lateral ridges narrowed inwards in the front half and slightly protruded in posterior half, forming small rounded angles at lateral posterior corners. Canthus (Fig. 2C) thin, dividing about 1/3 of the eye. Clypeolabrum (Fig. 2B) subhexagonal, about 1.5 times as wide as long, fused with frons, indistinct defined by a transverse suture; anterior margin straight, lateral margins with a distinct protrusion forming a small obtuse angle. Mandible (Fig. 2A) about 1.6 times longer than head, evenly incurved, apical fork with upper tooth slightly longer and finer than lower one; major inner tooth slender, with rounded tip, placed at near half the mandible; major inner tooth preceded by 2–3 smaller teeth and not followed by any teeth. Antennal club with 4 antennomeres; antennomere 7 slender and sharply pointed apically; antennomeres 8–10 lamellate. Pronotum transverse, 1.7 times wider than long, widest behind the middle. Anterior margin slightly protruding to the front at midline; anterior angle sharp and directed forwards. Lateral margins protrudent outwards widely. Posterior margin almost straight. Scutellum near triangular, punctuated, 1.6 times wider than long. Legs. Protibia (Fig. 2D) with 4–5 blunt teeth along outer margin, 1 spur at apex; apex bifurcate with branches blunt at tip. Mesotibia (Fig. 2E) with 1 small and 3 large lateral spines ever-greater from base to apex along outer margin in addition to terminal spines, 2 spurs at apex. Metatibia (Fig. 2F) with 1 small and 2 large lateral spines ever-greater from base to apex along the outer margin in addition to terminal spines, 2 spurs at apex. Elytra elongate, almost smooth, 1.4 times longer than wide, the anterior margin of elytra wider than pronotum. Male genitalia (Figs. 3A–D; 4A, E–H). Abdominal tergite 8 (Fig. 3A) with poorly-defined lateral angles, a crack from the base along the midline to half of tergite. Abdominal ventrite 8 (Fig. 3B) with a transverse indistinct membranous area in the middle of base, posterior margin completely sclerified with obvious black thickening weakly protruded at middle of posterior margin, the sides of ventrite dark. Ventral plate of the abdominal segment 9 (Fig. 3C) with a wide membranous stripe, slightly widened behind the apical base, then of the same width to the posterior side. Aedeagus (Fig. 4A, E–H) in dorsal view about 2.3 times longer than wide. Basal piece (Fig. 4F) triangular in dorsal view, nearly 1.6 times longer than parameres, without pair of sclerotized dorsal plates; ventral plate at apical end of basal piece membranous. Paramere with small basal process, apex of paramere upcurved. Penis short and wide, shorter and wider than paramere in ventral view. Flagellum rather long, about twice as long as aedeagus, apex of the flagellum (Fig. 4H) not enlarged. Male paratypes. Body length 27.2–31.3 mm (Figs. 8A–D; 9A–X; 10A–X). Variation. In small and medium sized males, number of inner teeth in mandible (Fig. 9A, G, M, S) only 1–2; the shape of clypeolabrum (Fig. 9B, H, N, T) variable, width/length ratio: 1.3–1.8; anterior ridge of head weakly elevated or not elevated at all. Protibia (Fig. 9D, J, P, V) with 2–5 teeth along outer margin; mesotibia (Fig. 9E, K, Q, W) with 2–3 lateral spines along outer margin; metatibia (Fig. 9F, L, R, X) with 1–2 lateral spines along outer margin. Variation of male genitalia see Fig. 10. Female paratype. Eclosion defects may exist (Fig. 5A–B). Body length 24.8 mm. Length of particular body parts: head (3.6 mm), mandible (2.7 mm), pronotum (5.0 mm), elytra (14.8 mm); width: head (5.9 mm), pronotum (9.0 mm), elytra (10.5 mm). Habitus (Fig. 5A–B). Color mostly blackish, including dorsal side blackish; ventral side blackish with gula, procoxa, mesocoxa, prosternal and mesosternal process red brown. Whole body with a certain luster, densely punctuated,; dorsal surface of the body nearly smooth, without visible pubescence; ventral surface of thorax clad with yellow pubescence, pubescence on metasternum markedly longer than on other areas. Head (Fig. 6A) covered with dense large punctures. Canthus (Fig. 6C) with anterior and posterior angles not defined and inside of eye; lateral margin short and straight, dividing about 1/4 of the eye. Anterior and lateral ridges absent. Clypeolabrum (Fig. 6B) transverse, trapezoidal, narrower at front and flat at apex, not protruding medially. Both mandibles without dorsal tooth, right mandible with a big and broad inner tooth, inner tooth of left mandible with broad and projecting inner ridge. Antennal club with 4 antennomeres; antennomere 7 slender and sharply pointed apically; antennomeres 8–10 lamellate. Pronotum (Fig. 6A) transverse, 1.8 times wider than long, widest at the middle; anterior margin slightly concave at midline; anterior angles rounded; lateral angles clearly defined and obtuse; posterior angles obtuse. Pronotum with a longitudinal depression along midline (maybe due to eclosion defects). Scutellum rounded, punctate, 1.6 times wider than long. Legs. Protibia (Fig. 6D) with 2–3 distinct teeth ever-greater from base to apex along outer margin, apex bifurcate with branches relatively apart, broad and blunt, 1 spur at apex. Mesotibia (Fig. 6E) with a large lateral spine preceded by a much smaller one along outer margin in addition to terminal spines, 2 spurs at apex. Metatibia (Fig. 6F) with 1 small lateral spine in addition to terminal spines, 2 spurs at apex. Elytra elongate, almost smooth, 1.4 times longer than wide, the anterior margin of elytra wider than pronotum. Female genitalia (Fig. 7A–E). Abdominal tergite 8 (Fig. 7A) without lateral angles. Abdominal ventrite 8 (Fig. 7B) with a membranous area in the middle and a emarginate at middle of posterior margin. Hemisternite (Fig. 7D) broadly rounded apically, with inner lateral margin of sclerotized part short. Spermatheca (Fig. 7E) J-shaped, weakly sclerotized at apex only. Spermathecal duct (Fig. 7C) short, almost the same length as spermatheca. Spermathecal gland (Fig. 7E) oval, significantly shorter than spermatheca. Differential diagnosis. The new species is close to Lucanus ludivinae, but can be clearly distinguished by a combination of external and genital characters (see keys). L. boileaui belongs to the same species-group, but differs greatly from L. jiaozishanus new species in external characters (see keys). Four moderately sized species (L. takeoi Adachi, 2020 from Sichuan, L. kanoi Kurosawa, 1966, L. kurosawai Sakaino, 1995 and L. ogakii Imanishi, 1990 all from Taiwan) of the L. maculifemoratus group are similar in external characters to the new species, but can be distinguished by genital characters and have different distribution ranges. The male genitalia of L. jiaozishanus new species have a rather long flagellum (Fig. 4A), nearly twice as long as aedeagus, the apex of the flagellum not enlarged (Fig. 4H), and not a short flagellum (Fig. 4C), usually as long as aedeagus, and its apex enlarged (Fig. 4P) like the four quoted species. The female genitalia of L. jiaozishanus new species show a completely not sclerotized spermathecal duct (Fig. 7C) and a mostly not sclerotized spermatheca (Fig. 7E), weakly sclerotized at apex only, and not a more or less sclerotized spermathecal duct (Fig. 7H) and a completely sclerotized spermatheca (Fig. 7J) as the four quoted species. Etymology. This new species is named after the type locality. Distribution. China (Yunnan). Remarks. This species should be assigned to the Lucanus boileaui group (sensu Huang & Chen 2010). All specimens of L. jiaozishanus new species were collected from nightfall to night (from 7 p. m. to 10 p. m.), in the forests of Jiaozishan National Nature Reserve at an altitude of about 2900 m (Fig. 11A). The adults were found on the trunk of Abies georgei (Pinaceae) or on the ground, but no feeding behavior was observed, and the true host plant remains to be found. In addition, no specimens of new taxon were attracted by the light traps at night, which means that the phototaxis of this species may be weak., Published as part of Qi, Zhi-Hao, He, Hao, Su, Rong-Xiang, Ai, Hong-Mu & Song, Hai-Tian, 2023, Revision of the Lucanus boileaui group and notes on. takeoi Adachi, 2020 from the. maculifemoratus group (Coleoptera: Lucanidae: Lucaninae), pp. 240-260 in Zootaxa 5263 (2) on pages 241-253, DOI: 10.11646/zootaxa.5263.2.4, http://zenodo.org/record/7801106, {"references":["Boucher, S. (1998) Deux Lucanus inedits des provinces chinoises du Yunnan et du Guangxi (Coleoptera, Lucanidae). Coleopteres, 4, 177 - 185.","Adachi, N. (2020) A new species of the genus Lucanus from Szechuan province, southwest China. Kogane, 23, 8 - 10.","Planet, L. (1897) Description de coleopteres nouveaux. Le Naturaliste, 19, 205 - 206.","Huang, H. & Chen, C. - C. (2017) Stag Beetles of China III. Formosa Ecological Company, Taipei, 524 pp.","Huang, H. & Chen, C. - C. (2010) Stag Beetles of China I. Formosa Ecological Company, Taipei, 288 pp."]}

Qi, Zhi-Hao, He, Hao, Su, Rong-Xiang, Ai, Hong-Mu, Song, Hai-Tian (2023): Revision of the Lucanus boileaui group and notes on . takeoi Adachi, 2020 from the . maculifemoratus group (Coleoptera: Lucanidae: Lucaninae). Zootaxa 5263 (2): 240-260, DOI: 10.11646/zootaxa.5263.2.4, URL: http://dx.doi.org/10.11646/zootaxa.5263.2.4

Lucanus takeoi Adachi, 2020 Figs. 1E–F; 2M–R; 3I–L; 4C, M–P; 5C–D; 6I–N; 7F–J; 13D–F Lucanus takeoi Adachi, 2020: 8. Type locality. China, Sichuan Province, Liangshan Yi Autonomous Prefecture, Mianning county, Tuowu township, Baku. Material examined. CHINA: 4♁♁ (3♁♁ CZHQ, 1♁ CRXS), 1♀ (CZHQ): Sichuan Province, Liangshan Yi Autonomous Prefecture, Huidong County [ĤŤB], Jiangzhou Town [ƊNJDz], Matoushan [ḢĿƜ]; alt. 2400– 2500 m, 15–20.VII.2022, local collector leg. Distribution. China (Sichuan). Remarks. This species should be assigned to the Lucanus maculifemoratus group (sensu Huang & Chen 2010). Adachi (2020) described the species on a single male specimen from Baku, Mianning county, Sichuan Province. The female and host plant of L. takeoi Adachi, 2020 are unknown. In 2021, the natives collected this species in Huidong County (Sichuan Province) for the first time. In 2022, we obtained some specimens of this species from the local collector in Huidong County, which enabled us to illustrate the female (Figs. 5C–D; 6I–N), the males of different sizes (Figs. 1E–F; 2M–R; 13D–F), and the genitalia of both sexes (Figs. 3I–L; 4C, M–P; 7F–J). In addition, we found that the female of the species has an almost completely sclerotized spermathecal duct (Fig. 7H), which is a feature distinct from other species of the same species-group. The adults of L. takeoi mainly inhabit the Quercus spp. (Fagaceae, Fig. 14A–D) at an altitude about 2400 m in Huidong County and can be found from June to August. These plants are also the host plants of L. delavayi Fairmaire, 1887, L. kraatzi kraatzi Nagel, 1926 (Fig. 14D), L. moae Qi, 2021 and L. thibetanus thibetanus Planet, 1898 in Huidong County (Zhi-Hao Qi’s personal communication with the local collector in 2022)., Published as part of Qi, Zhi-Hao, He, Hao, Su, Rong-Xiang, Ai, Hong-Mu & Song, Hai-Tian, 2023, Revision of the Lucanus boileaui group and notes on. takeoi Adachi, 2020 from the. maculifemoratus group (Coleoptera: Lucanidae: Lucaninae), pp. 240-260 in Zootaxa 5263 (2) on pages 257-258, DOI: 10.11646/zootaxa.5263.2.4, http://zenodo.org/record/7801106, {"references":["Adachi, N. (2020) A new species of the genus Lucanus from Szechuan province, southwest China. Kogane, 23, 8 - 10.","Huang, H. & Chen, C. - C. (2010) Stag Beetles of China I. Formosa Ecological Company, Taipei, 288 pp.","Qi, Z. - H. (2021) Lucanus moae sp. nov., a new species from Sichuan, China (Coleoptera: Lucanidae: Lucaninae). Faunitaxys, 9 (23), 1 - 7."]}

Lucanus boileaui Planet, 1897 Figs. 1G–H; 2S–X; 3M–P; 4D, Q–T; 5E–F; 6O–T; 7K–O; 12A–K; 13B–C Lucanus boileavi Planet, 1897: 205. Lucanus maculifemoratus ab. boileaui: Benesh, 1960: 144. Lucanus maculifemoratus boileaui: Mizunuma & Nagai, 1994: 58, plate 12. Lucanus bidentis: Schenk, 2013: 4, fig. 2, new synonymy. Type locality. China, Thibet (now Western Sichuan Province), Mou-Pin (now Baoxing County) and Ya Tcheou (now Ya-an City), Se-Pin-Lou-Chan. Material examined. CHINA: 2♁♁ (CZHQ), Sichuan Province, Ya-an City, Yingjing County [ẾḦB], Daxiangling [kffiṅ], alt. 1400 m, VI.2015, Huang-Shun Xi leg.; 4♁♁, 1♀ (CZHQ), Sichuan Province, Leshan City, Mabian County [ḢŮB], Yonghong Town [AEIJØ], Dafengding Nature Reserve [kṃữbẍOiḞffl], alt. 1500 m, 12.VII.2022, Yuan Li leg.; 1♁ (CRXS), Sichuan Province, Emeishan City, Emeishan [Ẃ眉Ɯ], Wanfoding [hdzữ], alt. 3099 m, 1.VIII.2022, Tian-Xuan Gu leg. Distribution. China (Sichuan). Remarks. Recently, we examined a small sized particular specimen of L. boileaui (Fig. 12A–B) from Emeishan, Sichuan Province, China, which is indistinguishable from the holotype of L. bidentis on external characters (see fig. 2 in Schenk, 2013). Thus, we propose L. bidentis as a new synonymy for L. boileaui. In addition, because the unreasonable distribution of the location that in the Southeastern Vietnam is far from the other species distribution ranges of the same species-group, and it seems that no more individuals of the species have been found in Vietnam since 2013, we wonder it may be a wrong distribution data., Published as part of Qi, Zhi-Hao, He, Hao, Su, Rong-Xiang, Ai, Hong-Mu & Song, Hai-Tian, 2023, Revision of the Lucanus boileaui group and notes on. takeoi Adachi, 2020 from the. maculifemoratus group (Coleoptera: Lucanidae: Lucaninae), pp. 240-260 in Zootaxa 5263 (2) on page 253, DOI: 10.11646/zootaxa.5263.2.4, http://zenodo.org/record/7801106, {"references":["Planet, L. (1897) Description de coleopteres nouveaux. Le Naturaliste, 19, 205 - 206.","Benesh, B. (1960) Lucanidae. Coleopterorum Catalogus. 2 nd Edition. Supplement 8. Published by W. Junk, The Hague, 178 pp.","Mizunuma, T. & Nagai, S. (1994) The lucanid beetles of the World. Mushi-sha, Tokyo, 337 pp.","Schenk, K. - D. (2013) Notes on Asian stag beetles and description of new taxa (Coleoptera, Lucanidae). Beetles World, 8, 1 - 12."]}

Lucanus ludivinae Boucher, 1998 Figs. 1C–D; 2G–L; 3E–H; 4B, I–L; 6G–H; 13A Lucanus ludivinae Boucher, 1998: 178. Type locality. China, Yunnan Province, Baoshan City, Eastern Gaoligongshan. Material examined. CHINA: 1♁ (CZHQ), Yunnan Province, Nujiang of the Lisu Autonomous Prefecture, Lushui City, Pianma Town [HḢDz], Gangfang Village [ṀĦḤ], alt. 2600 m, VII.2015, Xin-Xiong Deng leg.; 1♁ (CZHQ), Yunnan, Nujiang of the Lisu Autonomous Prefecture, Gongshan County [ỮƜB], Gaoligongshan [ṘN ỮƜ], alt. 2800 m, 30.VI.2018, Ying-Bing Li leg. Distribution. China (Yunnan); Myanmar (Kachin)., Published as part of Qi, Zhi-Hao, He, Hao, Su, Rong-Xiang, Ai, Hong-Mu & Song, Hai-Tian, 2023, Revision of the Lucanus boileaui group and notes on. takeoi Adachi, 2020 from the. maculifemoratus group (Coleoptera: Lucanidae: Lucaninae), pp. 240-260 in Zootaxa 5263 (2) on page 253, DOI: 10.11646/zootaxa.5263.2.4, http://zenodo.org/record/7801106, {"references":["Boucher, S. (1998) Deux Lucanus inedits des provinces chinoises du Yunnan et du Guangxi (Coleoptera, Lucanidae). Coleopteres, 4, 177 - 185."]}

LC-MS/MS analysis of lipid metabolites in PDX BL0269

PTUPB did not increase cisplatin cytotoxicity in the J82, T24 and TCCSUP bladder cancer cell lines

Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474–83. ©2017 AACR.

Blood counts, Hemoglobin and Platelets determination and biochemistry panel

Supplementary Figure Legends

IHC staining of bladder PDX tumor tissues (BL0293)

Body weight change during PDX bladder cancer mice experiment

Histopathological evaluation of major organs

PTUPB structure

Supplementary Figure from Phototherapy with Cancer-Specific Nanoporphyrin Potentiates Immunotherapy in Bladder Cancer

Purpose:Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer–specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI.Experimental Design:SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies.Results:PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial.Conclusions:In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

Ki67 and cleaved caspase 3 expression in BL0440 tumors

Cell cycle analysis, Flow cytometric analysis and p-AKT expression in TCCSUP cells treated with pictilisib

Purpose: Activation of the PI3K pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action, and the resistance mechanisms of drugs targeting the PI3K pathway.Experimental Design: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small-molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated, and RNA sequencing was performed to explore drug resistance mechanisms.Results: The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type PIK3CA. Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth, and prolonged survival compared with single-drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as a biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by cotreatment with the RAF inhibitor sorafenib. RNA sequencing of tumors resistant to treatment suggested that LSP1 downregulation correlated with drug resistance.Conclusions: These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. Clin Cancer Res; 23(21); 6580–91. ©2017 AACR.

Ki67 and cleaved caspase 3 expression in BL0269 tumors

The heat map of autophagy related genes in pictilisib (PIC), cisplatin (CIS) and combination (COM) resistant tumors of PDX BL0269 model

The mutation status and absolute IC50 of bladder cancer cells

Combination index of pictilisib and other drugs in TCCSUP cells

Analysis of survival curves, tumor volumes and body weights

p-p70S6K, pS6 and p-ERK expression in bladder cancer cells treated with pictilisib

miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine-derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. Cancer Res; 75(24); 5309–17. ©2015 AACR.

Legend for Supplementary Figures S1-S5.

Description of additional methods and procedures used in the study. Also includes Supplementary Reference.

Immunostaining of AR-V7 in CWR22 xenografts.

The inappropriate activation of androgen receptor (AR) by nonsteroids is considered a potential mechanism in the emergence of hormone-refractory prostate tumors, but little is known about the properties of these “pseudoactivated” AR. Here, we present the first comprehensive analysis closely examining the properties of AR activated by the neuropeptide bombesin that distinguish it from androgen-activated AR. We show that bombesin-activated AR (a) is required for bombesin-induced growth of LNCaP cells, (b) has a transcriptional profile overlapping with, but not identical to, androgen-activated AR, (c) activates prostate-specific antigen by preferentially binding to its proximal promoter, and (d) assembles a distinct coactivator complex. Significantly, we found that Src kinase is critical for bombesin-induced AR-mediated activity and is required for translocation and transactivation of AR. Additionally, we identify c-Myc, a Src target gene, to be activated by bombesin and a potential coactivator of AR-mediated activity specific to bombesin-induced signaling. Because Src kinase is often activated by other nonsteroids, such as other neuropeptides, growth factors, chemokines, and cytokines, our findings have general applicability and provide rationale for investigating the efficacy of the Src kinase pathway as a target for the prevention of relapsed prostate cancers. (Cancer Res 2006; 66(21): 10449-59)

Supplementary Table 2 from Inappropriate Activation of the Androgen Receptor by Nonsteroids: Involvement of the Src Kinase Pathway and Its Therapeutic Implications

Immunostaining of AR-V7 in miR-124-treated 22Rv1-EnzR cells.

Function assay of AR variant's constitutive activity in yeast.

The combination treatment with miR-124 and bicalutamide (Bic) significantly inhibited proliferation of C4-2B prostate cancer cells.

Supplementary Table 3 from Inappropriate Activation of the Androgen Receptor by Nonsteroids: Involvement of the Src Kinase Pathway and Its Therapeutic Implications

Supplementary Table 1 from Inappropriate Activation of the Androgen Receptor by Nonsteroids: Involvement of the Src Kinase Pathway and Its Therapeutic Implications

Zearalenone (ZEN), one of the most prevalent non-steroidal oestrogenic mycotoxins, is primarily produced by Fusarium fungi. Due to its toxicity as an oestrogenic compound and wide distribution in feed and foods, the reproductive toxicology of ZEN exposure is of public concern. The aim of the present study was to investigate the effect of ZEN on Sertoli cells to identify apoptotic pathways induced by this compound. We found that ZEN reduced the viability and caused apoptosis in Sertoli cells in vitro. Notably, we observed that such effects were associated with a significant increase in reactive oxygen species (ROS) and the number of cells that showed positive staining for γH2AX and RAD51, enzymes essential for repairing DNA damage. There was a parallel decrease in the expression of occludin and connexin 43, proteins that are present in the testis-blood barrier and gap junctions of Sertoli cells, respectively. Overall, the present study confirms that ZEN exposure can have serious deleterious effects on mammalian Sertoli cells and offers novel insight about its molecular targets in these cells.

The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.

To retrospectively analyze the clinical features and treatment outcomes of patients with diabetic foot ulcers (DFU), and to investigate the effect of controlling nutritional status (CONUT) scores on the amputation risks and hospital length-of-stay of DFU patients.A total of 357 DFU inpatients admitted to the Department of Endocrinology, PLA Strategic Support Force Characteristic Medical Center between January 1, 2016 and December 31, 2018 were enrolled and analyzed retrospectively. Based on their CONUT scores, the patients were divided into 3 groups, a normal nutritional status group consisting of patients with CONUT scores 0-1 (The total amputation rate of DFU patients was 30.6%. Among all amputations, the major amputation (above-the-ankle amputation) rate was 1.8%, and the minor amputation rate was 98.2%. The amputation rate in patients with mild and moderate-to-severe malnutrition were 1.5 and 3.0 times higher than those in the normal nutritional status group, respectively. Logistic regression analysis showed that the moderate-to-severe nutritional status (5-12 scores), white blood cell, Wagner classification and ankle-brachial index were independent risk factors for amputation.CONUT score is closely associated with amputations in DFU patients. Improving the nutritional status of patients in the early stage could reduce the risk of amputation.

Purpose: Immune checkpoint inhibitors (ICI) in general have shown poor efficacy in bladder cancer. The purpose of this project was to determine whether photodynamic therapy (PDT) with bladder cancer–specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. Experimental Design: SV40 T/Ras double-transgenic mice bearing spontaneous bladder cancer and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. Results: PDT with PNP generated reactive oxygen species, and induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared with 44.8 (P = 0.0123), 52.6 (P = 0.0054), and over 75 (P = 0.0001) days in the anti-programmed cell death-1 antibody (anti-PD-1), PNP PDT, and combination groups, respectively. At Day 75 when all mice in other groups died, only 1 in 7 mice in the combination group died. For the direct anti-tumor activity, compared with the control, the anti-PD-1, PNP PDT, and combination groups induced a 40.25% (P = 0.0003), 80.72% (P < 0.0001), and 93.03% (P < 0.0001) tumor reduction, respectively. For the abscopal anticancer immunity, the anti-PD-1, PNP PDT, and combination groups induced tumor reduction of 45.73% (P = 0.0001), 54.92% (P < 0.0001), and 75.96% (P < 0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. Conclusions: In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.